@article {963, title = {Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.}, journal = {Blood}, volume = {137}, year = {2021}, month = {2021 01 28}, pages = {493-499}, abstract = {

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

}, keywords = {Adult, Agammaglobulinemia, Animals, B-Lymphocytes, Cardiomyopathy, Hypertrophic, Carrier Proteins, Child, Child, Preschool, Chromosomes, Human, Pair 5, Codon, Nonsense, Consanguinity, Crohn Disease, Developmental Disabilities, Disease Models, Animal, Disease Susceptibility, DNA Copy Number Variations, Female, Heart Defects, Congenital, Humans, Immunologic Deficiency Syndromes, Infections, Loss of Function Mutation, Lymphopenia, Male, Mice, Neutropenia, Pedigree, Uniparental Disomy, Whole Exome Sequencing}, issn = {1528-0020}, doi = {10.1182/blood.2020006441}, author = {Saettini, Francesco and Poli, Cecilia and Vengoechea, Jaime and Bonanomi, Sonia and Orellana, Julio C and Fazio, Grazia and Rodriguez, Fred H and Noguera, Loreani P and Booth, Claire and Jarur-Chamy, Valentina and Shams, Marissa and Iascone, Maria and Vukic, Maja and Gasperini, Serena and Quadri, Manuel and Barroeta Seijas, Amairelys and Rivers, Elizabeth and Mauri, Mario and Badolato, Raffaele and Cazzaniga, Gianni and Bugarin, Cristina and Gaipa, Giuseppe and Kroes, Wilma G M and Moratto, Daniele and van Oostaijen-Ten Dam, Monique M and Baas, Frank and van der Maarel, Silv{\`e}re and Piazza, Rocco and Coban-Akdemir, Zeynep H and Lupski, James R and Yuan, Bo and Chinn, Ivan K and Daxinger, Lucia and Biondi, Andrea} } @article {923, title = {Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 01}, pages = {119-133}, abstract = {

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48\%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26\%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61926}, author = {Dyment, David A and O{\textquoteright}Donnell-Luria, Anne and Agrawal, Pankaj B and Coban Akdemir, Zeynep and Aleck, Kyrieckos A and Antaki, Danny and Al Sharhan, Hind and Au, Ping-Yee B and Aydin, Hatip and Beggs, Alan H and Bilguvar, Kaya and Boerwinkle, Eric and Brand, Harrison and Brownstein, Catherine A and Buyske, Steve and Chodirker, Bernard and Choi, Jungmin and Chudley, Albert E and Clericuzio, Carol L and Cox, Gerald F and Curry, Cynthia and de Boer, Elke and de Vries, Bert B A and Dunn, Kathryn and Dutmer, Cullen M and England, Eleina M and Fahrner, Jill A and Geckinli, Bilgen B and Genetti, Casie A and Gezdirici, Alper and Gibson, William T and Gleeson, Joseph G and Greenberg, Cheryl R and Hall, April and Hamosh, Ada and Hartley, Taila and Jhangiani, Shalini N and Karaca, Ender and Kernohan, Kristin and Lauzon, Julie L and Lewis, M E Suzanne and Lowry, R Brian and L{\'o}pez-Gir{\'a}ldez, Francesc and Matise, Tara C and McEvoy-Venneri, Jennifer and McInnes, Brenda and Mhanni, Aziz and Garcia Minaur, Sixto and Moilanen, Jukka and Nguyen, An and Nowaczyk, Malgorzata J M and Posey, Jennifer E and {\~O}unap, Katrin and Pehlivan, Davut and Pajusalu, Sander and Penney, Lynette S and Poterba, Timothy and Prontera, Paolo and Doriqui, Maria Juliana Rodovalho and Sawyer, Sarah L and Sobreira, Nara and Stanley, Valentina and Torun, Deniz and Wargowski, David and Witmer, P Dane and Wong, Isaac and Xing, Jinchuan and Zaki, MAH S and Zhang, Yeting and Boycott, Kym M and Bamshad, Michael J and Nickerson, Deborah A and Blue, Elizabeth E and Innes, A Micheil} } @article {1019, title = {Association of De Novo Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy.}, journal = {Neurology}, volume = {96}, year = {2021}, month = {2021 03 30}, pages = {e1783-e1791}, abstract = {

OBJECTIVE: To test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.

METHODS: Exome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.

RESULTS: We identified 3 novel rare de novo variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.

CONCLUSIONS: These results indicate a novel syndrome associated with rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

}, keywords = {Adenosine Triphosphatases, Adult, Age of Onset, Aortic Diseases, Arterial Occlusive Diseases, Child, Preschool, Female, Femoral Artery, Humans, Iliac Artery, Male, Moyamoya Disease, Mutation, Renal Artery Obstruction, Ubiquitin-Protein Ligases}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000011653}, author = {Pinard, Amelie and Fiander, Maximillian D J and Cecchi, Alana C and Rideout, Andrea L and Azouz, Mohamed and Fraser, Stuart M and McNeely, P Daniel and Walling, Simon and Novara, Sarah C and Hurst, Anna C E and Guo, Dongchuan and Parkash, Sandhya and Bamshad, Michael J and Nickerson, Deborah A and Vandersteen, Anthony M and Milewicz, Dianna M} } @article {893, title = {Association of structural variation with cardiometabolic traits in Finns.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 04 01}, pages = {583-596}, abstract = {

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47~{\texttimes} 10) and is also associated with increased levels of total cholesterol (p = 1.22~{\texttimes} 10) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81~{\texttimes} 10) and alanine (p = 6.14~{\texttimes} 10) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24~{\texttimes} 10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53~{\texttimes} 10). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

}, keywords = {Alleles, Cardiovascular Diseases, Cholesterol, DNA Copy Number Variations, Female, Finland, Genome, Human, Genomic Structural Variation, Genotype, High-Throughput Nucleotide Sequencing, Humans, Male, Mitochondrial Proteins, Promoter Regions, Genetic, Pyruvate Dehydrogenase (Lipoamide)-Phosphatase, Pyruvic Acid, Serum Albumin, Human}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.03.008}, author = {Chen, Lei and Abel, Haley J and Das, Indraniel and Larson, David E and Ganel, Liron and Kanchi, Krishna L and Regier, Allison A and Young, Erica P and Kang, Chul Joo and Scott, Alexandra J and Chiang, Colby and Wang, Xinxin and Lu, Shuangjia and Christ, Ryan and Service, Susan K and Chiang, Charleston W K and Havulinna, Aki S and Kuusisto, Johanna and Boehnke, Michael and Laakso, Markku and Palotie, Aarno and Ripatti, Samuli and Freimer, Nelson B and Locke, Adam E and Stitziel, Nathan O and Hall, Ira M} } @article {1016, title = {Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 04 05}, abstract = {

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10\% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

}, keywords = {Adolescent, Adult, Aged, Antibodies, Neutralizing, Autoantibodies, Autoimmune Diseases, COVID-19, Female, Genetic Diseases, Inborn, HEK293 Cells, Humans, Interferon-alpha, Male, Middle Aged, Receptor, Interferon alpha-beta, SARS-CoV-2, Vaccines, Attenuated, Yellow Fever Vaccine, Yellow fever virus}, issn = {1540-9538}, doi = {10.1084/jem.20202486}, author = {Bastard, Paul and Michailidis, Eleftherios and Hoffmann, Hans-Heinrich and Chbihi, Marwa and Le Voyer, Tom and Rosain, J{\'e}r{\'e}mie and Philippot, Quentin and Seeleuthner, Yoann and Gervais, Adrian and Materna, Marie and de Oliveira, Patricia Mouta Nunes and Maia, Maria de Lourdes S and Dinis Ano Bom, Ana Paula and Azamor, Tamiris and Ara{\'u}jo da Concei{\c c}{\~a}o, Deborah and Goudouris, Ekaterini and Homma, Akira and Slesak, G{\"u}nther and Sch{\"a}fer, Johannes and Pulendran, Bali and Miller, Joseph D and Huits, Ralph and Yang, Rui and Rosen, Lindsey B and Bizien, Lucy and Lorenzo, Lazaro and Chrabieh, Maya and Erazo, Lucia V and Rozenberg, Flore and Jeljeli, Mohamed Maxime and B{\'e}ziat, Vivien and Holland, Steven M and Cobat, Aurelie and Notarangelo, Luigi D and Su, Helen C and Ahmed, Rafi and Puel, Anne and Zhang, Shen-Ying and Abel, Laurent and Seligman, Stephen J and Zhang, Qian and MacDonald, Margaret R and Jouanguy, Emmanuelle and Rice, Charles M and Casanova, Jean-Laurent} } @article {916, title = {Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 03}, pages = {524-533}, abstract = {

PURPOSE: Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown.

METHODS: We applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD.

RESULTS: We identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways.

CONCLUSION: The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.

}, keywords = {4-Hydroxyphenylpyruvate Dioxygenase, Animals, Dioxygenases, Exons, Mice, Mice, Knockout, Phenotype}, issn = {1530-0366}, doi = {10.1038/s41436-020-01010-y}, author = {Ghosh, Shereen G and Lee, Sangmoon and Fabunan, Rudy and Chai, Guoliang and Zaki, MAH S and Abdel-Salam, Ghada and Sultan, Tipu and Ben-Omran, Tawfeg and Alvi, Javeria Raza and McEvoy-Venneri, Jennifer and Stanley, Valentina and Patel, Aakash and Ross, Danica and Ding, Jeffrey and Jain, Mohit and Pan, Daqiang and L{\"u}bbert, Philipp and Kammerer, Bernd and Wiedemann, Nils and Verhoeven-Duif, Nanda M and Jans, Judith J and Murphy, David and Toosi, Mehran Beiraghi and Ashrafzadeh, Farah and Imannezhad, Shima and Karimiani, Ehsan Ghayoor and Ibrahim, Khalid and Waters, Elizabeth R and Maroofian, Reza and Gleeson, Joseph G} } @article {847, title = {Chromosome-scale, haplotype-resolved assembly of human genomes.}, journal = {Nat Biotechnol}, volume = {39}, year = {2021}, month = {2021 03}, pages = {309-312}, abstract = {

Haplotype-resolved or phased genome assembly provides a complete picture of genomes and their complex genetic variations. However, current algorithms for phased assembly either do not generate chromosome-scale phasing or require pedigree information, which limits their application. We present a method named diploid assembly (DipAsm) that uses long, accurate reads and long-range conformation data for single individuals to generate a chromosome-scale phased assembly within 1 day. Applied to four public human genomes, PGP1, HG002, NA12878 and HG00733, DipAsm produced haplotype-resolved assemblies with minimum contig length needed to cover 50\% of the known genome (NG50) up to 25 Mb and phased ~99.5\% of heterozygous sites at 98-99\% accuracy, outperforming other approaches in terms of both contiguity and phasing completeness. We demonstrate the importance of chromosome-scale phased assemblies for the discovery of structural variants (SVs), including thousands of new transposon insertions, and of highly polymorphic and medically important regions such as the human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) regions. DipAsm will facilitate high-quality precision medicine and studies of individual haplotype variation and population diversity.

}, keywords = {Algorithms, Chromosomes, Human, Genome, Human, Haplotypes, Heterozygote, Humans, Polymorphism, Single Nucleotide}, issn = {1546-1696}, doi = {10.1038/s41587-020-0711-0}, author = {Garg, Shilpa and Fungtammasan, Arkarachai and Carroll, Andrew and Chou, Mike and Schmitt, Anthony and Zhou, Xiang and Mac, Stephen and Peluso, Paul and Hatas, Emily and Ghurye, Jay and Maguire, Jared and Mahmoud, Medhat and Cheng, Haoyu and Heller, David and Zook, Justin M and Moemke, Tobias and Marschall, Tobias and Sedlazeck, Fritz J and Aach, John and Chin, Chen-Shan and Church, George M and Li, Heng} } @article {948, title = {Clinical and molecular evaluation of 13 Brazilian patients with Gomez-L{\'o}pez-Hern{\'a}ndez syndrome.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 04}, pages = {1047-1058}, abstract = {

We aim to characterize patients with Gomez-L{\'o}pez-Hern{\'a}ndez syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4\%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3\% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62059}, author = {Perrone, Eduardo and Perez, Ana Beatriz Alvarez and D{\textquoteright}Almeida, V{\^a}nia and de Mello, Claudia Berlim and Jacobina, Marcela Amaral Avelino and Loureiro, Rafael Maffei and Burlin, St{\^e}nio and Migliavacca, Michele and do Amaral Virmond, Luiza and Graziadio, Carla and Pedroso, Jos{\'e} Luiz and Mendes, Elaine Lustosa and Gomy, Israel and de Macena Sobreira, Nara Lygia} } @article {975, title = {Clinical presentation and evolution of Xia-Gibbs syndrome due to p.Gly375ArgfsTer3 variant in a patient from DR Congo (Central Africa).}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 03}, pages = {990-994}, abstract = {

Xia-Gibbs syndrome (XGS) is a very rare genetic condition. The clinical spectrum is very broad and variable. The phenotype and evolution in a Congolese boy with XGS have been reported. At 6 years he had speech delay, drooling, marked hyperactivity, attention deficit, aggressive behavior, and intellectual disability. Dysmorphological evaluation revealed strabismus, mild unilateral ptosis, uplifted ear lobes, flat philtrum, thin upper lip vermillion, high arched palate, and flat feet. Patient-only whole exome sequencing identified a known pathogenic frameshift variant in the AHDC1 gene [NM_001029882.3(AHDC1):c.1122dupC;(p.Gly375ArgfsTer3)]. The clinical follow-up revealed the deterioration of his fine motor skills and significant cerebellar phenotype including tremor, pes cavus, and gait instability at the age of 12 years. This patient was compared with three previously reported patients with the same variant but did not identify a consistent pattern in the evolution of symptoms with age.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62049}, author = {Mubungu, Gerrye and Makay, Prince and Boujemla, Bouchra and Yanda, Stephane and Posey, Jennifer E and Lupski, James R and Bours, Vincent and Lukusa, Prosper and Devriendt, Koenraad and Lumaka, Aim{\'e}} } @article {1005, title = {Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 Jul 05}, abstract = {

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1{\textquoteright}s critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

}, issn = {1540-9538}, doi = {10.1084/jem.20201750}, author = {Le Coz, Carole and Nguyen, David N and Su, Chun and Nolan, Brian E and Albrecht, Amanda V and Xhani, Suela and Sun, Di and Demaree, Benjamin and Pillarisetti, Piyush and Khanna, Caroline and Wright, Francis and Chen, Peixin Amy and Yoon, Samuel and Stiegler, Amy L and Maurer, Kelly and Garifallou, James P and Rymaszewski, Amy and Kroft, Steven H and Olson, Timothy S and Seif, Alix E and Wertheim, Gerald and Grant, Struan F A and Vo, Linda T and Puck, Jennifer M and Sullivan, Kathleen E and Routes, John M and Zakharova, Viktoria and Shcherbina, Anna and Mukhina, Anna and Rudy, Natasha L and Hurst, Anna C E and Atkinson, T Prescott and Boggon, Titus J and Hakonarson, Hakon and Abate, Adam R and Hajjar, Joud and Nicholas, Sarah K and Lupski, James R and Verbsky, James and Chinn, Ivan K and Gonzalez, Michael V and Wells, Andrew D and Marson, Alex and Poon, Gregory M K and Romberg, Neil} } @article {998, title = {CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.}, journal = {Epilepsia}, year = {2021}, month = {2021 May 26}, abstract = {

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

}, issn = {1528-1167}, doi = {10.1111/epi.16931}, author = {Ernst, Michelle E and Baugh, Evan H and Thomas, Amanda and Bier, Louise and Lippa, Natalie and Stong, Nicholas and Mulhern, Maureen S and Kushary, Sulagna and Akman, Cigdem I and Heinzen, Erin L and Yeh, Raymond and Bi, Weimin and Hanchard, Neil A and Burrage, Lindsay C and Leduc, Magalie S and Chong, Josephine S C and Bend, Renee and Lyons, Michael J and Lee, Jennifer A and Suwannarat, Pim and Brilstra, Eva and Simon, Marleen and Koopmans, Marije and van Binsbergen, Ellen and Groepper, Daniel and Fleischer, Julie and Nava, Caroline and Keren, Boris and Mignot, Cyril and Mathieu, Sophie and Mancini, Grazia M S and Madan-Khetarpal, Suneeta and Infante, Elena M and Bluvstein, Judith and Seeley, Andrea and Bachman, Kristine and Klee, Eric W and Schultz-Rogers, Laura E and Hasadsri, Linda and Barnett, Sarah and Ellingson, Marissa S and Ferber, Matthew J and Narayanan, Vinodh and Ramsey, Keri and Rauch, Anita and Joset, Pascal and Steindl, Katharina and Sheehan, Theodore and Poduri, Annapurna and Vasquez, Alejandra and Ruivenkamp, Claudia and White, Susan M and Pais, Lynn and Monaghan, Kristin G and Goldstein, David B and Sands, Tristan T and Aggarwal, Vimla} } @article {1007, title = {De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 02 04}, pages = {357-367}, abstract = {

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28~{\texttimes} 10). In all six cases with available parental DNA, we demonstrated de novo inheritance (p~=~2.21~{\texttimes} 10). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

}, keywords = {Adult, Animals, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities, Epilepsy, Female, Glomerulosclerosis, Focal Segmental, Humans, Intranuclear Space, Kidney, Male, Mice, Mutation, Nephrotic Syndrome, Nerve Tissue Proteins, Phenotype, Podocytes, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.01.008}, author = {Weng, Patricia L and Majmundar, Amar J and Khan, Kamal and Lim, Tze Y and Shril, Shirlee and Jin, Gina and Musgrove, John and Wang, Minxian and Ahram, Dina F and Aggarwal, Vimla S and Bier, Louise E and Heinzen, Erin L and Onuchic-Whitford, Ana C and Mann, Nina and Buerger, Florian and Schneider, Ronen and Deutsch, Konstantin and Kitzler, Thomas M and Kl{\"a}mbt, Verena and Kolb, Amy and Mao, Youying and Moufawad El Achkar, Christelle and Mitrotti, Adele and Martino, Jeremiah and Beck, Bodo B and Altm{\"u}ller, Janine and Benz, Marcus R and Yano, Shoji and Mikati, Mohamad A and Gunduz, Talha and Cope, Heidi and Shashi, Vandana and Trachtman, Howard and Bodria, Monica and Caridi, Gianluca and Pisani, Isabella and Fiaccadori, Enrico and AbuMaziad, Asmaa S and Martinez-Agosto, Julian A and Yadin, Ora and Zuckerman, Jonathan and Kim, Arang and John-Kroegel, Ulrike and Tyndall, Amanda V and Parboosingh, Jillian S and Innes, A Micheil and Bierzynska, Agnieszka and Koziell, Ania B and Muorah, Mordi and Saleem, Moin A and Hoefele, Julia and Riedhammer, Korbinian M and Gharavi, Ali G and Jobanputra, Vaidehi and Pierce-Hoffman, Emma and Seaby, Eleanor G and O{\textquoteright}Donnell-Luria, Anne and Rehm, Heidi L and Mane, Shrikant and D{\textquoteright}Agati, Vivette D and Pollak, Martin R and Ghiggeri, Gian Marco and Lifton, Richard P and Goldstein, David B and Davis, Erica E and Hildebrandt, Friedhelm and Sanna-Cherchi, Simone} } @article {918, title = {De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 04}, pages = {653-660}, abstract = {

PURPOSE: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

METHODS: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

RESULTS: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

CONCLUSION: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."

}, keywords = {Brain Diseases, Child, Preschool, Epilepsy, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, Synaptosomal-Associated Protein 25}, issn = {1530-0366}, doi = {10.1038/s41436-020-01020-w}, author = {Kl{\"o}ckner, Chiara and Sticht, Heinrich and Zacher, Pia and Popp, Bernt and Babcock, Holly E and Bakker, Dewi P and Barwick, Katy and Bonfert, Michaela V and B{\"o}nnemann, Carsten G and Brilstra, Eva H and Chung, Wendy K and Clarke, Angus J and Devine, Patrick and Donkervoort, Sandra and Fraser, Jamie L and Friedman, Jennifer and Gates, Alyssa and Ghoumid, Jamal and Hobson, Emma and Horvath, Gabriella and Keller-Ramey, Jennifer and Keren, Boris and Kurian, Manju A and Lee, Virgina and Leppig, Kathleen A and Lundgren, Johan and McDonald, Marie T and McLaughlin, Heather M and McTague, Amy and Mefford, Heather C and Mignot, Cyril and Mikati, Mohamad A and Nava, Caroline and Raymond, F Lucy and Sampson, Julian R and Sanchis-Juan, Alba and Shashi, Vandana and Shieh, Joseph T C and Shinawi, Marwan and Slavotinek, Anne and St{\"o}dberg, Tommy and Stong, Nicholas and Sullivan, Jennifer A and Taylor, Ashley C and Toler, Tomi L and van den Boogaard, Marie-Jos{\'e} and van der Crabben, Saskia N and van Gassen, Koen L I and van Jaarsveld, Richard H and Van Ziffle, Jessica and Wadley, Alexandrea F and Wagner, Matias and Wigby, Kristen and Wortmann, Saskia B and Zarate, Yuri A and M{\o}ller, Rikke S and Lemke, Johannes R and Platzer, Konrad} } @article {1010, title = {De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder.}, journal = {Am J Med Genet A}, year = {2021}, month = {2021 May 18}, abstract = {

TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants{\textquoteright} pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62254}, author = {Dias, Caroline and Pfundt, Rolph and Kleefstra, Tjitske and Shuurs-Hoeijmakers, Janneke and Boon, Elles M J and van Hagen, Johanna M and Zwijnenburg, Petra and Weiss, Marjan M and Keren, Boris and Mignot, Cyril and Isapof, Arnaud and Weiss, Karin and Hershkovitz, Tova and Iascone, Maria and Maitz, Silvia and Feichtinger, Ren{\'e} G and Kotzot, Dieter and Mayr, Johannes A and Ben-Omran, Tawfeg and Mahmoud, Laila and Pais, Lynn S and Walsh, Christopher A and Shashi, Vandana and Sullivan, Jennifer A and Stong, Nicholas and Lecoquierre, Francois and Guerrot, Anne-Marie and Charollais, Aude and Rodan, Lance H} } @article {796, title = {Deforming Polyarthritis in a North Indian Family-Clinical Expansion of STING-Associated Vasculopathy with Onset in Infancy (SAVI).}, journal = {J Clin Immunol}, volume = {41}, year = {2021}, month = {2021 Jan}, pages = {209-211}, issn = {1573-2592}, doi = {10.1007/s10875-020-00872-w}, author = {Anjani, Gummadi and Jindal, Ankur Kumar and Prithvi, Ashwini and Kaur, Anit and Rawat, Amit and Sharma, Madhubala and Yuan, Bo and Chinn, Ivan K and Singh, Surjit} } @article {1021, title = {Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 16}, pages = {2282}, abstract = {

Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer-promoter interactions.

}, keywords = {Animals, Binding Sites, CCCTC-Binding Factor, Chromatin Immunoprecipitation Sequencing, Disease Models, Animal, Embryo, Mammalian, Enhancer Elements, Genetic, Exons, Extremities, Female, Foot Deformities, Congenital, Gene Expression Regulation, Developmental, Genetic Loci, Genetic Testing, Hand Deformities, Congenital, Hedgehog Proteins, Humans, Introns, Male, Membrane Proteins, Mice, Mice, Knockout, Promoter Regions, Genetic, Sequence Deletion, Species Specificity, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-021-22470-z}, author = {Ushiki, Aki and Zhang, Yichi and Xiong, Chenling and Zhao, Jingjing and Georgakopoulos-Soares, Ilias and Kane, Lauren and Jamieson, Kirsty and Bamshad, Michael J and Nickerson, Deborah A and Shen, Yin and Lettice, Laura A and Silveira-Lucas, Elizabeth Lemos and Petit, Florence and Ahituv, Nadav} } @article {1006, title = {Detection of homozygous and hemizygous complete or partial exon deletions by whole-exome sequencing.}, journal = {NAR Genom Bioinform}, volume = {3}, year = {2021}, month = {2021 Jun}, pages = {lqab037}, abstract = {

The detection of copy number variations (CNVs) in whole-exome sequencing (WES) data is important, as CNVs may underlie a number of human genetic disorders. The recently developed HMZDelFinder algorithm can detect rare homozygous and hemizygous (HMZ) deletions in WES data more effectively than other widely used tools. Here, we present HMZDelFinder_opt, an approach that outperforms HMZDelFinder for the detection of HMZ deletions, including partial exon deletions in particular, in WES data from laboratory patient collections that were generated over time in different experimental conditions. We show that using an optimized reference control set of WES data, based on a PCA-derived Euclidean distance for coverage, strongly improves the detection of HMZ complete exon deletions both in real patients carrying validated disease-causing deletions and in simulated data. Furthermore, we develop a sliding window approach enabling HMZDelFinder_opt to identify HMZ partial deletions of exons that are undiscovered by HMZDelFinder. HMZDelFinder_opt is a timely and powerful approach for detecting HMZ deletions, particularly partial exon deletions, in WES data from inherently heterogeneous laboratory patient collections.

}, issn = {2631-9268}, doi = {10.1093/nargab/lqab037}, author = {Bigio, Benedetta and Seeleuthner, Yoann and Kerner, Gaspard and Migaud, M{\'e}lanie and Rosain, J{\'e}r{\'e}mie and Boisson, Bertrand and Nasca, Carla and Puel, Anne and Bustamante, Jacinta and Casanova, Jean-Laurent and Abel, Laurent and Cobat, Aurelie} } @article {789, title = {Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS).}, journal = {J Med Genet}, volume = {58}, year = {2021}, month = {2021 Jan}, pages = {41-47}, abstract = {

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening.

METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited.

RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6\%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis.

CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106823}, author = {Zhao, Sen and Zhang, Yuanqiang and Chen, Weisheng and Li, Weiyu and Wang, Shengru and Wang, Lianlei and Zhao, Yanxue and Lin, Mao and Ye, Yongyu and Lin, Jiachen and Zheng, Yu and Liu, Jiaqi and Zhao, Hengqiang and Yan, Zihui and Yang, Yongxin and Huang, Yingzhao and Lin, Guanfeng and Chen, Zefu and Zhang, Zhen and Liu, Sen and Jin, Lichao and Wang, Zhaoyang and Chen, Jingdan and Niu, Yuchen and Li, Xiaoxin and Wu, Yong and Wang, Yipeng and Du, Renqian and Gao, Na and Zhao, Hong and Yang, Ying and Liu, Ying and Tian, Ye and Li, Wenli and Zhao, Yu and Liu, Jia and Yu, Bin and Zhang, Na and Yu, Keyi and Yang, Xu and Li, Shugang and Xu, Yuan and Hu, Jianhua and Liu, Zhe and Shen, Jianxiong and Zhang, Shuyang and Su, Jianzhong and Khanshour, Anas M and Kidane, Yared H and Ramo, Brandon and Rios, Jonathan J and Liu, Pengfei and Sutton, V Reid and Posey, Jennifer E and Wu, Zhihong and Qiu, Guixing and Wise, Carol A and Zhang, Feng and Lupski, James R and Zhang, Jianguo and Wu, Nan} } @article {999, title = {DLG4-related synaptopathy: a new rare brain disorder.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 05}, pages = {888-899}, abstract = {

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

METHODS: The clinical and genetic information were~collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.

RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not~be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.

CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

}, keywords = {Autism Spectrum Disorder, Brain, Brain Diseases, Disks Large Homolog 4 Protein, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype}, issn = {1530-0366}, doi = {10.1038/s41436-020-01075-9}, author = {Rodr{\'\i}guez-Palmero, Agust{\'\i} and Boerrigter, Melissa Maria and G{\'o}mez-Andr{\'e}s, David and Aldinger, Kimberly A and Marcos-Alcalde, {\'I}{\~n}igo and Popp, Bernt and Everman, David B and Lovgren, Alysia Kern and Arpin, Stephanie and Bahrambeigi, Vahid and Beunders, Gea and Bisgaard, Anne-Marie and Bjerregaard, V A and Bruel, Ange-Line and Challman, Thomas D and Cogn{\'e}, Benjamin and Coubes, Christine and de Man, Stella A and Denomm{\'e}-Pichon, Anne-Sophie and Dye, Thomas J and Elmslie, Frances and Feuk, Lars and Garcia-Minaur, Sixto and Gertler, Tracy and Giorgio, Elisa and Gruchy, Nicolas and Haack, Tobias B and Haldeman-Englert, Chad R and Haukanes, Bj{\o}rn Ivar and Hoyer, Juliane and Hurst, Anna C E and Isidor, Bertrand and Soller, Maria Johansson and Kushary, Sulagna and Kvarnung, Malin and Landau, Yuval E and Leppig, Kathleen A and Lindstrand, Anna and Kleinendorst, Lotte and MacKenzie, Alex and Mandrile, Giorgia and Mendelsohn, Bryce A and Moghadasi, Setareh and Morton, Jenny E and Moutton, S{\'e}bastien and M{\"u}ller, Amelie J and O{\textquoteright}Leary, Melanie and Pacio-Miguez, Marta and Palomares-Bralo, Maria and Parikh, Sumit and Pfundt, Rolph and Pode-Shakked, Ben and Rauch, Anita and Repnikova, Elena and Revah-Politi, Anya and Ross, Meredith J and Ruivenkamp, Claudia A L and Sarrazin, Elisabeth and Savatt, Juliann M and Schluter, Agatha and Sch{\"o}newolf-Greulich, Bitten and Shad, Zohra and Shaw-Smith, Charles and Shieh, Joseph T and Shohat, Motti and Spranger, Stephanie and Thiese, Heidi and Mau-Them, Frederic Tran and van Bon, Bregje and van de Burgt, Ineke and van de Laar, Ingrid M B H and van Drie, Esm{\'e}e and van Haelst, Mieke M and van Ravenswaaij-Arts, Conny M and Verdura, Edgard and Vitobello, Antonio and Waldm{\"u}ller, Stephan and Whiting, Sharon and Zweier, Christiane and Prada, Carlos E and de Vries, Bert B A and Dobyns, William B and Reiter, Simone F and G{\'o}mez-Puertas, Paulino and Pujol, Aurora and T{\"u}mer, Zeynep} } @article {1000, title = {A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 04 01}, pages = {749-756}, abstract = {

The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. The affected individuals have a consistent phenotype of hypotonia, mild to moderate intellectual disability, and similar facies, including horizontal or slightly bowed eyebrows, deep-set eyes, full cheeks, a short nose, and large, fleshy and forward-facing earlobes, demonstrated in the composite face generated from the cohort. Digital anomalies, including brachydactyly and syndactyly, were common. Three older individuals have obesity. We show that cells derived from affected individuals have altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage. Overall, our study adds to the growing family of neurodevelopmental phenotypes mediated by disruption of the CRL4 ubiquitin ligase pathway and begins to delineate the phenotypic and molecular effects of DDB1 misregulation.

}, keywords = {Adolescent, Alleles, Child, Child, Preschool, DNA Repair, DNA-Binding Proteins, Female, Humans, Male, Mutation, Neurodevelopmental Disorders, Phenotype, Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.03.007}, author = {White, Susan M and Bhoj, Elizabeth and Nellaker, Christoffer and Lachmeijer, Augusta M A and Marshall, Aren E and Boycott, Kym M and Li, Dong and Smith, Wendy and Hartley, Taila and McBride, Arran and Ernst, Michelle E and May, Alison S and Wieczorek, Dagmar and Abou Jamra, Rami and Koch-Hogrebe, Margarete and {\~O}unap, Katrin and Pajusalu, Sander and van Gassen, K L I and Sadedin, Simon and Ellingwood, Sara and Tan, Tiong Yang and Christodoulou, John and Barea, Jaime and Lockhart, Paul J and Nezarati, Marjan M and Kernohan, Kristin D} } @article {942, title = {Dominant mitochondrial membrane protein-associated neurodegeneration (MPAN) variants cluster within a specific C19orf12 isoform.}, journal = {Parkinsonism Relat Disord}, volume = {82}, year = {2021}, month = {2021 01}, pages = {84-86}, abstract = {

Mitochondria membrane protein-associated neurodegeneration (MPAN) neurodegenerative disorder is typically associated with biallelic C19orf12 variants. Here we describe a new and review candidate previous monoallelic de novo C19orf12 variants to define loss of function mutations located in the putative non-membrane spanning C19orf12 isoform as the potential basis of monoallelic MPAN.

}, issn = {1873-5126}, doi = {10.1016/j.parkreldis.2020.10.041}, author = {Rickman, Olivia J and Salter, Claire G and Gunning, Adam C and Fasham, James and Voutsina, Nikol and Leslie, Joseph S and McGavin, Lucy and Cross, Harold E and Posey, Jennifer E and Akdemir, Zeynep Coban and Jhangiani, Shalini N and Lupski, James R and Baple, Emma L and Crosby, Andrew H} } @article {979, title = {Exome sequencing identifies novel missense and deletion variants in RTN4IP1 associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 01}, pages = {203-207}, abstract = {

Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy-10 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in RTN4IP1, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo-reductase. Here we report novel compound heterozygous mutations in RTN4IP1 in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate-to-pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T>G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing RTN4IP1. To our knowledge, this is the first report of a non-single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between "syndromic" cases and severe RTN4IP1 mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61910}, author = {D{\textquoteright}Gama, Alissa M and England, Eleina and Madden, Jill A and Shi, JiAHi and Chao, Katherine R and Wojcik, Monica H and Torres, Alcy R and Tan, Wen-Hann and Berry, Gerard T and Prabhu, Sanjay P and Agrawal, Pankaj B} } @article {1004, title = {Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.}, journal = {Hum Genet}, year = {2021}, month = {2021 Mar 12}, abstract = {

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75\% of these variants in known ID genes were de novo or suspected de novo (64\% autosomal dominant; 11\% X-linked) and 25\% were inherited (14\% autosomal recessive; 7\% X-linked; and 4\% autosomal dominant). A dual molecular diagnosis was suggested in two families (5\%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7~Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64\% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.

}, issn = {1432-1203}, doi = {10.1007/s00439-021-02268-1}, author = {J{\"a}rvel{\"a}, Irma and M{\"a}{\"a}tt{\"a}, Tuomo and Acharya, Anushree and Lepp{\"a}l{\"a}, Juha and Jhangiani, Shalini N and Arvio, Maria and Siren, Auli and Kankuri-Tammilehto, Minna and Kokkonen, Hannaleena and Palom{\"a}ki, Maarit and Varilo, Teppo and Fang, Mary and Hadley, Trevor D and Jolly, Angad and Linnankivi, Tarja and Paetau, Ritva and Saarela, Anni and K{\"a}lvi{\"a}inen, Reetta and Olme, Jan and Nouel-Saied, Liz M and Cornejo-Sanchez, Diana M and Llaci, Lorida and Lupski, James R and Posey, Jennifer E and Leal, Suzanne M and Schrauwen, Isabelle} } @article {936, title = {Exome-wide rare variant analysis in familial essential tremor.}, journal = {Parkinsonism Relat Disord}, volume = {82}, year = {2021}, month = {2021 01}, pages = {109-116}, abstract = {

INTRODUCTION: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing.

METHODS: We studied eight multigenerational families (N~=~40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521~ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789~ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes.

RESULTS: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders.

CONCLUSIONS: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.

}, issn = {1873-5126}, doi = {10.1016/j.parkreldis.2020.11.021}, author = {Diez-Fairen, Monica and Houle, Gabrielle and Ortega-Cubero, Sara and Bandres-Ciga, Sara and Alvarez, Ignacio and Carcel, Maria and Iba{\~n}ez, Laura and Fernandez, Maria Victoria and Budde, John P and Trotta, Jean-R{\'e}mi and Tonda, Ra{\'u}l and Chong, Jessica X and Bamshad, Michael J and Nickerson, Deborah A and Aguilar, Miquel and Tartari, Juan P and Gironell, Alexandre and Garc{\'\i}a-Mart{\'\i}n, Elena and Agundez, Jose Ag and Alonso-Navarro, Hortensia and Jimenez-Jimenez, Felix Javier and Fernandez, Manel and Valldeoriola, Francesc and Marti, Maria Jose and Tolosa, Eduard and Coria, Francisco and Pastor, Maria A and Vilari{\~n}o-G{\"u}ell, Carles and Rajput, Alex and Dion, Patrick A and Cruchaga, Carlos and Rouleau, Guy A and Pastor, Pau} } @article {997, title = {Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG.}, journal = {J Inherit Metab Dis}, year = {2021}, month = {2021 Feb 13}, abstract = {

Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man GlcNAc consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.

}, issn = {1573-2665}, doi = {10.1002/jimd.12367}, author = {Alsharhan, Hind and Ng, Bobby G and Daniel, Earnest James Paul and Friedman, Jennifer and Pivnick, Eniko K and Al-Hashem, Amal and Faqeih, Eissa Ali and Liu, Pengfei and Engelhardt, Nicole M and Keller, Kierstin N and Chen, Jie and Mazzeo, Pamela A and Rosenfeld, Jill A and Bamshad, Michael J and Nickerson, Deborah A and Raymond, Kimiyo M and Freeze, Hudson H and He, Miao and Edmondson, Andrew C and Lam, Christina} } @article {996, title = {Further delineation of van den Ende-Gupta syndrome: Genetic heterogeneity and overlap with congenital heart defects and skeletal malformations syndrome.}, journal = {Am J Med Genet A}, year = {2021}, month = {2021 Mar 30}, abstract = {

Van den Ende-Gupta syndrome (VDEGS) is a rare autosomal recessive condition characterized by distinctive facial and skeletal features, and in most affected persons, by biallelic pathogenic variants in SCARF2. We review the type and frequency of the clinical features in 36 reported individuals with features of VDEGS, 15 (42\%) of whom had known pathogenic variants in SCARF2, 6 (16\%) with negative SCARF2 testing, and 15 (42\%) not tested. We also report three new individuals with pathogenic variants in SCARF2 and clinical features of VDEGS. Of the six persons without known pathogenic variants in SCARF2, three remain unsolved despite extensive genetic testing. Three were found to have pathogenic ABL1 variants using whole exome sequencing (WES) or whole genome sequencing (WGS). Their phenotype was consistent with the congenital heart disease and skeletal malformations syndrome (CHDSKM), which has been associated with ABL1 variants. Of the three unsolved cases, two were brothers who underwent WGS and targeted long-range sequencing of both SCARF2 and ABL1, and the third person who underwent WES and RNA sequencing for SCARF2. Because these affected individuals with classical features of VDEGS lacked a detectable pathogenic SCARF2 variant, genetic heterogeneity is likely. Our study shows the importance of performing genetic testing on individuals with the VDEGS "phenotype," either as a targeted gene analysis (SCARF2, ABL1) or WES/WGS. Additionally, individuals with the combination of arachnodactyly and blepharophimosis should undergo echocardiography while awaiting results of molecular testing due to the overlapping physical features of VDEGS and CHDSKM.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62194}, author = {Hildebrandt, Clara C and Patel, Nisha and GrAHm, John M and Bamshad, Michael and Nickerson, Deborah A and White, Janson J and Marvin, Colby T and Miller, Danny E and Grand, Katheryn L and Sanchez-Lara, Pedro A and Schweitzer, Daniela and Al-Zaidan, Hamad I and Al Masseri, Zainab and Alkuraya, Fowzan S and Lin, Angela E} } @article {894, title = {Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.}, journal = {Genome Med}, volume = {13}, year = {2021}, month = {2021 04 21}, pages = {66}, abstract = {

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

}, keywords = {Adult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, Asthma, Bronchi, Cardiovascular Diseases, COVID-19, Gene Expression, Genetic Variation, Humans, Middle Aged, Obesity, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Respiratory Mucosa, Risk Factors, SARS-CoV-2, Smoking}, issn = {1756-994X}, doi = {10.1186/s13073-021-00866-2}, author = {Kasela, Silva and Ortega, Victor E and Martorella, Molly and Garudadri, Suresh and Nguyen, Jenna and Ampleford, Elizabeth and Pasanen, Anu and Nerella, Srilaxmi and Buschur, Kristina L and Barjaktarevic, Igor Z and Barr, R Graham and Bleecker, Eugene R and Bowler, Russell P and Comellas, Alejandro P and Cooper, Christopher B and Couper, David J and Criner, Gerard J and Curtis, Jeffrey L and Han, MeiLan K and Hansel, Nadia N and Hoffman, Eric A and Kaner, Robert J and Krishnan, Jerry A and Martinez, Fernando J and McDonald, Merry-Lynn N and Meyers, Deborah A and Paine, Robert and Peters, Stephen P and Castro, Mario and Denlinger, Loren C and Erzurum, Serpil C and Fahy, John V and Israel, Elliot and Jarjour, Nizar N and Levy, Bruce D and Li, Xingnan and Moore, Wendy C and Wenzel, Sally E and Zein, Joe and Langelier, Charles and Woodruff, Prescott G and Lappalainen, Tuuli and Christenson, Stephanie A} } @article {896, title = {Genetic Predictor to Identify Individuals With High Lipoprotein(a) Concentrations.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 Feb}, pages = {e003182}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.120.003182}, author = {Dron, Jacqueline S and Wang, Minxian and Patel, Aniruddh P and Kartoun, Uri and Ng, Kenney and Hegele, Robert A and Khera, Amit V} } @article {891, title = {Germline mutation in : a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.}, journal = {HGG Adv}, volume = {2}, year = {2021}, month = {2021 Jan 14}, abstract = {

germline variation in was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic or inherited variants in , detail their phenotypes, and map all known variants to the domain structure of and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7\%) than previously reported (3/15, 20\%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7\%) than previously reported (14/15, 93.3\%) (p value = 0.076309). -related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

}, issn = {2666-2477}, doi = {10.1016/j.xhgg.2020.100014}, author = {Hansen, Adam W and Arora, Payal and Khayat, Michael M and Smith, Leah J and Lewis, Andrea M and Rossetti, Linda Z and Jayaseelan, Joy and Cristian, Ingrid and Haynes, Devon and DiTroia, Stephanie and Meeks, Naomi and Delgado, Mauricio R and Rosenfeld, Jill A and Pais, Lynn and White, Susan M and Meng, Qingchang and Pehlivan, Davut and Liu, Pengfei and Gingras, Marie-Claude and Wangler, Michael F and Muzny, Donna M and Lupski, James R and Kaplan, Craig D and Gibbs, Richard A} } @article {1009, title = {GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 Jul 05}, abstract = {

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

}, issn = {1540-9538}, doi = {10.1084/jem.20201745}, author = {Drzewiecki, Kaela and Choi, Jungmin and Brancale, Joseph and Leney-Greene, Michael A and Sari, Sinan and Dalgi{\c c}, Buket and {\"U}nl{\"u}soy Aksu, Aysel and Evirgen {\c S}ahin, G{\"u}lseren and Ozen, Ahmet and Baris, Safa and Karakoc-Aydiner, Elif and Jain, Dhanpat and Kleiner, David and Schmalz, Michael and Radhakrishnan, Kadakkal and Zhang, Junhui and Hoebe, Kasper and Su, Helen C and Pereira, Jo{\~a}o P and Lenardo, Michael J and Lifton, Richard P and Vilarinho, S{\'\i}lvia} } @article {898, title = {Haplotype-resolved diverse human genomes and integrated analysis of structural variation.}, journal = {Science}, volume = {372}, year = {2021}, month = {2021 04 02}, abstract = {

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50\% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68\% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63\% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

}, keywords = {Female, Genetic Variation, Genome, Human, Genotype, Haplotypes, High-Throughput Nucleotide Sequencing, Humans, INDEL Mutation, Interspersed Repetitive Sequences, Male, Population Groups, Quantitative Trait Loci, Retroelements, Sequence Analysis, DNA, Sequence Inversion, Whole Genome Sequencing}, issn = {1095-9203}, doi = {10.1126/science.abf7117}, author = {Ebert, Peter and Audano, Peter A and Zhu, Qihui and Rodriguez-Martin, Bernardo and Porubsky, David and Bonder, Marc Jan and Sulovari, Arvis and Ebler, Jana and Zhou, Weichen and Serra Mari, Rebecca and Yilmaz, Feyza and Zhao, Xuefang and Hsieh, PingHsun and Lee, Joyce and Kumar, Sushant and Lin, Jiadong and Rausch, Tobias and Chen, Yu and Ren, Jingwen and Santamarina, Martin and H{\"o}ps, Wolfram and Ashraf, Hufsah and Chuang, Nelson T and Yang, Xiaofei and Munson, Katherine M and Lewis, Alexandra P and Fairley, Susan and Tallon, Luke J and Clarke, Wayne E and Basile, Anna O and Byrska-Bishop, Marta and Corvelo, Andr{\'e} and Evani, Uday S and Lu, Tsung-Yu and Chaisson, Mark J P and Chen, Junjie and Li, Chong and Brand, Harrison and Wenger, Aaron M and Ghareghani, Maryam and Harvey, William T and Raeder, Benjamin and Hasenfeld, Patrick and Regier, Allison A and Abel, Haley J and Hall, Ira M and Flicek, Paul and Stegle, Oliver and Gerstein, Mark B and Tubio, Jose M C and Mu, Zepeng and Li, Yang I and Shi, Xinghua and Hastie, Alex R and Ye, Kai and Chong, Zechen and Sanders, Ashley D and Zody, Michael C and Talkowski, Michael E and Mills, Ryan E and Devine, Scott E and Lee, Charles and Korbel, Jan O and Marschall, Tobias and Eichler, Evan E} } @article {831, title = {Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells.}, journal = {Cell}, volume = {184}, year = {2021}, month = {2021 01 07}, pages = {92-105.e16}, abstract = {

To better understand host-virus genetic dependencies and find potential therapeutic targets for COVID-19, we performed a genome-scale CRISPR loss-of-function screen to identify host factors required for SARS-CoV-2 viral infection of human alveolar epithelial cells. Top-ranked genes cluster into distinct pathways, including the vacuolar ATPase proton pump, Retromer, and Commander complexes. We validate these gene targets using several orthogonal methods such as CRISPR knockout, RNA interference knockdown, and small-molecule inhibitors. Using single-cell RNA-sequencing, we identify shared transcriptional changes in cholesterol biosynthesis upon loss of top-ranked genes. In addition, given the key role of the ACE2 receptor in the early stages of viral entry, we show that loss of RAB7A reduces viral entry by sequestering the ACE2 receptor inside cells. Overall, this work provides a genome-scale, quantitative resource of the impact of the loss of each host gene on fitness/response to viral infection.

}, keywords = {A549 Cells, Alveolar Epithelial Cells, Angiotensin-Converting Enzyme 2, Biosynthetic Pathways, Cholesterol, Clustered Regularly Interspaced Short Palindromic Repeats, COVID-19, Endosomes, Gene Expression Profiling, Gene Knockdown Techniques, Gene Knockout Techniques, Genome-Wide Association Study, Host-Pathogen Interactions, Humans, rab GTP-Binding Proteins, RNA Interference, SARS-CoV-2, Single-Cell Analysis, Viral Load}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.10.030}, author = {Daniloski, Zharko and Jordan, Tristan X and Wessels, Hans-Hermann and Hoagland, Daisy A and Kasela, Silva and Legut, Mateusz and Maniatis, Silas and Mimitou, Eleni P and Lu, Lu and Geller, Evan and Danziger, Oded and Rosenberg, Brad R and Phatnani, Hemali and Smibert, Peter and Lappalainen, Tuuli and tenOever, Benjamin R and Sanjana, Neville E} } @article {988, title = {Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea.}, journal = {J Clin Endocrinol Metab}, volume = {106}, year = {2021}, month = {2021 Mar 08}, pages = {e1441-e1452}, abstract = {

CONTEXT: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility.

OBJECTIVE: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls.

DESIGN: We compared patients with HA to control women.

SETTING: The study was conducted at secondary referral centers.

PATIENTS AND OTHER PARTICIPANTS: Women with HA (n = 106) and control women (ClinSeq study; n = 468).

INTERVENTIONS: We performed exome sequencing in all patients and controls.

MAIN OUTCOME MEASURE(S): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests.

RESULTS: RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8\% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2\%).

CONCLUSIONS: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.

}, issn = {1945-7197}, doi = {10.1210/clinem/dgaa609}, author = {Delaney, Angela and Burkholder, Adam B and Lavender, Christopher A and Plummer, Lacey and Mericq, Veronica and Merino, Paulina M and Quinton, Richard and Lewis, Katie L and Meader, Brooke N and Albano, Alessandro and Shaw, Natalie D and Welt, Corrine K and Martin, Kathryn A and Seminara, Stephanie B and Biesecker, Leslie G and Bailey-Wilson, Joan E and Hall, Janet E} } @article {1003, title = {Inhibition of HECT E3 ligases as potential therapy for COVID-19.}, journal = {Cell Death Dis}, volume = {12}, year = {2021}, month = {2021 03 24}, pages = {310}, abstract = {

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

}, keywords = {Adult, Aged, Animals, Antiviral Agents, Chlorocebus aethiops, COVID-19, Endosomal Sorting Complexes Required for Transport, Female, Humans, Indoles, Male, Mice, Mice, Inbred BALB C, Middle Aged, Nedd4 Ubiquitin Protein Ligases, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Ubiquitin-Protein Ligases, Ubiquitination, Vero Cells}, issn = {2041-4889}, doi = {10.1038/s41419-021-03513-1}, author = {Novelli, Giuseppe and Liu, Jing and Biancolella, Michela and Alonzi, Tonino and Novelli, Antonio and Patten, J J and Cocciadiferro, Dario and Agolini, Emanuele and Colona, Vito Luigi and Rizzacasa, Barbara and Giannini, Rosalinda and Bigio, Benedetta and Goletti, Delia and Capobianchi, Maria Rosaria and Grelli, Sandro and Mann, Justin and McKee, Trevor D and Cheng, Ke and Amanat, Fatima and Krammer, Florian and Guarracino, Andrea and Pepe, Gerardo and Tomino, Carlo and Tandjaoui-Lambiotte, Yacine and Uzunhan, Yurdagul and Tubiana, Sarah and Ghosn, Jade and Notarangelo, Luigi D and Su, Helen C and Abel, Laurent and Cobat, Aurelie and Elhanan, Gai and Grzymski, Joseph J and Latini, Andrea and Sidhu, Sachdev S and Jain, Suresh and Davey, Robert A and Casanova, Jean-Laurent and Wei, Wenyi and Pandolfi, Pier Paolo} } @article {1020, title = {Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19.}, journal = {bioRxiv}, year = {2021}, month = {2021 Mar 10}, abstract = {

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19\% of critical, 6\% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.

}, doi = {10.1101/2021.03.09.434529}, author = {van der Wijst, Monique G P and Vazquez, Sara E and Hartoularos, George C and Bastard, Paul and Grant, Tianna and Bueno, Raymund and Lee, David S and Greenland, John R and Sun, Yang and Perez, Richard and Ogorodnikov, Anton and Ward, Alyssa and Mann, Sabrina A and Lynch, Kara L and Yun, Cassandra and Havlir, Diane V and Chamie, Gabriel and Marquez, Carina and Greenhouse, Bryan and Lionakis, Michail S and Norris, Philip J and Dumont, Larry J and Kelly, Kathleen and Zhang, Peng and Zhang, Qian and Gervais, Adrian and Voyer, Tom Le and Whatley, Alexander and Si, Yichen and Byrne, Ashley and Combes, Alexis J and Rao, Arjun Arkal and Song, Yun S and Fragiadakis, Gabriela K and Kangelaris, Kirsten and Calfee, Carolyn S and Erle, David J and Hendrickson, Carolyn and Krummel, Matthew F and Woodruff, Prescott G and Langelier, Charles R and Casanova, Jean-Laurent and Derisi, Joseph L and Anderson, Mark S and Ye, Chun Jimmie} } @article {1001, title = {Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 05 07}, pages = {2558}, abstract = {

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.

}, keywords = {Alleles, Amino Acid Sequence, Animals, Child, Preschool, Developmental Disabilities, Drosophila, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Gene Ontology, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Loss of Function Mutation, Male, Muscle Hypotonia, Myoclonic Cerebellar Dyssynergia, Neurodevelopmental Disorders, Neurons, Pedigree, Polymorphism, Single Nucleotide, Ribonucleoproteins, Small Nuclear, Rigor Mortis, RNA-Seq, SMN Complex Proteins}, issn = {2041-1723}, doi = {10.1038/s41467-021-22627-w}, author = {Kour, Sukhleen and Rajan, Deepa S and Fortuna, Tyler R and Anderson, Eric N and Ward, Caroline and Lee, Youngha and Lee, Sangmoon and Shin, Yong Beom and Chae, Jong-Hee and Choi, Murim and Siquier, Karine and Cantagrel, Vincent and Amiel, Jeanne and Stolerman, Elliot S and Barnett, Sarah S and Cousin, Margot A and Castro, Diana and McDonald, Kimberly and Kirmse, Brian and Nemeth, Andrea H and Rajasundaram, Dhivyaa and Innes, A Micheil and Lynch, Danielle and Frosk, Patrick and Collins, Abigail and Gibbons, Melissa and Yang, Michele and Desguerre, Isabelle and Boddaert, Nathalie and Gitiaux, Cyril and Rydning, Siri Lynne and Selmer, Kaja K and Urreizti, Roser and Garcia-Oguiza, Alberto and Osorio, Andr{\'e}s Nascimento and Verdura, Edgard and Pujol, Aurora and McCurry, Hannah R and Landers, John E and Agnihotri, Sameer and Andriescu, E Corina and Moody, Shade B and Phornphutkul, Chanika and Sacoto, Maria J Guillen and Begtrup, Amber and Houlden, Henry and Kirschner, Janbernd and Schorling, David and Rudnik-Sch{\"o}neborn, Sabine and Strom, Tim M and Leiz, Steffen and Juliette, Kali and Richardson, Randal and Yang, Ying and Zhang, Yuehua and Wang, Minghui and Wang, Jia and Wang, Xiaodong and Platzer, Konrad and Donkervoort, Sandra and B{\"o}nnemann, Carsten G and Wagner, Matias and Issa, Mahmoud Y and Elbendary, Hasnaa M and Stanley, Valentina and Maroofian, Reza and Gleeson, Joseph G and Zaki, MAH S and Senderek, Jan and Pandey, Udai Bhan} } @article {941, title = {MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia.}, journal = {Ann Neurol}, volume = {89}, year = {2021}, month = {2021 04}, pages = {828-833}, abstract = {

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Cataract, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Dystonia, Epilepsy, Genetic Variation, Humans, Infant, Mediator Complex, Nervous System Malformations, Phenotype, Whole Exome Sequencing}, issn = {1531-8249}, doi = {10.1002/ana.26019}, author = {Meng, Linyan and Isohanni, Pirjo and Shao, Yunru and GrAHm, Brett H and Hickey, Scott E and Brooks, Stephanie and Suomalainen, Anu and Joset, Pascal and Steindl, Katharina and Rauch, Anita and Hackenberg, Annette and High, Frances A and Armstrong-Javors, Amy and Mencacci, Niccol{\`o} E and Gonz{\`a}lez-Latapi, Paulina and Kamel, Walaa A and Al-Hashel, Jasem Y and Bustos, Bernab{\'e} I and Hernandez, Alejandro V and Krainc, Dimitri and Lubbe, Steven J and Van Esch, Hilde and De Luca, Chiara and Ballon, Katleen and Ravelli, Claudia and Burglen, Lydie and Qebibo, Leila and Calame, Daniel G and Mitani, Tadahiro and Marafi, Dana and Pehlivan, Davut and Saadi, Nebal W and Sahin, Yavuz and Maroofian, Reza and Efthymiou, Stephanie and Houlden, Henry and Maqbool, Shazia and Rahman, Fatima and Gu, Shen and Posey, Jennifer E and Lupski, James R and Hunter, Jill V and Wangler, Michael F and Carroll, Christopher J and Yang, Yaping} } @article {957, title = {Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10.}, journal = {Hum Mutat}, volume = {42}, year = {2021}, month = {2021 Jan}, pages = {19-24}, abstract = {

The diagnosis of Mendelian disorders following uninformative exome and genome sequencing remains a challenging and often unmet need. Following uninformative exome and genome sequencing of a family quartet including two siblings with suspected mitochondrial disorder, RNA sequencing (RNAseq) was pursued in one sibling. Long-read amplicon sequencing was used to determine and quantify transcript structure. Immunoblotting studies and quantitative proteomics were performed to demonstrate functional impact. Differential expression analysis of RNAseq data identified significantly decreased expression of the mitochondrial OXPHOS Complex I subunit NDUFB10 associated with a cryptic exon in intron 1 of NDUFB10, that included an in-frame stop codon. The cryptic exon contained a rare intronic variant that was homozygous in both affected siblings. Immunoblot and quantitative proteomic analysis of fibroblasts revealed decreased abundance of Complex I subunits, providing evidence of isolated Complex I deficiency. Through multiomic analysis we present data implicating a deep intronic variant in NDUFB10 as the cause of mitochondrial disease in two individuals, providing further support of the gene-disease association. This study highlights the importance of transcriptomic and proteomic analyses as complementary diagnostic tools in patients undergoing genome-wide diagnostic evaluation.

}, issn = {1098-1004}, doi = {10.1002/humu.24135}, author = {Helman, Guy and Compton, Alison G and Hock, Daniella H and Walkiewicz, Marzena and Brett, Gemma R and Pais, Lynn and Tan, Tiong Y and De Paoli-Iseppi, Ricardo and Clark, Michael B and Christodoulou, John and White, Susan M and Thorburn, David R and Stroud, David A and Stark, Zornitza and Simons, Cas} } @article {924, title = {Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.}, journal = {Neuron}, volume = {109}, year = {2021}, month = {2021 01 20}, pages = {241-256.e9}, abstract = {

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

}, keywords = {Amino Acid Sequence, Animals, Cell Cycle Proteins, Cerebellar Diseases, Cohort Studies, Female, Gene Knockout Techniques, HEK293 Cells, Heredodegenerative Disorders, Nervous System, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microcephaly, Mutation, Pedigree, Peptidylprolyl Isomerase, Protein Structure, Secondary, Protein Structure, Tertiary, RNA Splicing Factors, Spliceosomes}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.10.035}, author = {Chai, Guoliang and Webb, Alice and Li, Chen and Antaki, Danny and Lee, Sangmoon and Breuss, Martin W and Lang, Nhi and Stanley, Valentina and Anzenberg, Paula and Yang, Xiaoxu and Marshall, Trevor and Gaffney, Patrick and Wierenga, Klaas J and Chung, Brian Hon-Yin and Tsang, Mandy Ho-Yin and Pais, Lynn S and Lovgren, Alysia Kern and VanNoy, Grace E and Rehm, Heidi L and Mirzaa, Ghayda and Leon, Eyby and Diaz, Jullianne and Neumann, Alexander and Kalverda, Arnout P and Manfield, Iain W and Parry, David A and Logan, Clare V and Johnson, Colin A and Bonthron, David T and Valleley, Elizabeth M A and Issa, Mahmoud Y and Abdel-Ghafar, Sherif F and Abdel-Hamid, Mohamed S and Jennings, Patricia and Zaki, MAH S and Sheridan, Eamonn and Gleeson, Joseph G} } @article {1014, title = {Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 04}, pages = {1288-1293}, abstract = {

Alkylated DNA repair protein AlkB homolog 8 (ALKBH8) is a member of the AlkB family of dioxygenases. ALKBH8 is a methyltransferase of the highly variable wobble nucleoside position in the anticodon loop of tRNA and thus plays a critical role in tRNA modification by preserving codon recognition and preventing errors in amino acid incorporation during translation. Moreover, its activity catalyzes uridine modifications that are proposed to be critical for accurate protein translation. Previously, two distinct homozygous truncating variants in the final exon of ALKBH8 were described in two unrelated large Saudi Arabian kindreds with intellectual developmental disorder and autosomal recessive 71 (MRT71) syndrome (MIM$\#$ 618504). Here, we report a third family-of Egyptian descent-harboring a novel homozygous frame-shift variant in the last exon of ALKBH8. Two affected siblings in this family exhibit global developmental delay and intellectual disability as shared characteristic features of MRT71 syndrome, and we further characterize their observed dysmorphic features and brain MRI findings. This description of a third family with a truncating ALKBH8 variant from a distinct population broadens the phenotypic and genotypic spectrum of MRT71 syndrome, affirms that perturbations in tRNA biogenesis can contribute to neurogenetic disease traits, and firmly establishes ALKBH8 as a novel neurodevelopmental disease gene.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62100}, author = {Saad, Ahmed K and Marafi, Dana and Mitani, Tadahiro and Du, Haowei and Rafat, Karima and Fatih, Jawid M and Jhangiani, Shalini N and Coban-Akdemir, Zeynep and Gibbs, Richard A and Pehlivan, Davut and Hunter, Jill V and Posey, Jennifer E and Zaki, MAH S and Lupski, James R} } @article {995, title = {Neutralizing Autoantibodies to Type I IFNs in >10\% of Patients with Severe COVID-19 Pneumonia Hospitalized in Madrid, Spain.}, journal = {J Clin Immunol}, year = {2021}, month = {2021 Apr 13}, abstract = {

BACKGROUND: In a recent study, autoantibodies neutralizing type I interferons (IFNs) were present in at least 10\% of cases of critical COVID-19 pneumonia. These autoantibodies neutralized most type I IFNs but rarely IFN-beta.

OBJECTIVES: We aimed to define the prevalence of autoantibodies neutralizing type I IFN in a cohort of patients with severe COVID-19 pneumonia treated with IFN-beta-1b during hospitalization and to analyze their impact on various clinical variables and outcomes.

METHODS: We analyzed stored serum/plasma samples and clinical data of COVID-19 patients treated subcutaneously with IFN-beta-1b from March to May 2020, at the Infanta Leonor University Hospital in Madrid, Spain.

RESULTS: The cohort comprised 47 COVID-19 patients with severe pneumonia, 16 of whom (34\%) had a critical progression requiring ICU admission. The median age was 71~years, with 28 men (58.6\%). Type I IFN-alpha- and omega-neutralizing autoantibodies were found in 5 of 47 patients with severe pneumonia or critical disease (10.6\%), while they were not found in any of the 118 asymptomatic controls (p = 0.0016). The autoantibodies did not neutralize IFN-beta. No demographic, comorbidity, or clinical differences were seen between individuals with or without autoantibodies. We found a significant correlation between the presence of neutralizing autoantibodies and higher C-reactive protein levels (p = 5.10e) and lower lymphocyte counts (p = 1.80e). No significant association with response to IFN-beta-1b therapy (p = 0.34) was found. Survival analysis suggested that neutralizing autoantibodies may increase the risk of death (4/5, 80\% vs 12/42, 28.5\%).

CONCLUSION: Autoantibodies neutralizing type I IFN underlie severe/critical COVID-19 stages in at least 10\% of cases, correlate with increased C-RP and lower lymphocyte counts, and confer a trend towards increased risk of death. Subcutaneous IFN-beta treatment of hospitalized patients did not seem to improve clinical outcome. Studies of earlier, ambulatory IFN-beta treatment are warranted.

}, issn = {1573-2592}, doi = {10.1007/s10875-021-01036-0}, author = {Troya, Jes{\'u}s and Bastard, Paul and Planas-Serra, Laura and Ryan, Pablo and Ruiz, Montse and de Carranza, Mar{\'\i}a and Torres, Juan and Mart{\'\i}nez, Amalia and Abel, Laurent and Casanova, Jean-Laurent and Pujol, Aurora} } @article {987, title = {NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity.}, journal = {Hum Mol Genet}, volume = {29}, year = {2021}, month = {2021 01 06}, pages = {3516-3531}, abstract = {

Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddaa237}, author = {Nistala, Harikiran and Dronzek, John and Gonzaga-Jauregui, Claudia and Chim, Shek Man and Rajamani, Saathyaki and Nuwayhid, Samer and Delgado, Dennis and Burke, Elizabeth and Karaca, Ender and Franklin, Matthew C and Sarangapani, Prasad and Podgorski, Michael and Tang, Yajun and Dominguez, Melissa G and Withers, Marjorie and Deckelbaum, Ron A and Scheonherr, Christopher J and Gahl, William A and Malicdan, May C and Zambrowicz, Brian and Gale, Nicholas W and Gibbs, Richard A and Chung, Wendy K and Lupski, James R and Economides, Aris N} } @article {1015, title = {A novel homozygous SLC13A5 whole-gene deletion generated by Alu/Alu-mediated rearrangement in an Iraqi family with epileptic encephalopathy.}, journal = {Am J Med Genet A}, year = {2021}, month = {2021 Apr 02}, abstract = {

Biallelic loss-of-function (LoF) of SLC13A5 (solute carrier family 13, member 5) induced deficiency in sodium/citrate transporter (NaCT) causes autosomal recessive developmental epileptic encephalopathy 25 with hypoplastic amelogenesis imperfecta (DEE25; MIM $\#$615905). Many pathogenic SLC13A5 single nucleotide variants (SNVs) and small indels have been described; however, no cases with copy number variants (CNVs) have been sufficiently investigated. We describe a consanguineous Iraqi family harboring an 88.5 kb homozygous deletion including SLC13A5 in Chr17p13.1. The three affected male siblings exhibit neonatal-onset epilepsy with fever-sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability (GDD/ID), and other variable neurological findings as shared phenotypical features of DEE25. Two of the three affected subjects exhibit hypoplastic amelogenesis imperfecta (AI), while the proband shows no evidence of dental abnormalities or AI at 2 years of age with apparently unaffected primary dentition. Characterization of the genomic architecture at this locus revealed evidence for genomic instability generated by an Alu/Alu-mediated rearrangement; confirmed by break-point junction Sanger sequencing. This multiplex family from a distinct population elucidates the phenotypic consequence of complete LoF of SLC13A5 and illustrates the importance of read-depth-based CNV detection in comprehensive exome sequencing analysis to solve cases that otherwise remain molecularly unsolved.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62192}, author = {Duan, Ruizhi and Saadi, Nebal Waill and Grochowski, Christopher M and Bhadila, Ghalia and Faridoun, Afnan and Mitani, Tadahiro and Du, Haowei and Fatih, Jawid M and Jhangiani, Shalini N and Akdemir, Zeynep C and Gibbs, Richard A and Pehlivan, Davut and Posey, Jennifer E and Marafi, Dana and Lupski, James R} } @article {1013, title = {Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.}, journal = {Eur J Hum Genet}, volume = {29}, year = {2021}, month = {2021 May}, pages = {816-826}, abstract = {

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.

}, issn = {1476-5438}, doi = {10.1038/s41431-020-00804-7}, author = {Jurgens, Julie A and Barry, Brenda J and Lemire, Gabrielle and Chan, Wai-Man and Whitman, Mary C and Shaaban, Sherin and Robson, Caroline D and MacKinnon, Sarah and England, Eleina M and McMillan, Hugh J and Kelly, Christopher and Pratt, Brandon M and O{\textquoteright}Donnell-Luria, Anne and MacArthur, Daniel G and Boycott, Kym M and Hunter, David G and Engle, Elizabeth C} } @article {1012, title = {Pathogenic variants in , a chromatin remodeler, cause a range of syndromic neurodevelopmental features.}, journal = {Sci Adv}, volume = {7}, year = {2021}, month = {2021 May}, abstract = {

Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50\% of the patients remains elusive. We describe pathogenic variants in , encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 ortholog led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

}, issn = {2375-2548}, doi = {10.1126/sciadv.abf2066}, author = {Li, Dong and Wang, Qin and Gong, Naihua N and Kurolap, Alina and Feldman, Hagit Baris and Boy, Nikolas and Brugger, Melanie and Grand, Katheryn and McWalter, Kirsty and Guillen Sacoto, Maria J and Wakeling, Emma and Hurst, Jane and March, Michael E and Bhoj, Elizabeth J and Nowaczyk, Ma{\l}gorzata J M and Gonzaga-Jauregui, Claudia and Mathew, Mariam and Dava-Wala, Ashita and Siemon, Amy and Bartholomew, Dennis and Huang, Yue and Lee, Hane and Martinez-Agosto, Julian A and Schwaibold, Eva M C and Brunet, Theresa and Choukair, Daniela and Pais, Lynn S and White, Susan M and Christodoulou, John and Brown, Dana and Lindstrom, Kristin and Grebe, Theresa and Tiosano, Dov and Kayser, Matthew S and Tan, Tiong Yang and Deardorff, Matthew A and Song, Yuanquan and Hakonarson, Hakon} } @article {983, title = {Perturbations of genes essential for M{\"u}llerian duct and W{\"o}lffian duct development in Mayer-Rokitansky-K{\"u}ster-Hauser syndrome.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 02 04}, pages = {337-345}, abstract = {

Mayer-Rokitansky-K{\"u}ster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the M{\"u}llerian ducts (MD)/W{\"o}lffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

}, keywords = {46, XX Disorders of Sex Development, Adult, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein 7, Codon, Nonsense, Congenital Abnormalities, Female, Genetic Association Studies, Genetic Pleiotropy, Homeobox A10 Proteins, Homeodomain Proteins, Humans, Mullerian Ducts, Mutation, Paternal Inheritance, PAX8 Transcription Factor, Penetrance, T-Box Domain Proteins, Transcription Factors, Wnt Proteins, Wolffian Ducts}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.12.014}, author = {Chen, Na and Zhao, Sen and Jolly, Angad and Wang, Lianlei and Pan, Hongxin and Yuan, Jian and Chen, Shaoke and Koch, Andr{\'e} and Ma, Congcong and Tian, Weijie and Jia, Ziqi and Kang, Jia and Zhao, Lina and Qin, Chenglu and Fan, Xin and Rall, Katharina and Coban-Akdemir, Zeynep and Chen, Zefu and Jhangiani, Shalini and Liang, Ze and Niu, Yuchen and Li, Xiaoxin and Yan, Zihui and Wu, Yong and Dong, Shuangshuang and Song, Chengcheng and Qiu, Guixing and Zhang, Shuyang and Liu, Pengfei and Posey, Jennifer E and Zhang, Feng and Luo, Guangnan and Wu, Zhihong and Su, Jianzhong and Zhang, Jianguo and Chen, Eugenia Y and Rouskas, Konstantinos and Glentis, Stavros and Bacopoulou, Flora and Deligeoroglou, Efthymios and Chrousos, George and Lyonnet, Stanislas and Polak, Michel and Rosenberg, Carla and Dingeldein, Irene and Bonilla, Ximena and Borel, Christelle and Gibbs, Richard A and Dietrich, Jennifer E and Dimas, Antigone S and Antonarakis, Stylianos E and Brucker, Sara Y and Lupski, James R and Wu, Nan and Zhu, Lan} } @article {900, title = {Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome.}, journal = {Hum Mutat}, volume = {42}, year = {2021}, month = {2021 May}, pages = {577-591}, abstract = {

Xia-Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop-gain or frameshift mutations in the AT-hook DNA binding motif containing 1 (AHDC1) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80\% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid-protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome.

}, issn = {1098-1004}, doi = {10.1002/humu.24190}, author = {Khayat, Michael M and Li, He and Chander, Varuna and Hu, Jianhong and Hansen, Adam W and Li, Shoudong and Traynelis, Josh and Shen, Hua and Weissenberger, George and Stossi, Fabio and Johnson, Hannah L and Lupski, James R and Posey, Jennifer E and Sabo, Aniko and Meng, Qingchang and Murdock, David R and Wangler, Michael and Gibbs, Richard A} } @article {899, title = {Phylogenetic history of patrilineages rare in northern and eastern Europe from large-scale re-sequencing of human Y-chromosomes.}, journal = {Eur J Hum Genet}, year = {2021}, month = {2021 May 07}, abstract = {

The most frequent Y-chromosomal (chrY) haplogroups in northern and eastern Europe (NEE) are well-known and thoroughly characterised. Yet a considerable number of men in every population carry rare paternal lineages with estimated frequencies around 5\%. So far, limited sample-sizes and insufficient resolution of genotyping have obstructed a truly comprehensive look into the variety of rare paternal lineages segregating within populations and potential signals of population history that such lineages might convey. Here we harness the power of massive re-sequencing of human Y chromosomes to identify previously unknown population-specific clusters among rare paternal lineages in NEE. We construct dated phylogenies for haplogroups E2-M215, J2-M172, G-M201 and Q-M242 on the basis of 421 (of them 282 novel) high-coverage chrY sequences collected from large-scale databases focusing on populations of NEE. Within these otherwise rare haplogroups we disclose lineages that began to radiate ~1-3 thousand years ago in Estonia and Sweden and reveal male phylogenetic patterns testifying of comparatively recent local demographic expansions. Conversely, haplogroup Q lineages bear evidence of ancient Siberian influence lingering in the modern paternal gene pool of northern Europe. We assess the possible direction of influx of ancestral carriers for some of these male lineages. In addition, we demonstrate the congruency of paternal haplogroup composition of our dataset with two independent population-based cohorts from Estonia and Sweden.

}, issn = {1476-5438}, doi = {10.1038/s41431-021-00897-8}, author = {Ilum{\"a}e, Anne-Mai and Post, Helen and Flores, Rodrigo and Karmin, Monika and Sahakyan, Hovhannes and Mondal, Mayukh and Montinaro, Francesco and Saag, Lauri and Bormans, Concetta and Sanchez, Luisa Fernanda and Ameur, Adam and Gyllensten, Ulf and Kals, Mart and M{\"a}gi, Reedik and Pagani, Luca and Behar, Doron M and Rootsi, Siiri and Villems, Richard} } @article {1022, title = {POLRMT mutations impair mitochondrial transcription causing neurological disease.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 02 18}, pages = {1135}, abstract = {

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.

}, keywords = {Adolescent, Adult, Child, DNA, Mitochondrial, DNA-Directed RNA Polymerases, Female, Fibroblasts, Humans, Infant, Male, Mitochondria, Mutation, Nervous System Diseases, Oxidative Phosphorylation, Pedigree, Protein Domains, Protein Subunits, RNA, Messenger, Transcription, Genetic, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-021-21279-0}, author = {Ol{\'a}hov{\'a}, Monika and Peter, Bradley and Szilagyi, Zsolt and Diaz-Maldonado, Hector and Singh, Meenakshi and Sommerville, Ewen W and Blakely, Emma L and Collier, Jack J and Hoberg, Emily and Str{\'a}neck{\'y}, Viktor and Hartmannov{\'a}, Hana and Bleyer, Anthony J and McBride, Kim L and Bowden, Sasigarn A and Korandov{\'a}, Zuzana and Pecinov{\'a}, Alena and Ropers, Hans-Hilger and Kahrizi, Kimia and Najmabadi, Hossein and Tarnopolsky, Mark A and Brady, Lauren I and Weaver, K Nicole and Prada, Carlos E and {\~O}unap, Katrin and Wojcik, Monica H and Pajusalu, Sander and Syeda, Safoora B and Pais, Lynn and Estrella, Elicia A and Bruels, Christine C and Kunkel, Louis M and Kang, Peter B and Bonnen, Penelope E and Mr{\'a}{\v c}ek, Tom{\'a}{\v s} and Kmoch, Stanislav and Gorman, Gr{\'a}inne S and Falkenberg, Maria and Gustafsson, Claes M and Taylor, Robert W} } @article {1017, title = {Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 07 05}, abstract = {

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10\% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86\%) were hospitalized for COVID-19 pneumonia, including 15 (68\%) admitted to an intensive care unit, 11 (50\%) who required mechanical ventilation, and four (18\%) who died. Ambulatory disease in three patients (14\%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

}, keywords = {Adolescent, Adult, Autoantibodies, Child, COVID-19, Female, Humans, Interferon Type I, Male, Middle Aged, Pneumonia, Polyendocrinopathies, Autoimmune, SARS-CoV-2, Young Adult}, issn = {1540-9538}, doi = {10.1084/jem.20210554}, author = {Bastard, Paul and Orlova, Elizaveta and Sozaeva, Leila and L{\'e}vy, Romain and James, Alyssa and Schmitt, Monica M and Ochoa, Sebastian and Kareva, Maria and Rodina, Yulia and Gervais, Adrian and Le Voyer, Tom and Rosain, J{\'e}r{\'e}mie and Philippot, Quentin and Neehus, Anna-Lena and Shaw, Elana and Migaud, M{\'e}lanie and Bizien, Lucy and Ekwall, Olov and Berg, Stefan and Beccuti, Guglielmo and Ghizzoni, Lucia and Thiriez, G{\'e}rard and Pavot, Arthur and Goujard, C{\'e}cile and Fr{\'e}mond, Marie-Louise and Carter, Edwin and Rothenbuhler, Anya and Linglart, Agn{\`e}s and Mignot, Brigite and Comte, Aur{\'e}lie and Cheikh, Nathalie and Hermine, Olivier and Breivik, Lars and Husebye, Eystein S and Humbert, S{\'e}bastien and Rohrlich, Pierre and Coaquette, Alain and Vuoto, Fanny and Faure, Karine and Mahlaoui, Nizar and Kotnik, Primo{\v z} and Battelino, Tadej and Trebu{\v s}ak Podkraj{\v s}ek, Katarina and Kisand, Kai and Ferr{\'e}, Elise M N and DiMaggio, Thomas and Rosen, Lindsey B and Burbelo, Peter D and McIntyre, Martin and Kann, Nelli Y and Shcherbina, Anna and Pavlova, Maria and Kolodkina, Anna and Holland, Steven M and Zhang, Shen-Ying and Crow, Yanick J and Notarangelo, Luigi D and Su, Helen C and Abel, Laurent and Anderson, Mark S and Jouanguy, Emmanuelle and Neven, B{\'e}n{\'e}dicte and Puel, Anne and Casanova, Jean-Laurent and Lionakis, Michail S} } @article {949, title = {A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.}, journal = {Eur J Hum Genet}, volume = {29}, year = {2021}, month = {2021 Feb}, pages = {271-279}, abstract = {

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

}, issn = {1476-5438}, doi = {10.1038/s41431-020-00717-5}, author = {Ghosh, Shereen G and Scala, Marcello and Beetz, Christian and Helman, Guy and Stanley, Valentina and Yang, Xiaoxu and Breuss, Martin W and Mazaheri, Neda and Selim, Laila and Hadipour, Fatemeh and Pais, Lynn and Stutterd, Chloe A and Karageorgou, Vasiliki and Begtrup, Amber and Crunk, Amy and Juusola, Jane and Willaert, Rebecca and Flore, Leigh A and Kennelly, Kelly and Spencer, Christopher and Brown, Martha and Trapane, Pamela and Hurst, Anna C E and Lane Rutledge, S and Goodloe, Dana H and McDonald, Marie T and Shashi, Vandana and Schoch, Kelly and Tomoum, Hoda and Zaitoun, Raghda and Hadipour, Zahra and Galehdari, Hamid and Pagnamenta, Alistair T and Mojarrad, Majid and Sedaghat, Alireza and Dias, Patr{\'\i}cia and Quintas, Sofia and Eslahi, Atiyeh and Shariati, Gholamreza and Bauer, Peter and Simons, Cas and Houlden, Henry and Issa, Mahmoud Y and Zaki, MAH S and Maroofian, Reza and Gleeson, Joseph G} } @article {1024, title = {SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 04 05}, abstract = {

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.

}, keywords = {Biomarkers, Cell Plasticity, COVID-19, Cytokines, Dendritic Cells, Host-Pathogen Interactions, Humans, Hydroxychloroquine, Immunomodulation, Immunophenotyping, Inflammation Mediators, Interferon Type I, Interferons, Interleukin-1 Receptor-Associated Kinases, Membrane Transport Proteins, SARS-CoV-2}, issn = {1540-9538}, doi = {10.1084/jem.20201387}, author = {Onodi, Fanny and Bonnet-Madin, Lucie and Meertens, Laurent and Karpf, L{\'e}a and Poirot, Justine and Zhang, Shen-Ying and Picard, Capucine and Puel, Anne and Jouanguy, Emmanuelle and Zhang, Qian and Le Goff, J{\'e}r{\^o}me and Molina, Jean-Michel and Delaugerre, Constance and Casanova, Jean-Laurent and Amara, Ali and Soumelis, Vassili} } @article {981, title = {SARS-CoV-2 induces human plasmacytoid pre-dendritic cell diversification via UNC93B and IRAK4.}, journal = {bioRxiv}, year = {2021}, month = {2021 Jan 08}, abstract = {

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here, we have isolated primary SARS-CoV-2 viral strains, and studied their interaction with human plasmacytoid pre-dendritic cells (pDC), a key player in antiviral immunity. We show that pDC are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.

}, doi = {10.1101/2020.07.10.197343}, author = {Onodi, Fanny and Bonnet-Madin, Lucie and Meertens, Laurent and Karpf, L{\'e}a and Poirot, Justine and Zhang, Shen-Ying and Picard, Capucine and Puel, Anne and Jouanguy, Emmanuelle and Zhang, Qian and Le Goff, J{\'e}r{\^o}me and Molina, Jean-Michel and Delaugerre, Constance and Casanova, Jean-Laurent and Amara, Ali and Soumelis, Vassili} } @article {1008, title = {SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 03 04}, pages = {502-516}, abstract = {

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

}, keywords = {Adolescent, Autism Spectrum Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Haploinsufficiency, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.01.015}, author = {Radio, Francesca Clementina and Pang, Kaifang and Ciolfi, Andrea and Levy, Michael A and Hernandez-Garcia, Andres and Pedace, Lucia and Pantaleoni, Francesca and Liu, Zhandong and de Boer, Elke and Jackson, Adam and Bruselles, Alessandro and McConkey, Haley and Stellacci, Emilia and Lo Cicero, Stefania and Motta, Marialetizia and Carrozzo, Rosalba and Dentici, Maria Lisa and McWalter, Kirsty and Desai, Megha and Monaghan, Kristin G and Telegrafi, Aida and Philippe, Christophe and Vitobello, Antonio and Au, Margaret and Grand, Katheryn and Sanchez-Lara, Pedro A and Baez, Joanne and Lindstrom, Kristin and Kulch, Peggy and Sebastian, Jessica and Madan-Khetarpal, Suneeta and Roadhouse, Chelsea and MacKenzie, Jennifer J and Monteleone, Berrin and Saunders, Carol J and Jean Cuevas, July K and Cross, Laura and Zhou, Dihong and Hartley, Taila and Sawyer, Sarah L and Monteiro, Fabiola Paoli and Secches, Tania Vertemati and Kok, Fernando and Schultz-Rogers, Laura E and Macke, Erica L and Morava, Eva and Klee, Eric W and Kemppainen, Jennifer and Iascone, Maria and Selicorni, Angelo and Tenconi, Romano and Amor, David J and Pais, Lynn and Gallacher, Lyndon and Turnpenny, Peter D and Stals, Karen and Ellard, Sian and Cabet, Sara and Lesca, Gaetan and Pascal, Joset and Steindl, Katharina and Ravid, Sarit and Weiss, Karin and Castle, Alison M R and Carter, Melissa T and Kalsner, Louisa and de Vries, Bert B A and van Bon, Bregje W and Wevers, Marijke R and Pfundt, Rolph and Stegmann, Alexander P A and Kerr, Bronwyn and Kingston, Helen M and Chandler, Kate E and Sheehan, Willow and Elias, Abdallah F and Shinde, Deepali N and Towne, Meghan C and Robin, Nathaniel H and Goodloe, Dana and Vanderver, Adeline and Sherbini, Omar and Bluske, Krista and Hagelstrom, R Tanner and Zanus, Caterina and Faletra, Flavio and Musante, Luciana and Kurtz-Nelson, Evangeline C and Earl, Rachel K and Anderlid, Britt-Marie and Morin, Gilles and van Slegtenhorst, Marjon and Diderich, Karin E M and Brooks, Alice S and Gribnau, Joost and Boers, Ruben G and Finestra, Teresa Robert and Carter, Lauren B and Rauch, Anita and Gasparini, Paolo and Boycott, Kym M and Barakat, Tahsin Stefan and GrAHm, John M and Faivre, Laurence and Banka, Siddharth and Wang, Tianyun and Eichler, Evan E and Priolo, Manuela and Dallapiccola, Bruno and Vissers, Lisenka E L M and Sadikovic, Bekim and Scott, Daryl A and Holder, Jimmy Lloyd and Tartaglia, Marco} } @article {982, title = {TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes.}, journal = {HGG Adv}, volume = {2}, year = {2021}, month = {2021 Jan 14}, abstract = {

The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, allowing them to respond to extracellular signals. The cilium is partitioned from the cell body by the transition zone, a known hotspot for ciliopathy-related proteins. Despite years of Joubert syndrome (JBTS) gene discovery, the genetic cause cannot be identified in up to 30\% of individuals with JBTS, depending on the cohort, sequencing method, and criteria for pathogenic variants. Using exome and targeted sequencing of 655 families with JBTS, we identified three individuals from two families harboring biallelic, rare, predicted-deleterious missense variants. Via MatchMaker Exchange, we identified biallelic variants in four additional families with ciliopathy phenotypes. Of note, four of the six families carry missense variants affecting the same highly conserved amino acid position 115. Clinical features included the molar tooth sign (N = 2), occipital encephalocele (N = 5, all fetuses), retinal dystrophy (N = 4, all living individuals), polycystic kidneys (N = 2), and polydactyly (N = 2), without liver involvement. Combined with existing functional data linking TMEM218 to ciliary transition zone function, our human genetic data make a strong case for TMEM218 dysfunction as a cause of ciliopathy phenotypes including JBTS with retinal dystrophy and Meckel syndrome. Identifying all genetic causes of the Joubert-Meckel spectrum enables diagnostic testing, prognostic and recurrence risk counseling, and medical monitoring, as well as work to delineate the underlying biological mechanisms and identify targets for future therapies.

}, issn = {2666-2477}, doi = {10.1016/j.xhgg.2020.100016}, author = {Van De Weghe, Julie C and Giordano, Jessica L and Mathijssen, Inge B and Mojarrad, Majid and Lugtenberg, Dorien and Miller, Caitlin V and Dempsey, Jennifer C and Mohajeri, Mahsa Sadat Asl and van Leeuwen, Elizabeth and Pajkrt, Eva and Klaver, Caroline C W and Houlden, Henry and Eslahi, Atieh and Waters, Aoife M and Bamshad, Michael J and Nickerson, Deborah A and Aggarwal, Vimla S and de Vries, Bert B A and Maroofian, Reza and Doherty, Dan} } @article {1026, title = {Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features.}, journal = {Am J Med Genet A}, year = {2021}, month = {2021 May 08}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62221}, author = {Efthymiou, Stephanie and Herman, Isabella and Rahman, Fatima and Anwar, Najwa and Maroofian, Reza and Yip, Janice and Mitani, Tadahiro and Calame, Daniel G and Hunter, Jill V and Sutton, V Reid and Yilmaz Gulec, Elif and Duan, Ruizhi and Fatih, Jawid M and Marafi, Dana and Pehlivan, Davut and Jhangiani, Shalini N and Gibbs, Richard A and Posey, Jennifer E and Maqbool, Shazia and Lupski, James R and Houlden, Henry} } @article {952, title = {Typical achondroplasia secondary to a unique insertional variant of FGFR3 with in vitro demonstration of its effect on FGFR3 function.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 03}, pages = {798-805}, abstract = {

We describe an individual in whom clinical and radiographic features are typical for achondroplasia, but in whom the common variants of FGFR3 that result in achondroplasia are absent. Whole exome sequencing demonstrated a novel, de novo 6 base pair tandem duplication in FGFR3 that results in the insertion of Ser-Phe after position Leu324. in vitro studies showed that this variant results in aberrant dimerization, excessive spontaneous phosphorylation of FGFR3 dimers and excessive, ligand-independent tyrosine kinase activity. Together, these data suggest that this variant leads to constitutive disulfide bond-mediated dimerization, and that this, surprisingly, occurs to an extent similar to the neonatal lethal thanatophoric dysplasia type I Ser249Cys variant.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62043}, author = {Meyer, April N and Modaff, Peggy and Wang, Clark G and Wohler, Elizabeth and Sobreira, Nara L and Donoghue, Daniel J and Pauli, Richard M} } @article {974, title = {Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 05}, pages = {881-887}, abstract = {

PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene.

METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual.

RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy.

CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

}, keywords = {Child, Developmental Disabilities, Humans, Intellectual Disability, Muscle Hypotonia, Neurodevelopmental Disorders, Seizures, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-01076-8}, author = {Muir, Alison M and Gardner, Jennifer F and van Jaarsveld, Richard H and de Lange, Iris M and van der Smagt, Jasper J and Wilson, Golder N and Dubbs, Holly and Goldberg, Ethan M and Zitano, Lia and Bupp, Caleb and Martinez, Jose and Srour, Myriam and Accogli, Andrea and Alhakeem, Afnan and Meltzer, Meira and Gropman, Andrea and Brewer, Carole and Caswell, Richard C and Montgomery, Tara and McKenna, Caoimhe and McKee, Shane and Powell, Corinna and Vasudevan, Pradeep C and Brady, Angela F and Joss, Shelagh and Tysoe, Carolyn and Noh, Grace and Tarnopolsky, Mark and Brady, Lauren and Zafar, Muhammad and Schrier Vergano, Samantha A and Murray, Brianna and Sawyer, Lindsey and Hainline, Bryan E and Sapp, Katherine and DeMarzo, Danielle and Huismann, Darcy J and Wentzensen, Ingrid M and Schnur, Rhonda E and Monaghan, Kristin G and Juusola, Jane and Rhodes, Lindsay and Dobyns, William B and Lecoquierre, Francois and Goldenberg, Alice and Polster, Tilman and Axer-Schaefer, Susanne and Platzer, Konrad and Kl{\"o}ckner, Chiara and Hoffman, Trevor L and MacArthur, Daniel G and O{\textquoteright}Leary, Melanie C and VanNoy, Grace E and England, Eleina and Varghese, Vinod C and Mefford, Heather C} } @article {897, title = {Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 03 04}, pages = {431-445}, abstract = {

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

}, keywords = {African Americans, Aged, Aged, 80 and over, Calbindin 2, Colitis, Ulcerative, Crohn Disease, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Receptors, Prostaglandin E, EP4 Subtype, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.001}, author = {Somineni, Hari K and Nagpal, Sini and Venkateswaran, Suresh and Cutler, David J and Okou, David T and Haritunians, Talin and Simpson, Claire L and Begum, Ferdouse and Datta, Lisa W and Quiros, Antonio J and Seminerio, Jenifer and Mengesha, Emebet and Alexander, Jonathan S and Baldassano, Robert N and Dudley-Brown, Sharon and Cross, Raymond K and Dassopoulos, Themistocles and Denson, Lee A and Dhere, Tanvi A and Iskandar, Heba and Dryden, Gerald W and Hou, Jason K and Hussain, Sunny Z and Hyams, Jeffrey S and Isaacs, Kim L and Kader, Howard and Kappelman, Michael D and Katz, Jeffry and Kellermayer, Richard and Kuemmerle, John F and Lazarev, Mark and Li, Ellen and Mannon, Peter and Moulton, Dedrick E and Newberry, Rodney D and Patel, Ashish S and Pekow, Joel and Saeed, Shehzad A and Valentine, John F and Wang, Ming-Hsi and McCauley, Jacob L and Abreu, Maria T and Jester, Traci and Molle-Rios, Zarela and Palle, Sirish and Scherl, Ellen J and Kwon, John and Rioux, John D and Duerr, Richard H and Silverberg, Mark S and Zwick, Michael E and Stevens, Christine and Daly, Mark J and Cho, Judy H and Gibson, Greg and McGovern, Dermot P B and Brant, Steven R and Kugathasan, Subra} } @article {950, title = {8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 03 23}, pages = {1523}, abstract = {

The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9\% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.

}, keywords = {Aged, Case-Control Studies, Chromosomes, Human, Pair 8, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Heterozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Mutation, Prostatic Neoplasms, Protective Factors, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-15122-1}, author = {Dupont, William D and Breyer, Joan P and Plummer, W Dale and Chang, Sam S and Cookson, Michael S and Smith, Joseph A and Blue, Elizabeth E and Bamshad, Michael J and Smith, Jeffrey R} } @article {821, title = {Adult-onset very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD).}, journal = {Eur J Neurol}, volume = {27}, year = {2020}, month = {2020 11}, pages = {2257-2266}, abstract = {

BACKGROUND AND PURPOSE: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a hereditary disorder of mitochondrial long-chain fatty acid oxidation that has variable presentations, including exercise intolerance, cardiomyopathy and liver disease. The aim of this study was to describe the clinical and genetic manifestations of six patients with adult-onset VLCADD.

METHODS: In this study, the clinical, pathological and genetic findings of six adult patients (four from Iran and two from Serbia) with VLCADD and their response to treatment are described.

RESULTS: The median (range) age of patients at first visit was 31 (27-38) years, and the median (range) age of onset was 26.5 (19-33) years. Parental consanguinity was present for four patients. Four patients had a history of rhabdomyolysis, and the recorded CK level ranged between 67 and 90~000~IU/l. Three patients had a history of exertional myalgia, and one patient had a non-fluctuating weakness. Through next-generation sequencing analysis, we identified six cases with variants in the ACADVL gene and a confirmed diagnosis of VLCADD. Of the total six variants identified, five were missense, and one was a novel frameshift mutation identified in two unrelated individuals. Two variants were novel, and three were previously reported. We treated the patients with a combination of L-carnitine, Coenzyme Q10 and riboflavin. Three patients responded favorably to the treatment.

CONCLUSION: Adult-onset VLCADD is a rare entity with various presentations. Patients may respond favorably to a cocktail of L-carnitine, Coenzyme Q10, and riboflavin.

}, issn = {1468-1331}, doi = {10.1111/ene.14402}, author = {Fatehi, F and Okhovat, A A and Nilipour, Y and Mroczek, M and Straub, V and T{\"o}pf, A and Palibrk, A and Peric, S and Rakocevic Stojanovic, V and Najmabadi, H and Nafissi, S} } @article {850, title = {Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 05 07}, pages = {2254}, abstract = {

Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we report a genome-wide association study of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 36,041 UK Biobank participants, with replication in 2184 participants from the Multi-Ethnic Study of Atherosclerosis. We identify 45 previously unreported loci associated with cardiac structure and function, many near well-established genes for Mendelian cardiomyopathies. A polygenic score of MRI-derived left ventricular end systolic volume strongly associates with incident DCM in the general population. Even among carriers of TTN truncating mutations, this polygenic score influences the size and function of the human heart. These results further implicate common genetic polymorphisms in the pathogenesis of DCM.

}, keywords = {Cardiomyopathy, Dilated, Genome-Wide Association Study, Heart, Humans, Magnetic Resonance Imaging, Myocardium, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/s41467-020-15823-7}, author = {Pirruccello, James P and Bick, Alexander and Wang, Minxian and Chaffin, Mark and Friedman, Samuel and Yao, Jie and Guo, Xiuqing and Venkatesh, Bharath Ambale and Taylor, Kent D and Post, Wendy S and Rich, Stephen and Lima, Joao A C and Rotter, Jerome I and Philippakis, Anthony and Lubitz, Steven A and Ellinor, Patrick T and Khera, Amit V and Kathiresan, Sekar and Aragam, Krishna G} } @article {737, title = {ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy.}, journal = {Ann Neurol}, volume = {87}, year = {2020}, month = {2020 02}, pages = {217-232}, abstract = {

OBJECTIVE: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations.

METHODS: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells.

RESULTS: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction.

INTERPRETATION: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232.

}, keywords = {Adult, Amino Acid Transport System y+, Cell Cycle, Cells, Cultured, Child, Child, Preschool, Female, Fibroblasts, Humans, Infant, Male, Middle Aged, Muscle Proteins, Muscle, Skeletal, Muscular Diseases, Mutation, Pedigree, Phenotype, Transcription Factors}, issn = {1531-8249}, doi = {10.1002/ana.25660}, author = {Villar-Quiles, Roc{\'\i}o N and Catervi, Fabio and Cabet, Eva and Juntas-Morales, Raul and Genetti, Casie A and Gidaro, Teresa and Koparir, Asuman and Yuksel, Adnan and Coppens, Sandra and Deconinck, Nicolas and Pierce-Hoffman, Emma and Lornage, Xavi{\`e}re and Durigneux, Julien and Laporte, Jocelyn and Rendu, John and Romero, Norma B and Beggs, Alan H and Servais, Laurent and Coss{\'e}e, Mireille and Oliv{\'e}, Montse and B{\"o}hm, Johann and Duband-Goulet, Isabelle and Ferreiro, Ana} } @article {880, title = {Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 04 01}, pages = {e203959}, abstract = {

Importance: Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening.

Objectives: To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care.

Design, Setting, and Participants: This cohort study used gene-sequencing data from 49 738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019.

Exposures: Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist.

Main Outcomes and Measures: Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome.

Results: Among 49 738 participants (mean [SD] age, 57 [8] years; 27 144 female [55\%]), 441 (0.9\%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3\%) for familial hypercholesterolemia, 235 (0.5\%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2\%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4\%) vs 4663 of 49 607 noncarriers (9.4\%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6\%) vs 2080 of 27 028 female noncarriers (7.7\%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4\%) vs 929 of 49 662 noncarriers (1.9\%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3\% for carriers of familial hypercholesterolemia, 41.1\% for hereditary breast and ovarian cancer syndrome, and 38.3\% for Lynch syndrome. Across the 3 conditions, 39.7\% (175 of 441) of the carriers reported a family history of disease vs 23.2\% (34 517 of 148 772) of noncarriers.

Conclusions and Relevance: The findings suggest that approximately 1\% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history.

}, keywords = {Aged, Cohort Studies, Colorectal Neoplasms, Hereditary Nonpolyposis, Female, Genetic Predisposition to Disease, Hereditary Breast and Ovarian Cancer Syndrome, Heterozygote, Humans, Hyperlipoproteinemia Type II, Male, Middle Aged, Pedigree, Proportional Hazards Models, United Kingdom, Whole Exome Sequencing}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.3959}, author = {Patel, Aniruddh P and Wang, Minxian and Fahed, Akl C and Mason-Suares, Heather and Brockman, Deanna and Pelletier, Renee and Amr, Sami and Machini, Kalotina and Hawley, Megan and Witkowski, Leora and Koch, Christopher and Philippakis, Anthony and Cassa, Christopher A and Ellinor, Patrick T and Kathiresan, Sekar and Ng, Kenney and Lebo, Matthew and Khera, Amit V} } @article {904, title = {Autoantibodies against type I IFNs in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, abstract = {

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6\% of women and 12.5\% of men.

}, keywords = {Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing, Asymptomatic Infections, Autoantibodies, Betacoronavirus, Case-Control Studies, Coronavirus Infections, COVID-19, Critical Illness, Female, Humans, Immunoglobulin G, Interferon alpha-2, Interferon Type I, Male, Middle Aged, Pandemics, Pneumonia, Viral, SARS-CoV-2}, issn = {1095-9203}, doi = {10.1126/science.abd4585}, author = {Bastard, Paul and Rosen, Lindsey B and Zhang, Qian and Michailidis, Eleftherios and Hoffmann, Hans-Heinrich and Zhang, Yu and Dorgham, Karim and Philippot, Quentin and Rosain, J{\'e}r{\'e}mie and B{\'e}ziat, Vivien and Manry, Jeremy and Shaw, Elana and Haljasm{\"a}gi, Liis and Peterson, P{\"a}rt and Lorenzo, Lazaro and Bizien, Lucy and Trouillet-Assant, Sophie and Dobbs, Kerry and de Jesus, Adriana Almeida and Belot, Alexandre and Kallaste, Anne and Catherinot, Emilie and Tandjaoui-Lambiotte, Yacine and Le Pen, J{\'e}r{\'e}mie and Kerner, Gaspard and Bigio, Benedetta and Seeleuthner, Yoann and Yang, Rui and Bolze, Alexandre and Spaan, Andr{\'a}s N and Delmonte, Ottavia M and Abers, Michael S and Aiuti, Alessandro and Casari, Giorgio and Lampasona, Vito and Piemonti, Lorenzo and Ciceri, Fabio and Bilguvar, Kaya and Lifton, Richard P and Vasse, Marc and Smadja, David M and Migaud, M{\'e}lanie and Hadjadj, J{\'e}rome and Terrier, Benjamin and Duffy, Darragh and Quintana-Murci, Lluis and van de Beek, Diederik and Roussel, Lucie and Vinh, Donald C and Tangye, Stuart G and Haerynck, Filomeen and Dalmau, David and Martinez-Picado, Javier and Brodin, Petter and Nussenzweig, Michel C and Boisson-Dupuis, St{\'e}phanie and Rodr{\'\i}guez-Gallego, Carlos and Vogt, Guillaume and Mogensen, Trine H and Oler, Andrew J and Gu, Jingwen and Burbelo, Peter D and Cohen, Jeffrey I and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio, Mariella and Bonfanti, Paolo and Rossignol, Patrick and Mayaux, Julien and Rieux-Laucat, Fr{\'e}d{\'e}ric and Husebye, Eystein S and Fusco, Francesca and Ursini, Matilde Valeria and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Castagnoli, Riccardo and Montagna, Daniela and Licari, Amelia and Marseglia, Gian Luigi and Duval, Xavier and Ghosn, Jade and Tsang, John S and Goldbach-Mansky, Raphaela and Kisand, Kai and Lionakis, Michail S and Puel, Anne and Zhang, Shen-Ying and Holland, Steven M and Gorochov, Guy and Jouanguy, Emmanuelle and Rice, Charles M and Cobat, Aurelie and Notarangelo, Luigi D and Abel, Laurent and Su, Helen C and Casanova, Jean-Laurent} } @article {779, title = {Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 04 02}, pages = {467-483}, abstract = {

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in~vitro assays with recombinant proteins in HEK293T cells and ex~vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.

}, keywords = {Adenosine Deaminase, Alleles, Alternative Splicing, Child, Child, Preschool, Genetic Predisposition to Disease, Genetic Variation, HEK293 Cells, Humans, Intellectual Disability, Male, Microcephaly, RNA Splicing, RNA-Binding Proteins, Seizures}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.02.015}, author = {Tan, Tiong Yang and Sedm{\'\i}k, Ji{\v r}{\'\i} and Fitzgerald, Mark P and Halevy, Rivka Sukenik and Keegan, Liam P and Helbig, Ingo and Basel-Salmon, Lina and Cohen, Lior and Straussberg, Rachel and Chung, Wendy K and Helal, Mayada and Maroofian, Reza and Houlden, Henry and Juusola, Jane and Sadedin, Simon and Pais, Lynn and Howell, Katherine B and White, Susan M and Christodoulou, John and O{\textquoteright}Connell, Mary A} } @article {790, title = {Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 05 01}, pages = {1447-1461}, abstract = {

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

}, keywords = {Abnormalities, Multiple, Epileptic Syndromes, Female, Glutamate Decarboxylase, Humans, Infant, Newborn, Male, Mutation, Pedigree}, issn = {1460-2156}, doi = {10.1093/brain/awaa085}, author = {Chatron, Nicolas and Becker, Felicitas and Morsy, Heba and Schmidts, Miriam and Hardies, Katia and Tuysuz, Beyhan and Roselli, Sandra and Najafi, Maryam and Alkaya, Dilek Uludag and Ashrafzadeh, Farah and Nabil, Amira and Omar, Tarek and Maroofian, Reza and Karimiani, Ehsan Ghayoor and Hussien, Haytham and Kok, Fernando and Ramos, Luiza and Gunes, Nilay and Bilguvar, Kaya and Labalme, Audrey and Alix, Eudeline and Sanlaville, Damien and de Bellescize, Julitta and Poulat, Anne-Lise and Moslemi, Ali-Reza and Lerche, Holger and May, Patrick and Lesca, Gaetan and Weckhuysen, Sarah and Tajsharghi, Homa} } @article {758, title = {Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.}, journal = {Ann Clin Transl Neurol}, volume = {7}, year = {2020}, month = {2020 05}, pages = {610-627}, abstract = {

OBJECTIVE: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.

METHODS: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.

RESULTS: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2~years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.

CONCLUSION: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

}, keywords = {Adolescent, Alleles, Atrophy, Child, Child, Preschool, Cohort Studies, Consanguinity, Epilepsy, Female, Humans, Infant, Male, Microcephaly, Neurodevelopmental Disorders, Pedigree, Phenotype, Receptors, Metabotropic Glutamate, Whole Exome Sequencing}, issn = {2328-9503}, doi = {10.1002/acn3.51003}, author = {Marafi, Dana and Mitani, Tadahiro and Isikay, Sedat and Hertecant, Jozef and Almannai, Mohammed and Manickam, Kandamurugu and Abou Jamra, Rami and El-Hattab, Ayman W and Rajah, Jaishen and Fatih, Jawid M and Du, Haowei and Karaca, Ender and Bayram, Yavuz and Punetha, Jaya and Rosenfeld, Jill A and Jhangiani, Shalini N and Boerwinkle, Eric and Akdemir, Zeynep C and Erdin, Serkan and Hunter, Jill V and Gibbs, Richard A and Pehlivan, Davut and Posey, Jennifer E and Lupski, James R} } @article {945, title = {Biallelic in-frame deletion in TRAPPC4 in a family with developmental delay and cerebellar atrophy.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 10 01}, pages = {e83}, keywords = {Atrophy, Cerebellar Diseases, Humans, Intellectual Disability, Sequence Deletion}, issn = {1460-2156}, doi = {10.1093/brain/awaa256}, author = {Saad, Ahmed K and Marafi, Dana and Mitani, Tadahiro and Jolly, Angad and Du, Haowei and Elbendary, Hasnaa M and Jhangiani, Shalini N and Akdemir, Zeynep C and Gibbs, Richard A and Hunter, Jill V and Carvalho, Claudia M B C and Pehlivan, Davut and Posey, Jennifer E and Zaki, MAH S and Lupski, James R} } @article {962, title = {Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 06 04}, pages = {779-792}, abstract = {

The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.

}, keywords = {Alleles, Base Sequence, Child, Child, Preschool, Cilia, Developmental Disabilities, Female, Hedgehog Proteins, Humans, Infant, Male, Models, Molecular, Neoplasms, Nerve Tissue Proteins, Nuclear Proteins, Pedigree, Signal Transduction, Smoothened Receptor, Zinc Finger Protein Gli2, Zinc Finger Protein Gli3}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.04.010}, author = {Le, Thuy-Linh and Sribudiani, Yunia and Dong, Xiaomin and Huber, Celine and Kois, Chelsea and Baujat, Genevi{\`e}ve and Gordon, Christopher T and Mayne, Valerie and Galmiche, Louise and Serre, Val{\'e}rie and Goudin, Nicolas and Zarhrate, Mohammed and Bole-Feysot, Christine and Masson, Cecile and Nitschk{\'e}, Patrick and Verheijen, Frans W and Pais, Lynn and Pelet, Anna and Sadedin, Simon and Pugh, John A and Shur, Natasha and White, Susan M and El Chehadeh, Salima and Christodoulou, John and Cormier-Daire, Val{\'e}rie and Hofstra, R M W and Lyonnet, Stanislas and Tan, Tiong Yang and Atti{\'e}-Bitach, Tania and Kerstjens-Frederikse, Wilhelmina S and Amiel, Jeanne and Thomas, Sophie} } @article {929, title = {Clinical genomics and contextualizing genome variation in the diagnostic laboratory.}, journal = {Expert Rev Mol Diagn}, volume = {20}, year = {2020}, month = {2020 10}, pages = {995-1002}, abstract = {

INTRODUCTION: The human genome contains the instructions for the development and biological homeostasis of the human organism and the genetic transmission of traits. Genome variation in human populations is the basis of evolution; individual or personal genomes vary tremendously, making each of us truly unique.

AREAS COVERED: Assaying this individual variation using genomic technologies has many applications in clinical medicine, from elucidating the biology of disease to designing strategies to ameliorate perturbations from homeostasis. Detecting pathogenic rare variation in a genome may provide a molecular diagnosis that can be informative for patient management and family healthcare.

EXPERT OPINION: Despite the increasing clinical use of unbiased genomic testing, including chromosome microarray analysis (CMA) with array comparative genomic hybridization (aCGH) or SNP arrays, clinical exome sequencing (cES), and whole-genome sequencing (WGS), to survey genome-wide for molecular aberrations, clinical acumen paired with an understanding of the limitations of each testing type will be needed to achieve molecular diagnoses. Potential opportunities for improving case solved rates, functionally annotating the majority of genes in the human genome, and further understanding genetic contributions to disease will empower clinical genomics and the precision medicine initiative.

}, issn = {1744-8352}, doi = {10.1080/14737159.2020.1826312}, author = {Lupski, James R and Liu, Pengfei and Stankiewicz, Pawel and Carvalho, Claudia M B and Posey, Jennifer E} } @article {782, title = {CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 10}, pages = {1633-1641}, abstract = {

PURPOSE: Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort.

METHODS: We retrospectively investigated the CNVs{\textquoteright} contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders.

RESULTS: CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3\% of AR-CNVs affected one gene; among these 41.4\% were single-exon and 35.0\% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses.

CONCLUSIONS: AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.

}, keywords = {Child, DNA Copy Number Variations, Exons, Humans, INDEL Mutation, Retrospective Studies, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-0864-8}, author = {Yuan, Bo and Wang, Lei and Liu, Pengfei and Shaw, Chad and Dai, Hongzheng and Cooper, Lance and Zhu, Wenmiao and Anderson, Stephanie A and Meng, Linyan and Wang, Xia and Wang, Yue and Xia, Fan and Xiao, Rui and Braxton, Alicia and Peacock, Sandra and Schmitt, Eric and Ward, Patricia A and Vetrini, Francesco and He, Weimin and Chiang, Theodore and Muzny, Donna and Gibbs, Richard A and Beaudet, Arthur L and Breman, Amy M and Smith, Janice and Cheung, Sau Wai and Bacino, Carlos A and Eng, Christine M and Yang, Yaping and Lupski, James R and Bi, Weimin} } @article {864, title = {Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage.}, journal = {Stroke}, volume = {51}, year = {2020}, month = {2020 07}, pages = {2153-2160}, abstract = {

BACKGROUND AND PURPOSE: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the () gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest.

METHODS: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and genotype predict ICH recurrence. We then developed and validated a combined -MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis.

RESULTS: Cortical superficial siderosis, cerebral microbleed, and ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all <0.05). Combining genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, =0.033). In the MGH (training) data set, CSS, cerebral microbleed, and ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6\%, 2.5\%, and 0.9\%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH.

CONCLUSIONS: Combining MRI and genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined -MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

}, keywords = {Aged, Anticoagulants, Apolipoprotein E4, Cerebral Hemorrhage, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Recurrence}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.120.028310}, author = {Biffi, Alessandro and Urday, Sebastian and Kubiszewski, Patryk and Gilkerson, Lee and Sekar, Padmini and Rodriguez-Torres, Axana and Bettin, Margaret and Charidimou, Andreas and Pasi, Marco and Kourkoulis, Christina and Schwab, Kristin and DiPucchio, Zora and Behymer, Tyler and Osborne, Jennifer and Morgan, Misty and Moomaw, Charles J and James, Michael L and Greenberg, Steven M and Viswanathan, Anand and Gurol, M Edip and Worrall, Bradford B and Testai, Fernando D and McCauley, Jacob L and Falcone, Guido J and Langefeld, Carl D and Anderson, Christopher D and Kamel, Hooman and Woo, Daniel and Sheth, Kevin N and Rosand, Jonathan} } @article {870, title = {Complex mosaic structural variations in human fetal brains.}, journal = {Genome Res}, volume = {30}, year = {2020}, month = {2020 12}, pages = {1695-1704}, abstract = {

Somatic mosaicism, manifesting as single nucleotide variants (SNVs), mobile element insertions, and structural changes in the DNA, is a common phenomenon in human brain cells, with potential functional consequences. Using a clonal approach, we previously detected 200-400 mosaic SNVs per cell in three human fetal brains (15-21 wk postconception). However, structural variation in the human fetal brain has not yet been investigated. Here, we discover and validate four mosaic structural variants (SVs) in the same brains and resolve their precise breakpoints. The SVs were of kilobase scale and complex, consisting of deletion(s) and rearranged genomic fragments, which sometimes originated from different chromosomes. Sequences at the breakpoints of these rearrangements had microhomologies, suggesting their origin from replication errors. One SV was found in two clones, and we timed its origin to \~{}14 wk postconception. No large scale mosaic copy number variants (CNVs) were detectable in normal fetal human brains, suggesting that previously reported megabase-scale CNVs in neurons arise at later stages of development. By reanalysis of public single nuclei data from adult brain neurons, we detected an extrachromosomal circular DNA event. Our study reveals the existence of mosaic SVs in the developing human brain, likely arising from cell proliferation during mid-neurogenesis. Although relatively rare compared to SNVs and present in \~{}10\% of neurons, SVs in developing human brain affect a comparable number of bases in the genome (\~{}6200 vs. \~{}4000 bp), implying that they may have similar functional consequences.

}, issn = {1549-5469}, doi = {10.1101/gr.262667.120}, author = {Sekar, Shobana and Tomasini, Livia and Proukakis, Christos and Bae, Taejeong and Manlove, Logan and Jang, Yeongjun and Scuderi, Soraya and Zhou, Bo and Kalyva, Maria and Amiri, Anahita and Mariani, Jessica and Sedlazeck, Fritz J and Urban, Alexander E and Vaccarino, Flora M and Abyzov, Alexej} } @article {798, title = {Congenital diaphragmatic hernia as a prominent feature of a SPECC1L-related syndrome.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 12}, pages = {2919-2925}, abstract = {

Congenital diaphragmatic hernias (CDH) confer substantial morbidity and mortality. Genetic defects, including chromosomal anomalies, copy number variants, and sequence variants are identified in ~30\% of patients with CDH. A genetic etiology is not yet found in 70\% of patients, however there is a growing number of genetic syndromes and single gene disorders associated with CDH. While there have been two reported individuals with X-linked Opitz G/BBB syndrome with MID1 mutations who have CDH as an associated feature, CDH appears to be a much more prominent feature of a SPECC1L-related autosomal dominant Opitz G/BBB syndrome. Features unique to autosomal dominant Opitz G/BBB syndrome include branchial fistulae, omphalocele, and a bicornuate uterus. Here we present one new individual and five previously reported individuals with CDH found to have SPECC1L mutations. These cases provide strong evidence that SPECC1L is a bona fide CDH gene. We conclude that a SPECC1L-related Opitz G/BBB syndrome should be considered in any patient with CDH who has additional features of hypertelorism, a prominent forehead, a broad nasal bridge, anteverted nares, cleft lip/palate, branchial fistulae, omphalocele, and/or bicornuate uterus.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61878}, author = {Wild, K Taylor and Gordon, Tia and Bhoj, Elizabeth J and Du, Haowei and Jhangiani, Shalini N and Posey, Jennifer E and Lupski, James R and Scott, Daryl A and Zackai, Elaine H} } @article {756, title = {Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 03}, pages = {373-377}, abstract = {

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.

}, keywords = {Adult, Female, Haplotypes, Homozygote, Humans, Intellectual Disability, Male, Mitochondrial Proteins, Muscle, Skeletal, Mutation, Missense, Myasthenic Syndromes, Congenital, Organic Anion Transporters}, issn = {1476-5438}, doi = {10.1038/s41431-019-0506-2}, author = {Balaraju, Sunitha and Topf, Ana and McMacken, Grace and Kumar, Veeramani Preethish and Pechmann, Astrid and Roper, Helen and Vengalil, Seena and Polavarapu, Kiran and Nashi, Saraswati and MAHjan, Niranjan Prakash and Barbosa, Ines A and Deshpande, Charu and Taylor, Robert W and Cossins, Judith and Beeson, David and Laurie, Steven and Kirschner, Janbernd and Horvath, Rita and McFarland, Robert and Nalini, Atchayaram and Lochm{\"u}ller, Hanns} } @article {881, title = {Copy number variants~and fixed duplications among 198 rhesus macaques (Macaca mulatta).}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 05}, pages = {e1008742}, abstract = {

The rhesus macaque is an abundant species of Old World monkeys and a valuable model organism for biomedical research due to its close phylogenetic relationship to humans. Copy number variation is one of the main sources of genomic diversity within and between species and a widely recognized cause of inter-individual differences in disease risk. However, copy number differences among rhesus macaques and between the human and macaque genomes, as well as the relevance of this diversity to research involving this nonhuman primate, remain understudied. Here we present a high-resolution map of sequence copy number for the rhesus macaque genome constructed from a dataset of 198 individuals. Our results show that about one-eighth of the rhesus macaque reference genome is composed of recently duplicated regions, either copy number variable regions or fixed duplications. Comparison with human genomic copy number maps based on previously published data shows that, despite overall similarities in the genome-wide distribution of these regions, there are specific differences at the chromosome level. Some of these create differences in the copy number profile between human disease genes and their rhesus macaque orthologs. Our results highlight the importance of addressing the number of copies of target genes in the design of experiments and cautions against human-centered assumptions in research conducted with model organisms. Overall, we present a genome-wide copy number map from a large sample of rhesus macaque individuals representing an important novel contribution concerning the evolution of copy number in primate genomes.

}, keywords = {Animals, Chromosome Mapping, DNA Copy Number Variations, Female, Gene Duplication, Genetics, Population, Genome, High-Throughput Nucleotide Sequencing, Humans, Macaca mulatta, Male, Open Reading Frames, Phylogeny, Sequence Analysis, DNA, Species Specificity}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008742}, author = {Bras{\'o}-Vives, Marina and Povolotskaya, Inna S and Hartas{\'a}nchez, Diego A and Farr{\'e}, Xavier and Fernandez-Callejo, Marcos and Raveendran, Muthuswamy and Harris, R Alan and Rosene, Douglas L and Lorente-Galdos, Belen and Navarro, Arcadi and Marques-Bonet, Tomas and Rogers, Jeffrey and Juan, David} } @article {711, title = {De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 03}, pages = {538-546}, abstract = {

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

}, keywords = {Adolescent, Autism Spectrum Disorder, Carrier Proteins, Child, Child, Preschool, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Male, Nerve Tissue Proteins, Neurodevelopmental Disorders, Neuroimaging, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-019-0693-9}, author = {Mirzaa, Ghayda M and Chong, Jessica X and Piton, Am{\'e}lie and Popp, Bernt and Foss, Kimberly and Guo, Hui and Harripaul, Ricardo and Xia, Kun and Scheck, Joshua and Aldinger, Kimberly A and Sajan, Samin A and Tang, Sha and Bonneau, Dominique and Beck, Anita and White, Janson and Mahida, Sonal and Harris, Jacqueline and Smith-Hicks, Constance and Hoyer, Juliane and Zweier, Christiane and Reis, Andr{\'e} and Thiel, Christian T and Jamra, Rami Abou and Zeid, Natasha and Yang, Amy and Farach, Laura S and Walsh, Laurence and Payne, Katelyn and Rohena, Luis and Velinov, Milen and Ziegler, Alban and Schaefer, Elise and Gatinois, Vincent and Genevi{\`e}ve, David and Simon, Marleen E H and Kohler, Jennefer and Rotenberg, Joshua and Wheeler, Patricia and Larson, Austin and Ernst, Michelle E and Akman, Cigdem I and Westman, Rachel and Blanchet, Patricia and Schillaci, Lori-Anne and Vincent-Delorme, Catherine and Gripp, Karen W and Mattioli, Francesca and Guyader, Gwena{\"e}l Le and Gerard, B{\'e}n{\'e}dicte and Mathieu-Dramard, Mich{\`e}le and Morin, Gilles and Sasanfar, Roksana and Ayub, Muhammad and Vasli, Nasim and Yang, Sandra and Person, Rick and Monaghan, Kristin G and Nickerson, Deborah A and van Binsbergen, Ellen and Enns, Gregory M and Dries, Annika M and Rowe, Leah J and Tsai, Anne C H and Svihovec, Shayna and Friedman, Jennifer and Agha, Zehra and Qamar, Raheel and Rodan, Lance H and Martinez-Agosto, Julian and Ockeloen, Charlotte W and Vincent, Marie and Sunderland, William James and Bernstein, Jonathan A and Eichler, Evan E and Vincent, John B and Bamshad, Michael J} } @article {955, title = {De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 08}, pages = {e002836}, abstract = {

BACKGROUND: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.

METHODS: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).

RESULTS: Two hundred ninety-four patients (11.7\%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (=5.63{\texttimes}10). In 1268 patients (50.4\%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; =5.33{\texttimes}10) and longer times to final extubation (hazard ratio, 0.74; =0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; =0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; =1.61{\texttimes}10) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.

CONCLUSIONS: In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002836}, author = {Boskovski, Marko T and Homsy, Jason and Nathan, Meena and Sleeper, Lynn A and Morton, Sarah and Manheimer, Kathryn B and Tai, Angela and Gorham, Joshua and Lewis, Matthew and Swartz, Michael and Alfieris, George M and Bacha, Emile A and Karimi, Mohsen and Meyer, David and Nguyen, Khanh and Bernstein, Daniel and Romano-Adesman, Angela and Porter, George A and Goldmuntz, Elizabeth and Chung, Wendy K and Srivastava, Deepak and Kaltman, Jonathan R and Tristani-Firouzi, Martin and Lifton, Richard and Roberts, Amy E and Gaynor, J William and Gelb, Bruce D and Kim, Richard and Seidman, Jonathan G and Brueckner, Martina and Mayer, John E and Newburger, Jane W and Seidman, Christine E} } @article {771, title = {Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 01 02}, pages = {507-522}, abstract = {

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

}, keywords = {Antigens, CD, Autoimmune Lymphoproliferative Syndrome, Cation Transport Proteins, CD4-CD8 Ratio, Female, Glycosylation, Humans, Magnesium Deficiency, Male, X-Linked Combined Immunodeficiency Diseases}, issn = {1558-8238}, doi = {10.1172/JCI131116}, author = {Ravell, Juan C and Matsuda-Lennikov, Mami and Chauvin, Samuel D and Zou, Juan and Biancalana, Matthew and Deeb, Sally J and Price, Susan and Su, Helen C and Notarangelo, Giulia and Jiang, Ping and Morawski, Aaron and Kanellopoulou, Chrysi and Binder, Kyle and Mukherjee, Ratnadeep and Anibal, James T and Sellers, Brian and Zheng, Lixin and He, Tingyan and George, Alex B and Pittaluga, Stefania and Powers, Astin and Kleiner, David E and Kapuria, Devika and Ghany, Marc and Hunsberger, Sally and Cohen, Jeffrey I and Uzel, Gulbu and Bergerson, Jenna and Wolfe, Lynne and Toro, Camilo and Gahl, William and Folio, Les R and Matthews, Helen and Angelus, Pam and Chinn, Ivan K and Orange, Jordan S and Trujillo-Vargas, Claudia M and Franco, Jose Luis and Orrego-Arango, Julio and Guti{\'e}rrez-Hincapi{\'e}, Sebastian and Patel, Niraj Chandrakant and Raymond, Kimiyo and Patiroglu, Turkan and Unal, Ekrem and Karakukcu, Musa and Day, Alexandre Gr and Mehta, Pankaj and Masutani, Evan and De Ravin, Suk S and Malech, Harry L and Altan-Bonnet, Gr{\'e}goire and Rao, V Koneti and Mann, Matthias and Lenardo, Michael J} } @article {738, title = {Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 01 01}, pages = {112-130}, abstract = {

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders.

}, keywords = {Atrophy, Autophagy, Cerebellum, Cerebral Cortex, Child, Child, Preschool, Craniofacial Abnormalities, Deafness, Developmental Disabilities, Epilepsy, Female, Fibroblasts, Hearing Loss, Sensorineural, Humans, Infant, Infant, Newborn, Intellectual Disability, Male, Microcephaly, Microscopy, Fluorescence, Muscle Spasticity, Nerve Tissue Proteins, Neurodevelopmental Disorders, Pedigree, Quadriplegia, RNA Splice Sites, Syndrome, Vesicular Transport Proteins}, issn = {1460-2156}, doi = {10.1093/brain/awz374}, author = {Van Bergen, Nicole J and Guo, Yiran and Al-Deri, Noraldin and Lipatova, Zhanna and Stanga, Daniela and Zhao, Sarah and Murtazina, Rakhilya and Gyurkovska, Valeriya and Pehlivan, Davut and Mitani, Tadahiro and Gezdirici, Alper and Antony, Jayne and Collins, Felicity and Willis, Mary J H and Coban Akdemir, Zeynep H and Liu, Pengfei and Punetha, Jaya and Hunter, Jill V and Jhangiani, Shalini N and Fatih, Jawid M and Rosenfeld, Jill A and Posey, Jennifer E and Gibbs, Richard A and Karaca, Ender and Massey, Sean and Ranasinghe, Thisara G and Sleiman, Patrick and Troedson, Chris and Lupski, James R and Sacher, Michael and Segev, Nava and Hakonarson, Hakon and Christodoulou, John} } @article {769, title = {Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 02 06}, pages = {234-245}, abstract = {

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.

}, keywords = {Adult, Amino Acid Sequence, Autistic Disorder, Child, Child, Preschool, Developmental Disabilities, Dioxygenases, DNA Demethylation, Embryonic Development, Female, Gene Expression Regulation, Developmental, Growth Disorders, Humans, Infant, Male, Middle Aged, Movement Disorders, Pedigree, Protein Conformation, Sequence Homology, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.12.007}, author = {Beck, David B and Petracovici, Ana and He, Chongsheng and Moore, Hannah W and Louie, Raymond J and Ansar, Muhammad and Douzgou, Sofia and Sithambaram, Sivagamy and Cottrell, Trudie and Santos-Cortez, Regie Lyn P and Prijoles, Eloise J and Bend, Renee and Keren, Boris and Mignot, Cyril and Nougues, Marie-Christine and {\~O}unap, Katrin and Reimand, Tiia and Pajusalu, Sander and Zahid, Muhammad and Saqib, Muhammad Arif Nadeem and Buratti, Julien and Seaby, Eleanor G and McWalter, Kirsty and Telegrafi, Aida and Baldridge, Dustin and Shinawi, Marwan and Leal, Suzanne M and Schaefer, G Bradley and Stevenson, Roger E and Banka, Siddharth and Bonasio, Roberto and Fahrner, Jill A} } @article {840, title = {Determinants of telomere length across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

}, keywords = {Aging, Genetic Markers, Genetic Variation, Humans, Organ Specificity, Telomere, Telomere Homeostasis, Telomere Shortening}, issn = {1095-9203}, doi = {10.1126/science.aaz6876}, author = {Demanelis, Kathryn and Jasmine, Farzana and Chen, Lin S and Chernoff, Meytal and Tong, Lin and Delgado, Dayana and Zhang, Chenan and Shinkle, Justin and Sabarinathan, Mekala and Lin, Hannah and Ramirez, Eduardo and Oliva, Meritxell and Kim-Hellmuth, Sarah and Stranger, Barbara E and Lai, Tsung-Po and Aviv, Abraham and Ardlie, Kristin G and Aguet, Francois and Ahsan, Habibul and Doherty, Jennifer A and Kibriya, Muhammad G and Pierce, Brandon L} } @article {883, title = {Development and validation of the VISAGE AmpliSeq basic tool to predict appearance and ancestry from DNA.}, journal = {Forensic Sci Int Genet}, volume = {48}, year = {2020}, month = {2020 09}, pages = {102336}, abstract = {

Forensic DNA phenotyping is gaining interest as the number of applications increases within the forensic genetics community. The possibility of providing investigative leads in addition to conventional DNA profiling for human identification provides new insights into otherwise "cold" police investigations. The ability of reporting on the bio-geographical ancestry (BGA), appearance characteristics and age based on DNA obtained from a crime scene sample of an unknown donor makes the exploration of such markers and the development of new methods meaningful for criminal investigations. The VISible Attributes through GEnomics (VISAGE) Consortium aims to disseminate and broaden the use of predictive markers and develop fully optimized and validated prototypes for forensic casework implementation. Here, the first VISAGE appearance and ancestry tool development, performance and validation is reported. A total of 153 SNPs (96.84 \% assay conversion rate) were successfully incorporated into a single multiplex reaction using the AmpliSeq{\texttrademark} design pipeline, and applied for massively parallel sequencing with the Ion S5 platform. A collaborative effort involving six VISAGE laboratory partners was devised to perform all validation tests. An extensive validation plan was carefully organized to explore the assay{\textquoteright}s overall performance with optimum and low-input samples, as well as with challenging and casework mock samples. In addition, forensic validation studies such as concordance and mixture tests recurring to the Coriell sample set with known genotypes were performed. Finally, inhibitor tolerance and specificity were also evaluated. Results showed a robust, highly sensitive assay with good overall concordance between laboratories.

}, issn = {1878-0326}, doi = {10.1016/j.fsigen.2020.102336}, author = {Xavier, Catarina and de la Puente, Maria and Mosquera-Miguel, Ana and Freire-Aradas, Ana and Kalamara, Vivian and Vidaki, Athina and E Gross, Theresa and Revoir, Andrew and Po{\'s}piech, Ewelina and Kartasi{\'n}ska, Ewa and Sp{\'o}lnicka, Magdalena and Branicki, Wojciech and E Ames, Carole and M Schneider, Peter and Hohoff, Carsten and Kayser, Manfred and Phillips, Christopher and Parson, Walther} } @article {712, title = {A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 02}, pages = {487-501}, abstract = {

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47\% with 24\% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7\%. For the combined cohort (n = 260), the total observed clinical detection rate was 52\% with 25\% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50\% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.

}, issn = {1098-1004}, doi = {10.1002/humu.23946}, author = {Ngo, Kathie J and Rexach, Jessica E and Lee, Hane and Petty, Lauren E and Perlman, Susan and Valera, Juliana M and Deignan, Joshua L and Mao, Yuanming and Aker, Mamdouh and Posey, Jennifer E and Jhangiani, Shalini N and Coban-Akdemir, Zeynep H and Boerwinkle, Eric and Muzny, Donna and Nelson, Alexandra B and Hassin-Baer, Sharon and Poke, Gemma and Neas, Katherine and Geschwind, Michael D and Grody, Wayne W and Gibbs, Richard and Geschwind, Daniel H and Lupski, James R and Below, Jennifer E and Nelson, Stanley F and Fogel, Brent L} } @article {878, title = {Discovery and population genomics of structural variation in a songbird genus.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 07 07}, pages = {3403}, abstract = {

Structural variation~(SV) constitutes an important type of genetic mutations providing the raw material for evolution. Here, we uncover the genome-wide spectrum of intra- and interspecific SV segregating in natural populations of seven songbird species in the genus Corvus. Combining short-read (N = 127) and long-read re-sequencing (N = 31), as well as optical mapping (N = 16), we apply both assembly- and read mapping approaches to detect SV and characterize a total of 220,452 insertions, deletions and inversions. We exploit sampling across wide phylogenetic timescales to validate SV genotypes and assess the contribution of SV to evolutionary processes in an avian model of incipient speciation. We reveal an evolutionary young (~530,000 years) cis-acting 2.25-kb LTR retrotransposon insertion reducing expression of the NDP gene with consequences for premating isolation. Our results attest to the wealth and evolutionary significance of SV segregating in natural populations and highlight the need for reliable SV genotyping.

}, keywords = {Animals, Chromosome Inversion, Gene Deletion, Genetic Variation, Genetics, Population, Genome, Genomic Structural Variation, Genotype, Phylogeny, Polymorphism, Single Nucleotide, Retroelements, Sequence Analysis, DNA, Songbirds}, issn = {2041-1723}, doi = {10.1038/s41467-020-17195-4}, author = {Weissensteiner, Matthias H and Bunikis, Ignas and Catal{\'a}n, Ana and Francoijs, Kees-Jan and Knief, Ulrich and Heim, Wieland and Peona, Valentina and Pophaly, Saurabh D and Sedlazeck, Fritz J and Suh, Alexander and Warmuth, Vera M and Wolf, Jochen B W} } @article {783, title = {Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 08 03}, pages = {4411-4422}, abstract = {

Patients with common variable immunodeficiency associated with autoimmune cytopenia (CVID+AIC) generate few isotype-switched B cells with severely decreased frequencies of somatic hypermutations (SHMs), but their underlying molecular defects remain poorly characterized. We identified a CVID+AIC patient who displays a rare homozygous missense M466V mutation in β-catenin-like protein 1 (CTNNBL1). Because CTNNBL1 binds activation-induced cytidine deaminase (AID) that catalyzes SHM, we tested AID interactions with the CTNNBL1 M466V variant. We found that the M466V mutation interfered with the association of CTNNBL1 with AID, resulting in decreased AID in the nuclei of patient EBV-transformed B cell lines and of CTNNBL1 466V/V Ramos B cells engineered to express only CTNNBL1 M466V using CRISPR/Cas9 technology. As a consequence, the scarce IgG+ memory B cells from the CTNNBL1 466V/V patient showed a low SHM frequency that averaged 6.7 mutations compared with about 18 mutations per clone in healthy-donor counterparts. In addition, CTNNBL1 466V/V Ramos B cells displayed a decreased incidence of SHM that was reduced by half compared with parental WT Ramos B cells, demonstrating that the CTNNBL1 M466V mutation is responsible for defective SHM induction. We conclude that CTNNBL1 plays an important role in regulating AID-dependent antibody diversification in humans.

}, keywords = {Amino Acid Substitution, Apoptosis Regulatory Proteins, B-Lymphocytes, Cell Line, Child, Preschool, Common Variable Immunodeficiency, Cytidine Deaminase, Female, Homozygote, Humans, Immunologic Memory, Mutation, Missense, Nuclear Proteins, Somatic Hypermutation, Immunoglobulin}, issn = {1558-8238}, doi = {10.1172/JCI131297}, author = {Kuhny, Marcel and Forbes, Lisa R and {\c C}akan, Elif and Vega-Loza, Andrea and Kostiuk, Valentyna and Dinesh, Ravi K and Glauzy, Salom{\'e} and Stray-Pedersen, Asbjorg and Pezzi, Ashley E and Hanson, I Celine and Vargas-Hernandez, Alexander and Xu, Mina LuQuing and Coban-Akdemir, Zeynep H and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and Chinn, Ivan K and Schatz, David G and Orange, Jordan S and Meffre, Eric} } @article {905, title = {Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.}, journal = {J Exp Med}, volume = {217}, year = {2020}, month = {2020 06 01}, abstract = {

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients{\textquoteright} heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

}, keywords = {Adolescent, Alleles, C-Reactive Protein, Cell Membrane, Cells, Cultured, Child, Cytokine Receptor gp130, Cytokines, Female, Fibroblasts, Genes, Dominant, Genetics, Population, HEK293 Cells, Humans, Job Syndrome, Kinetics, Loss of Function Mutation, Male, Middle Aged, Models, Biological, Mutation, Pedigree, Phenotype, Th2 Cells, Up-Regulation, Young Adult}, issn = {1540-9538}, doi = {10.1084/jem.20191804}, author = {B{\'e}ziat, Vivien and Tavernier, Simon J and Chen, Yin-Huai and Ma, Cindy S and Materna, Marie and Laurence, Arian and Staal, Jens and Aschenbrenner, Dominik and Roels, Lisa and Worley, Lisa and Claes, Kathleen and Gartner, Lisa and Kohn, Lisa A and De Bruyne, Marieke and Schmitz-Abe, Klaus and Charbonnier, Louis-Marie and Keles, Sevgi and Nammour, Justine and Vladikine, Natasha and Maglorius Renkilaraj, Majistor Raj Luxman and Seeleuthner, Yoann and Migaud, M{\'e}lanie and Rosain, J{\'e}r{\'e}mie and Jeljeli, Mohamed and Boisson, Bertrand and Van Braeckel, Eva and Rosenfeld, Jill A and Dai, Hongzheng and Burrage, Lindsay C and Murdock, David R and Lambrecht, Bart N and Avettand-Fenoel, V{\'e}ronique and Vogel, Tiphanie P and Esther, Charles R and Haskologlu, Sule and Dogu, Figen and Ciznar, Peter and Boutboul, David and Ouach{\'e}e-Chardin, Marie and Amourette, Jean and Lebras, Marie-No{\"e}lle and Gauvain, Cl{\'e}ment and Tcherakian, Colas and Ikinciogullari, Aydan and Beyaert, Rudi and Abel, Laurent and Milner, Joshua D and Grimbacher, Bodo and Couderc, Louis-Jean and Butte, Manish J and Freeman, Alexandra F and Catherinot, Emilie and Fieschi, Claire and Chatila, Talal A and Tangye, Stuart G and Uhlig, Holm H and Haerynck, Filomeen and Casanova, Jean-Laurent and Puel, Anne} } @article {851, title = {Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 07 01}, pages = {2106-2118}, abstract = {

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3\% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

}, keywords = {DNA Copy Number Variations, Epilepsy, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male}, issn = {1460-2156}, doi = {10.1093/brain/awaa171}, author = {Niestroj, Lisa-Marie and Perez-Palma, Eduardo and Howrigan, Daniel P and Zhou, Yadi and Cheng, Feixiong and Saarentaus, Elmo and N{\"u}rnberg, Peter and Stevelink, Remi and Daly, Mark J and Palotie, Aarno and Lal, Dennis} } @article {968, title = {Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 11}, pages = {e1508}, abstract = {

BACKGROUND: Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases.

METHODS: We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4-13~months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9-18~months considered all disease-associated genes. At 25-34~months we reviewed all cases and the strategies which solved them.

RESULTS: Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17\%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty-seven peer-reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15\% and median reanalysis timeframe of 22~months.

CONCLUSION: Our findings suggest that an interval of greater than 18~months from the original report may be optimal for reanalysis. We also recommend a multi-faceted strategy for cases remaining unsolved after singleton ES.

}, issn = {2324-9269}, doi = {10.1002/mgg3.1508}, author = {Tan, Natalie B and Stapleton, Rachel and Stark, Zornitza and Delatycki, Martin B and Yeung, Alison and Hunter, Matthew F and Amor, David J and Brown, Natasha J and Stutterd, Chloe A and McGillivray, George and Yap, Patrick and Regan, Matthew and Chong, Belinda and Fanjul Fernandez, Miriam and Marum, Justine and Phelan, Dean and Pais, Lynn S and White, Susan M and Lunke, Sebastian and Tan, Tiong Y} } @article {885, title = {Evaluation of the VISAGE Basic Tool for Appearance and Ancestry Prediction Using PowerSeq Chemistry on the MiSeq FGx System.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 06 26}, abstract = {

The study of DNA to predict externally visible characteristics (EVCs) and the biogeographical ancestry (BGA) from unknown samples is gaining relevance in forensic genetics. Technical developments in Massively Parallel Sequencing (MPS) enable the simultaneous analysis of hundreds of DNA markers, which improves successful Forensic DNA Phenotyping (FDP). The EU-funded VISAGE (VISible Attributes through GEnomics) Consortium has developed various targeted MPS-based lab tools to apply FDP in routine forensic analyses. Here, we present an evaluation of the VISAGE Basic tool for appearance and ancestry prediction based on PowerSeq chemistry (Promega) on a MiSeq FGx System (Illumina). The panel consists of 153 single nucleotide polymorphisms (SNPs) that provide information about EVCs (41 SNPs for eye, hair and skin color from HIrisPlex-S) and continental BGA (115 SNPs; three overlap with the EVCs SNP set). The assay was evaluated for sensitivity, repeatability and genotyping concordance, as well as its performance with casework-type samples. This targeted MPS assay provided complete genotypes at all 153 SNPs down to 125 pg of input DNA and 99.67\% correct genotypes at 50 pg. It was robust in terms of repeatability and concordance and provided useful results with casework-type samples. The results suggest that this MPS assay is a useful tool for basic appearance and ancestry prediction in forensic genetics for users interested in applying PowerSeq chemistry and MiSeq for this purpose.

}, keywords = {DNA Fingerprinting, Eye Color, Forensic Genetics, Genetic Markers, Genotype, Hair Color, High-Throughput Nucleotide Sequencing, Humans, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Skin Pigmentation, Software}, issn = {2073-4425}, doi = {10.3390/genes11060708}, author = {Palencia-Madrid, Leire and Xavier, Catarina and de la Puente, Maria and Hohoff, Carsten and Phillips, Christopher and Kayser, Manfred and Parson, Walther} } @article {914, title = {Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.}, journal = {Nat Med}, volume = {26}, year = {2020}, month = {2020 11}, pages = {1754-1765}, abstract = {

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17\% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22\% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

}, keywords = {Brain, Cerebral Ventricles, Exome, Female, Genetic Predisposition to Disease, Humans, Hydrocephalus, Male, Mutation, Neural Stem Cells, Neurogenesis, Neuroglia, Transcription Factors, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Whole Exome Sequencing}, issn = {1546-170X}, doi = {10.1038/s41591-020-1090-2}, author = {Jin, Sheng Chih and Dong, Weilai and Kundishora, Adam J and Panchagnula, Shreyas and Moreno-De-Luca, Andres and Furey, Charuta G and Allocco, August A and Walker, Rebecca L and Nelson-Williams, Carol and Smith, Hannah and Dunbar, Ashley and Conine, Sierra and Lu, Qiongshi and Zeng, Xue and Sierant, Michael C and Knight, James R and Sullivan, William and Duy, Phan Q and DeSpenza, Tyrone and Reeves, Benjamin C and Karimy, Jason K and Marlier, Arnaud and Castaldi, Christopher and Tikhonova, Irina R and Li, Boyang and Pe{\~n}a, Helena Perez and Broach, James R and Kabachelor, Edith M and Ssenyonga, Peter and Hehnly, Christine and Ge, Li and Keren, Boris and Timberlake, Andrew T and Goto, June and Mangano, Francesco T and Johnston, James M and Butler, William E and Warf, Benjamin C and Smith, Edward R and Schiff, Steven J and Limbrick, David D and Heuer, Gregory and Jackson, Eric M and Iskandar, Bermans J and Mane, Shrikant and Haider, Shozeb and Guclu, Bulent and Bayri, Yasar and Sahin, Yener and Duncan, Charles C and Apuzzo, Michael L J and DiLuna, Michael L and Hoffman, Ellen J and {\v S}estan, Nenad and Ment, Laura R and Alper, Seth L and Bilguvar, Kaya and Geschwind, Daniel H and G{\"u}nel, Murat and Lifton, Richard P and Kahle, Kristopher T} } @article {925, title = {Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.}, journal = {iScience}, volume = {23}, year = {2020}, month = {2020 Oct 23}, pages = {101552}, abstract = {

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated mutation (p.Cys188Trp) in the GABA receptor Cl channel γ-1 subunit () exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na and Ca channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca channel Ca3.2 (). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101552}, author = {Dong, Weilai and Jin, Sheng Chih and Allocco, August and Zeng, Xue and Sheth, Amar H and Panchagnula, Shreyas and Castonguay, Annie and Lorenzo, Louis-{\'E}tienne and Islam, Barira and Brindle, Genevi{\`e}ve and Bachand, Karine and Hu, Jamie and Sularz, Agata and Gaillard, Jonathan and Choi, Jungmin and Dunbar, Ashley and Nelson-Williams, Carol and Kiziltug, Emre and Furey, Charuta Gavankar and Conine, Sierra and Duy, Phan Q and Kundishora, Adam J and Loring, Erin and Li, Boyang and Lu, Qiongshi and Zhou, Geyu and Liu, Wei and Li, Xinyue and Sierant, Michael C and Mane, Shrikant and Castaldi, Christopher and L{\'o}pez-Gir{\'a}ldez, Francesc and Knight, James R and Sekula, Raymond F and Simard, J Marc and Eskandar, Emad N and Gottschalk, Christopher and Moliterno, Jennifer and G{\"u}nel, Murat and Gerrard, Jason L and Dib-Hajj, Sulayman and Waxman, Stephen G and Barker, Fred G and Alper, Seth L and Chahine, Mohamed and Haider, Shozeb and De Koninck, Yves and Lifton, Richard P and Kahle, Kristopher T} } @article {803, title = {Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population.}, journal = {Clin Genet}, volume = {98}, year = {2020}, month = {2020 11}, pages = {499-506}, abstract = {

Next-generation sequencing strategies have resulted in mutation detection rates of 21\% to 61\% in small cohorts of patients with microphthalmia, anophthalmia and coloboma (MAC), but despite progress in identifying novel causative genes, many patients remain without a genetic diagnosis. We studied a cohort of 19 patients with MAC who were ascertained from a population with high rates of consanguinity. Using single nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES), we identified one pathogenic variant in TENM3 in a patient with cataracts in addition to MAC. We also detected novel variants of unknown significance in genes that have previously been associated with MAC, including KIF26B, MICU1 and CDON, and identified variants in candidate genes for MAC from the Wnt signaling pathway, comprising LRP6, WNT2B and IQGAP1, but our findings do not prove causality. Plausible variants were not found for many of the cases, indicating that our current understanding of the pathogenesis of MAC, a highly heterogeneous group of ocular defects, remains incomplete.

}, issn = {1399-0004}, doi = {10.1111/cge.13830}, author = {Islam, Farrah and Htun, Stephanie and Lai, Li-Wen and Krall, Max and Poranki, Menitha and Martin, Pierre-Marie and Sobreira, Nara and Wohler, Elizabeth S and Yu, Jingwei and Moore, Anthony T and Slavotinek, Anne M} } @article {750, title = {Exome sequencing reveals a novel variant in causing intracranial aneurysm in a Chinese family.}, journal = {J Neurointerv Surg}, volume = {12}, year = {2020}, month = {2020 Feb}, pages = {221-226}, abstract = {

BACKGROUND: Genetic risk factors play an important role in the pathogenesis of familial intracranial aneurysms (FIAs); however, the molecular mechanisms remain largely unknown.

OBJECTIVE: To investigate potential FIA-causing genetic variants by rare variant interrogation and a family-based genomics approach in a large family with an extensive multigenerational pedigree with FIAs.

METHOD: Exome sequencing (ES) was performed in a dominant likely family with intracranial aneurysms (IAs). Variants were analyzed by an in-house developed pipeline and prioritized using various filtering strategies, including population frequency, variant type, and predicted variant pathogenicity. Sanger sequencing was also performed to evaluate the segregation of the variants with the phenotype.

RESULTS: Based on the ES data obtained from five individuals from a family with 7/21 living members affected with IAs, a total of 14 variants were prioritized as candidate variants. Familial segregation analysis revealed that c.2519T>C (p.Leu840Pro) segregated in accordance with Mendelian expectations with the phenotype within the family-that is, present in all IA-affected cases and absent from all unaffected members of the second generation. This missense variant is absent from public databases (1000genome, ExAC, gnomAD, ESP5400), and has damaging predictions by bioinformatics tools (Gerp ++ score = 5.88, CADD score = 16.43, MutationTaster score = 1, LRT score = 0). In addition, 840Leu in NFX1 is robustly conserved in mammals and maps in a region before the RING-type zinc finger domain.

CONCLUSION: c.2519T>C (p.Leu840Pro) may contribute to the pathogenetics of a subset of FIAs.

}, keywords = {Adult, Asian Continental Ancestry Group, Computational Biology, Exome, Female, Genetic Variation, Humans, Intracranial Aneurysm, Male, Middle Aged, Pedigree, Phenotype, Repressor Proteins}, issn = {1759-8486}, doi = {10.1136/neurintsurg-2019-014900}, author = {Ding, Xinghuan and Zhao, Sen and Zhang, Qianqian and Yan, Zihui and Wang, Yang and Wu, Yong and Li, Xiaoxin and Liu, Jian and Niu, Yuchen and Zhang, Yisen and Zhang, Mingqi and Wang, Huizi and Zhang, Ying and Chen, Weisheng and Yang, Xin-Zhuang and Liu, Pengfei and Posey, Jennifer E and Lupski, James R and Wu, Zhihong and Yang, Xinjian and Wu, Nan and Wang, Kun} } @article {766, title = {Expanding the phenotypic spectrum in RDH12-associated retinal disease.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {6}, year = {2020}, month = {2020 02}, abstract = {

Retinol dehydrogenase 12, RDH12, plays a pivotal role in the visual cycle to ensure the maintenance of normal vision. Alterations in activity of this protein result in photoreceptor death and decreased vision beginning at an early age and progressing to substantial vision loss later in life. Here we describe 11 patients with retinal degeneration that underwent next-generation sequencing (NGS) with a targeted panel of all currently known inherited retinal degeneration (IRD) genes and whole-exome sequencing to identify the genetic causality of their retinal disease. These patients display a range of phenotypic severity prompting clinical diagnoses of macular dystrophy, cone-rod dystrophy, retinitis pigmentosa, and early-onset severe retinal dystrophy all attributed to biallelic recessive mutations in We report 15 causal alleles and expand the repertoire of known mutations with four novel variants: c.215A > G (p.Asp72Gly); c.362T > C (p.Ile121Thr); c.440A > C (p.Asn147Thr); and c.697G > A (p.Val233Ille). The broad phenotypic spectrum observed with biallelic mutations has been observed in other genetic forms of IRDs, but the diversity is particularly notable here given the prior association of primarily with severe early-onset disease. This breadth emphasizes the importance of broad genetic testing for inherited retinal disorders and extends the pool of individuals who may benefit from imminent gene-targeted therapies.

}, keywords = {Adolescent, Adult, Alcohol Oxidoreductases, Alleles, Amino Acid Substitution, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Humans, Male, Mutation, Optical Imaging, Pedigree, Phenotype, Retinal Diseases, Tomography, Optical Coherence, Whole Exome Sequencing, Young Adult}, issn = {2373-2873}, doi = {10.1101/mcs.a004754}, author = {Scott, Hilary A and Place, Emily M and Ferenchak, Kevin and Zampaglione, Erin and Wagner, Naomi E and Chao, Katherine R and DiTroia, Stephanie P and Navarro-Gomez, Daniel and Mukai, Shizuo and Huckfeldt, Rachel M and Pierce, Eric A and Bujakowska, Kinga M} } @article {869, title = {Forensic evaluation of the Asia Pacific ancestry-informative MAPlex assay.}, journal = {Forensic Sci Int Genet}, volume = {48}, year = {2020}, month = {2020 09}, pages = {102344}, abstract = {

DNA intelligence, and particularly the inference of biogeographical ancestry (BGA) is increasing in interest, and relevance within the forensic genetics community. The majority of current MPS-based forensic ancestry-informative assays focus on the differentiation of major global populations. The recently published MAPlex (Multiplex for the Asia Pacific) panel contains 144 SNPs and 20 microhaplotypes and aims to improve the differentiation of populations in the Asia Pacific region. This study reports the first forensic evaluation of the MAPlex panel using AmpliSeq technology and Ion S5 sequencing. This study reports on the overall performance of MAPlex including the assay{\textquoteright}s sequence coverage distribution and stability, baseline noise and description of problematic SNPs. Dilution series, artificially degraded and mixed DNA samples were also analysed to evaluate the sensitivity of the panel with challenging or compromised forensic samples. As the first panel to combine biallelic SNPs, multiple-allele SNPs and microhaplotypes, the MAPlex assay demonstrated an enhanced capacity for mixture detection, not easily performed with common binary SNPs. This performance evaluation indicates that MAPlex is a robust, stable and highly sensitive assay that is applicable to forensic casework for the prediction of BGA.

}, issn = {1878-0326}, doi = {10.1016/j.fsigen.2020.102344}, author = {Xavier, C and de la Puente, M and Phillips, C and Eduardoff, M and Heidegger, A and Mosquera-Miguel, A and Freire-Aradas, A and Lagace, R and Wootton, S and Power, D and Parson, W and Lareu, M V and Daniel, R} } @article {973, title = {Four Individuals with a Homozygous Mutation in Exon 1f of the Gene and Associated Myasthenic Features.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 06 27}, abstract = {

We identified the known c.1_9del mutation in the gene in four unrelated females from consanguineous families of Turkish origin. All individuals presented with slowly progressive limb-girdle weakness without any dermatological findings, and dystrophic changes observed in their muscle biopsies. Additionally, the neurological examination revealed ptosis, facial weakness, fatigability, and muscle cramps in all four cases. In two patients, repetitive nerve stimulation showed a borderline decrement and a high jitter was detected in all patients by single-fiber electromyography. Clinical improvement was observed after treatment with pyridostigmine and salbutamol was started. We further characterize the phenotype of patients with limb-girdle muscular dystrophy R17 clinically, by muscle magnetic resonance imaging (MRI) features and by describing a common 3.8 Mb haplotype in three individuals from the same geographical region. In addition, we review the neuromuscular symptoms associated with mutations and the role of plectin in the neuromuscular junction.

}, keywords = {Adolescent, Adult, Child, Exons, Female, Homozygote, Humans, Muscular Dystrophies, Limb-Girdle, Mutation, Myasthenic Syndromes, Congenital, Phenotype, Plectin}, issn = {2073-4425}, doi = {10.3390/genes11070716}, author = {Mroczek, Magdalena and Durmus, Hacer and Topf, Ana and Parman, Yesim and Straub, Volker} } @article {777, title = {Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 09}, pages = {1243-1264}, abstract = {

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM $\#$615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

}, keywords = {Abnormalities, Multiple, Adolescent, Animals, Bone Development, Child, Child, Preschool, Consanguinity, Extracellular Matrix, Female, Fibrillar Collagens, Founder Effect, Gene Frequency, Hip Dislocation, Homozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Scoliosis, Syndrome}, issn = {1476-5438}, doi = {10.1038/s41431-020-0632-x}, author = {Gonzaga-Jauregui, Claudia and Yesil, G{\"o}zde and Nistala, Harikiran and Gezdirici, Alper and Bayram, Yavuz and Nannuru, Kalyan C and Pehlivan, Davut and Yuan, Bo and Jimenez, Johanna and Sahin, Yavuz and Paine, Ingrid S and Akdemir, Zeynep Coban and Rajamani, Saathyaki and Staples, Jeffrey and Dronzek, John and Howell, Kristen and Fatih, Jawid M and Smaldone, Silvia and Schlesinger, Alan E and Ram{\'\i}rez, Norman and Cornier, Alberto S and Kelly, Melissa A and Haber, Robert and Chim, Shek Man and Nieman, Kristy and Wu, Nan and Walls, Johnathon and Poueymirou, William and Siao, Chia-Jen and Sutton, V Reid and Williams, Marc S and Posey, Jennifer E and Gibbs, Richard A and Carlo, Simon and Tegay, David H and Economides, Aris N and Lupski, James R} } @article {786, title = {Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 08}, pages = {1338-1347}, abstract = {

PURPOSE: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized.

METHODS: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum.

RESULTS: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent.

CONCLUSION: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

}, keywords = {Blepharophimosis, Exons, Histone Acetyltransferases, Humans, Intellectual Disability, Mutation}, issn = {1530-0366}, doi = {10.1038/s41436-020-0811-8}, author = {Zhang, Li Xin and Lemire, Gabrielle and Gonzaga-Jauregui, Claudia and Molidperee, Sirinart and Galaz-Montoya, Carolina and Liu, David S and Verloes, Alain and Shillington, Amelle G and Izumi, Kosuke and Ritter, Alyssa L and Keena, Beth and Zackai, Elaine and Li, Dong and Bhoj, Elizabeth and Tarpinian, Jennifer M and Bedoukian, Emma and Kukolich, Mary K and Innes, A Micheil and Ediae, Grace U and Sawyer, Sarah L and Nair, Karippoth Mohandas and Soumya, Para Chottil and Subbaraman, Kinattinkara R and Probst, Frank J and Bassetti, Jennifer A and Sutton, Reid V and Gibbs, Richard A and Brown, Chester and Boone, Philip M and Holm, Ingrid A and Tartaglia, Marco and Ferrero, Giovanni Battista and Niceta, Marcello and Dentici, Maria Lisa and Radio, Francesca Clementina and Keren, Boris and Wells, Constance F and Coubes, Christine and Laquerri{\`e}re, Annie and Aziza, Jacqueline and Dubucs, Charlotte and Nampoothiri, Sheela and Mowat, David and Patel, Millan S and Bracho, Ana and Cammarata-Scalisi, Francisco and Gezdirici, Alper and Fern{\'a}ndez-Ja{\'e}n, Alberto and Hauser, Natalie and Zarate, Yuri A and Bosanko, Katherine A and Dieterich, Klaus and Carey, John C and Chong, Jessica X and Nickerson, Deborah A and Bamshad, Michael J and Lee, Brendan H and Yang, Xiang-Jiao and Lupski, James R and Campeau, Philippe M} } @article {822, title = {Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0234357}, abstract = {

Congenital heart defects (CHDs) affect approximately 1\% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that link CHDs to maternal effect genes as well as to maternal genes related to hypertension and proteostasis. Maternal effect genes, which provide the mRNAs and proteins in the oocyte that guide early embryonic development before zygotic gene activation, have not previously been implicated in CHD risk. Our findings support a role for and suggest new pathways by which the maternal genome may contribute to the development of CHDs in offspring.

}, keywords = {Adult, Case-Control Studies, Child, Preschool, Family, Female, Genetic Testing, Heart Defects, Congenital, Humans, Hypertension, Infant, Infant, Newborn, Male, Maternal Exposure, Maternal Inheritance, Middle Aged, Oocytes, Pregnancy, Prenatal Exposure Delayed Effects, Proteostasis, Risk Factors}, issn = {1932-6203}, doi = {10.1371/journal.pone.0234357}, author = {Sewda, Anshuman and Agopian, A J and Goldmuntz, Elizabeth and Hakonarson, Hakon and Morrow, Bernice E and Musfee, Fadi and Taylor, Deanne and Mitchell, Laura E} } @article {708, title = {Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 01}, pages = {e1023}, abstract = {

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS).

METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects~from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort.

RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject~with MPLS, a more complicated fibrillinopathy, and two subjects~with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the~classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro.

CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

}, keywords = {Adolescent, Adult, Child, Female, Fibrillin-1, HEK293 Cells, Humans, Lipodystrophy, Marfan Syndrome, Mutation, Phenotype, Progeria, Protein Domains, Smad2 Protein}, issn = {2324-9269}, doi = {10.1002/mgg3.1023}, author = {Lin, Mao and Liu, Zhenlei and Liu, Gang and Zhao, Sen and Li, Chao and Chen, Weisheng and Coban Akdemir, Zeynep and Lin, Jiachen and Song, Xiaofei and Wang, Shengru and Xu, Qiming and Zhao, Yanxue and Wang, Lianlei and Zhang, Yuanqiang and Yan, Zihui and Liu, Sen and Liu, Jiaqi and Chen, Yixin and Zuo, Yuzhi and Yang, Xu and Sun, Tianshu and Yang, Xin-Zhuang and Niu, Yuchen and Li, Xiaoxin and You, Wesley and Qiu, Bintao and Ding, Chen and Liu, Pengfei and Zhang, Shuyang and Carvalho, Claudia M B and Posey, Jennifer E and Qiu, Guixing and Lupski, James R and Wu, Zhihong and Zhang, Jianguo and Wu, Nan} } @article {972, title = {Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS).}, journal = {JBMR Plus}, volume = {4}, year = {2020}, month = {2020 Mar}, pages = {e10335}, abstract = {

Worldwide, one in five men aged over 50 years will experience osteoporosis or a clinical bone fracture, with a greater fracture-related mortality rate than women. However, the genetic etiology of osteoporosis in men is still poorly understood. We aimed to identify the genetic variants and candidate genes associated with extremely low or high BMD for a better understanding of the biology underlying low bone density that may point to potential therapeutic targets for increasing bone mass. Subjects from the Osteoporotic Fractures in Men Study (MrOS) cohort were evaluated by age and BMI-adjusted total hip BMD. Those with BMD values 3 SDs away from the mean were selected and the remaining individuals whose adjusted BMD ranked at the highest or lowest 100 were included. Men with the lowest adjusted BMD ( = 98) and highest adjusted BMD ( = 110) were chosen for exome sequencing. Controls ( = 82) were men of Northern and Western European descent from the US Utah population of the 1000 Genomes Project. Fisher{\textquoteright}s exact test was performed to compare low- or high-BMD subjects with controls for single-gene associations. Additionally, sets of candidate genes causative of heritable disorders of connective tissue, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), were grouped for multigene and mutation burden analyses. No single-gene associations with rare variants were found for either the low BMD group (33 genes) or high BMD group (18 genes). In the group of OI genes, we detected a significant threefold increased accumulation of rare variants in low-BMD subjects compared with controls ( = 0.009). Additionally, genes associated with EDS had a twofold increased frequency in low-BMD subjects compared with controls ( = 0.03). These findings reveal a rare variant burden in OI and EDS disease genes at low BMD, which suggests a potential gene-panel approach to screen for multivariant associations in larger cohorts. {\textcopyright} 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

}, issn = {2473-4039}, doi = {10.1002/jbm4.10335}, author = {Chen, Shan and Jain, Mahim and Jhangiani, Shalini and Akdemir, Zeynep C and Campeau, Philippe M and Klein, Robert F and Nielson, Carrie and Dai, Hongzheng and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Orwoll, Eric S and Lupski, James R and Posey, Jennifer E and Lee, Brendan} } @article {846, title = {Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort.}, journal = {Epilepsia}, volume = {61}, year = {2020}, month = {2020 02}, pages = {249-258}, abstract = {

OBJECTIVE: We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

METHODS: We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

RESULTS: Overall, we identified pathogenic or likely pathogenic variants in 40\% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26\% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25\%).

SIGNIFICANCE: Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

}, keywords = {Adolescent, Adult, Age of Onset, Brain Diseases, Child, Child, Preschool, Chromosomes, Human, Cohort Studies, Epilepsy, Epilepsy, Generalized, Exome, Female, Genetic Testing, Genetic Variation, Humans, Infant, Male, Microarray Analysis, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {1528-1167}, doi = {10.1111/epi.16427}, author = {Rochtus, Anne and Olson, Heather E and Smith, Lacey and Keith, Louisa G and El Achkar, Christelle and Taylor, Alan and Mahida, Sonal and Park, Meredith and Kelly, McKenna and Shain, Catherine and Rockowitz, Shira and Rosen Sheidley, Beth and Poduri, Annapurna} } @article {763, title = {Genetic diagnosis in the fetus.}, journal = {J Perinatol}, volume = {40}, year = {2020}, month = {2020 07}, pages = {997-1006}, abstract = {

Many genetic disorders are detectable in the prenatal period, and the capacity to identify them has increased remarkably as molecular genetic testing techniques continue to improve and become incorporated into clinical practice. The indications for prenatal genetic testing vary widely, including follow-up of an anomaly found by routine ultrasound or maternal aneuploidy screening, a family history of genetic disease, advanced maternal or paternal age, or evaluation of a low-risk pregnancy due to parental concern. The interpretation of genetic variants identified in the prenatal period poses unique challenges due to the lack of ability for deep phenotyping as well as the option to make critical decisions regarding pregnancy continuation and perinatal management. In this review, we address the various modalities currently available and commonly used for genetic testing, including preimplantation genetic testing of embryos, cell-free DNA testing, and diagnostic procedures such as chorionic villous sampling, amniocentesis, or percutaneous umbilical blood sampling, from which samples may be sent for a wide variety of genetic tests. We discuss the difference between these modalities for the genetic diagnosis of a fetus, their strengths and weaknesses, and strategies for their optimal use in order to direct perinatal care.

}, issn = {1476-5543}, doi = {10.1038/s41372-020-0627-z}, author = {Wojcik, Monica H and Reimers, Rebecca and Poorvu, Tabitha and Agrawal, Pankaj B} } @article {866, title = {Genetics of schizophrenia in the South African Xhosa.}, journal = {Science}, volume = {367}, year = {2020}, month = {2020 01 31}, pages = {569-573}, abstract = {

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.

}, keywords = {Age Factors, Autistic Disorder, Bipolar Disorder, Dopamine, Female, gamma-Aminobutyric Acid, Genetic Variation, Glutamine, Humans, Male, Mutation, Neural Pathways, Schizophrenia, Sex Factors, South Africa, Synapses, Synaptic Transmission}, issn = {1095-9203}, doi = {10.1126/science.aay8833}, author = {Gulsuner, S and Stein, D J and Susser, E S and Sibeko, G and Pretorius, A and Walsh, T and Majara, L and Mndini, M M and Mqulwana, S G and Ntola, O A and Casadei, S and Ngqengelele, L L and Korchina, V and van der Merwe, C and Malan, M and Fader, K M and Feng, M and Willoughby, E and Muzny, D and Baldinger, A and Andrews, H F and Gur, R C and Gibbs, R A and Zingela, Z and Nagdee, M and Ramesar, R S and King, M-C and McClellan, J M} } @article {748, title = {Genome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 04}, pages = {e1154}, abstract = {

BACKGROUND: Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH ), an essential cofactor for aromatic amino acid hydroxylases. Its dysfunction causes the condition of hyperphenylalaninemia together with the lack of neurotransmitters.

METHODS: We report a patient with biochemically diagnosed DHPR deficiency, with extensive molecular investigations undertaken to detect variations in quinoid dihydropteridine reductase (QDPR) gene. Sanger sequencing of QDPR coding regions, exome sequencing, QDPR mRNA PCR, and karyotyping were followed by trio genome sequencing.

RESULTS: Short-read genome sequencing revealed a homozygous 9-Mb inversion disrupting QDPR. Structural variant breakpoints in chromosome 4 were located to intron 2 of QDPR at Chr4(GRCh38):g.17505522 and in intron 8 of the ACOX3 gene, Chr4(GRCh38):g.8398067). Both nonrelated parents carried the variant in heterozygous state. The inversion was not present in gnomAD structural variant database.

CONCLUSION: Identification of the exact breakpoints now allows further straightforward molecular genetic testing of potential carriers of the inversion. This study extends the pathogenic variant spectrum of DHPR deficiency and highlights the role of structural variants in recessive metabolic disorders. To our knowledge, this is the first report on a large, canonical (rather than complex) homozygous pathogenic inversion detected by genome sequencing.

}, keywords = {Acyl-CoA Oxidase, Child, Chromosome Breakpoints, Chromosome Inversion, Chromosomes, Human, Pair 4, Female, Genetic Testing, Homozygote, Humans, Phenylketonurias, Whole Exome Sequencing}, issn = {2324-9269}, doi = {10.1002/mgg3.1154}, author = {Lillev{\"a}li, Hardo and Pajusalu, Sander and Wojcik, Monica H and Goodrich, Julia and Collins, Ryan L and Murumets, {\"U}lle and Tammur, Pille and Blau, Nenad and Lillev{\"a}li, Kersti and {\~O}unap, Katrin} } @article {863, title = {Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease.}, journal = {BMC Med Genomics}, volume = {13}, year = {2020}, month = {2020 08 26}, pages = {120}, abstract = {

BACKGROUND: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD.

METHODS: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants.

RESULTS: Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P~< 5 {\texttimes} 10), (ii) one previously suggested locus with experiment-wise significance (P~< 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism).

CONCLUSIONS: Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

}, keywords = {Case-Control Studies, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Macular Degeneration, Polymorphism, Single Nucleotide}, issn = {1755-8794}, doi = {10.1186/s12920-020-00760-7}, author = {Winkler, Thomas W and Grassmann, Felix and Brandl, Caroline and Kiel, Christina and G{\"u}nther, Felix and Strunz, Tobias and Weidner, Lorraine and Zimmermann, Martina E and Korb, Christina A and Poplawski, Alicia and Schuster, Alexander K and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Rauscher, Franziska G and Elze, Tobias and Horn, Katrin and Scholz, Markus and Ca{\~n}adas-Garre, Marisa and McKnight, Amy Jayne and Quinn, Nicola and Hogg, Ruth E and K{\"u}chenhoff, Helmut and Heid, Iris M and Stark, Klaus J and Weber, Bernhard H F} } @article {935, title = {Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 11}, pages = {1863-1873}, abstract = {

PURPOSE: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings.

METHODS: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts.

RESULTS: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro.

CONCLUSION: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.

}, keywords = {Humans, Liver Failure, Muscle Hypotonia, Mutation, Seizures}, issn = {1530-0366}, doi = {10.1038/s41436-020-0904-4}, author = {Lenz, Dominic and Smith, Desir{\'e}e E C and Crushell, Ellen and Husain, Ralf A and Salomons, Gajja S and Alhaddad, Bader and Bernstein, Jonathan A and Bianzano, Alyssa and Biskup, Saskia and Brennenstuhl, Heiko and Caldari, Dominique and Dikow, Nicola and Haack, Tobias B and Hanson-Kahn, Andrea and Harting, Inga and Horn, Denise and Hughes, Joanne and Huijberts, Maya and Isidor, Bertrand and Kathemann, Simone and Kopajtich, Robert and Kotzaeridou, Urania and K{\"u}ry, S{\'e}bastien and Lainka, Elke and Laugwitz, Lucia and Lupski, James R and Posey, Jennifer E and Reynolds, Claire and Rosenfeld, Jill A and Schr{\"o}ter, Julian and Vansenne, Fleur and Wagner, Matias and Wei{\ss}, Claudia and Wolffenbuttel, Bruce H R and Wortmann, Saskia B and K{\"o}lker, Stefan and Hoffmann, Georg F and Prokisch, Holger and Mendes, Marisa I and Staufner, Christian} } @article {757, title = {Gomez-L{\'o}pez-Hern{\'a}ndez syndrome: A case report with clinical and molecular evaluation and literature review.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 07}, pages = {1761-1766}, abstract = {

Gomez-L{\'o}pez-Hern{\'a}ndez syndrome (GLHS) is characterized by rhombencephalosynapsis (RES), alopecia, trigeminal anesthesia and a distinctive phenotype, including brachyturricephaly. It has been suggested that GLHS should be considered as part of the spectrum of RES-associated conditions that include alopecia, trigeminal anesthesia, and craniofacial anomalies, rather than a distinct entity. To the best of our knowledge, 57 patients with GLHS have been described. Despite its first description in 1979, the etiology of this syndrome remains unknown. Here, we describe, to our knowledge, the first case of a patient with GLHS who was molecularly evaluated and had been prenatally exposed to misoprostol. We also reviewed the clinical and morphological features of the patients described to date to better delineate the phenotype and focus on any evidence for adverse pregnancy outcomes or exposure, including teratogens.

}, keywords = {Abnormalities, Multiple, Alopecia, Cerebellum, Child, Child, Preschool, Craniofacial Abnormalities, Female, Growth Disorders, Humans, Magnetic Resonance Imaging, Misoprostol, Neurocutaneous Syndromes, Phenotype, Rhombencephalon, Trigeminal Nerve}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61594}, author = {Perrone, Eduardo and D{\textquoteright}Almeida, V{\^a}nia and de Macena Sobreira, Nara Lygia and de Mello, Claudia Berlim and de Oliveira, Allan Chiaratti and Burlin, St{\^e}nio and Soares, Maria de F{\'a}tima de Faria and Cernach, Mirlene Cec{\'\i}lia Soares Pinho and Alvarez Perez, Ana Beatriz} } @article {818, title = {HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 07 10}, pages = {202-207}, abstract = {

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in , which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.

}, keywords = {Actins, ADP-Ribosylation Factor 1, CD4-Positive T-Lymphocytes, Cell Proliferation, Cytokines, Humans, Immunologic Deficiency Syndromes, Lymphoproliferative Disorders, Mechanistic Target of Rapamycin Complex 2, Membrane Proteins, Pedigree, Phosphorylation, Wiskott-Aldrich Syndrome Protein Family}, issn = {1095-9203}, doi = {10.1126/science.aay5663}, author = {Cook, Sarah A and Comrie, William A and Poli, M Cecilia and Similuk, Morgan and Oler, Andrew J and Faruqi, Aiman J and Kuhns, Douglas B and Yang, Sheng and Vargas-Hernandez, Alexander and Carisey, Alexandre F and Fournier, Benjamin and Anderson, D Eric and Price, Susan and Smelkinson, Margery and Abou Chahla, Wadih and Forbes, Lisa R and Mace, Emily M and Cao, Tram N and Coban-Akdemir, Zeynep H and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Cuvelier, Geoffrey D E and Al Hassani, Moza and Al Kaabi, Nawal and Al Yafei, Zain and Jyonouchi, Soma and Raje, Nikita and Caldwell, Jason W and Huang, Yanping and Burkhardt, Janis K and Latour, Sylvain and Chen, Baoyu and ElGhazali, Gehad and Rao, V Koneti and Chinn, Ivan K and Lenardo, Michael J} } @article {857, title = {Heterozygous Gene Deficiency and Risk of Coronary Artery Disease.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 10}, pages = {417-423}, abstract = {

BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1\% in or .

RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1\% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95\% CI, 14-35]; =1.1{\texttimes}10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95\% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002871}, author = {Nomura, Akihiro and Emdin, Connor A and Won, Hong Hee and Peloso, Gina M and Natarajan, Pradeep and Ardissino, Diego and Danesh, John and Schunkert, Heribert and Correa, Adolfo and Bown, Matthew J and Samani, Nilesh J and Erdmann, Jeanette and McPherson, Ruth and Watkins, Hugh and Saleheen, Danish and Elosua, Roberto and Kawashiri, Masa-Aki and Tada, Hayato and Gupta, Namrata and Shah, Svati H and Rader, Daniel J and Gabriel, Stacey and Khera, Amit V and Kathiresan, Sekar} } @article {954, title = {Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome.}, journal = {Kidney Int}, volume = {98}, year = {2020}, month = {2020 10}, pages = {1020-1030}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUTs) are the most common cause of chronic kidney disease in children. Human 16p11.2 deletions have been associated with CAKUT, but the responsible molecular mechanism remains to be illuminated. To explore this, we investigated 102 carriers of 16p11.2 deletion from multi-center cohorts, among which we retrospectively ascertained kidney morphologic and functional data from 37 individuals (12 Chinese and 25 Caucasian/Hispanic). Significantly higher CAKUT rates were observed in 16p11.2 deletion carriers (about 25\% in Chinese and 16\% in Caucasian/Hispanic) than those found in the non-clinically ascertained general populations (about 1/1000 found at autopsy). Furthermore, we identified seven additional individuals with heterozygous loss-of-function variants in TBX6, a gene that maps to the 16p11.2 region. Four of these seven cases showed obvious CAKUT. To further investigate the role of TBX6 in kidney development, we engineered mice with mutated Tbx6 alleles. The Tbx6 heterozygous null (i.e., loss-of-function) mutant (Tbx6) resulted in 13\% solitary kidneys. Remarkably, this incidence increased to 29\% in a compound heterozygous model (Tbx6) that reduced Tbx6 gene dosage to below haploinsufficiency, by combining the null allele with a novel mild hypomorphic allele (mh). Renal hypoplasia was also frequently observed in these Tbx6-mutated mouse models. Thus, our findings in patients and mice establish TBX6 as a novel gene involved in CAKUT and its gene dosage insufficiency as a potential driver for kidney defects observed in the 16p11.2 microdeletion syndrome.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2020.04.045}, author = {Yang, Nan and Wu, Nan and Dong, Shuangshuang and Zhang, Ling and Zhao, Yanxue and Chen, Weisheng and Du, Renqian and Song, Chengcheng and Ren, Xiaojun and Liu, Jiaqi and Pehlivan, Davut and Liu, Zhenlei and Rao, Jia and Wang, Chunyan and Zhao, Sen and Breman, Amy M and Xue, Huadan and Sun, Hao and Shen, Jianxiong and Zhang, Shuyang and Posey, Jennifer E and Xu, Hong and Jin, Li and Zhang, Jianguo and Liu, Pengfei and Sanna-Cherchi, Simone and Qiu, Guixing and Wu, Zhihong and Lupski, James R and Zhang, Feng} } @article {937, title = {Human NK cell deficiency as a result of biallelic mutations in MCM10.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 10 01}, pages = {5272-5286}, abstract = {

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.

}, keywords = {Alleles, Cell Cycle Checkpoints, Cell Differentiation, Cell Line, Codon, Nonsense, DNA Damage, Fatal Outcome, Female, Gene Knockdown Techniques, Heterozygote, Humans, Induced Pluripotent Stem Cells, Infant, Killer Cells, Natural, Male, Minichromosome Maintenance Proteins, Models, Immunological, Mutation, Mutation, Missense, Pedigree, Primary Immunodeficiency Diseases}, issn = {1558-8238}, doi = {10.1172/JCI134966}, author = {Mace, Emily M and Paust, Silke and Conte, Matilde I and Baxley, Ryan M and Schmit, Megan M and Patil, Sagar L and Guilz, Nicole C and Mukherjee, Malini and Pezzi, Ashley E and Chmielowiec, Jolanta and Tatineni, Swetha and Chinn, Ivan K and Akdemir, Zeynep Coban and Jhangiani, Shalini N and Muzny, Donna M and Stray-Pedersen, Asbj{\o}rg and Bradley, Rachel E and Moody, Mo and Connor, Philip P and Heaps, Adrian G and Steward, Colin and Banerjee, Pinaki P and Gibbs, Richard A and Borowiak, Malgorzata and Lupski, James R and Jolles, Stephen and Bielinsky, Anja K and Orange, Jordan S} } @article {837, title = {The impact of sex on gene expression across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37\% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

}, keywords = {Chromosomes, Human, X, Disease, Epigenesis, Genetic, Female, Gene Expression, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Male, Organ Specificity, Promoter Regions, Genetic, Quantitative Trait Loci, Sex Characteristics, Sex Factors}, issn = {1095-9203}, doi = {10.1126/science.aba3066}, author = {Oliva, Meritxell and Mu{\~n}oz-Aguirre, Manuel and Kim-Hellmuth, Sarah and Wucher, Valentin and Gewirtz, Ariel D H and Cotter, Daniel J and Parsana, Princy and Kasela, Silva and Balliu, Brunilda and Vi{\~n}uela, Ana and Castel, Stephane E and Mohammadi, Pejman and Aguet, Francois and Zou, Yuxin and Khramtsova, Ekaterina A and Skol, Andrew D and Garrido-Mart{\'\i}n, Diego and Reverter, Ferran and Brown, Andrew and Evans, Patrick and Gamazon, Eric R and Payne, Anthony and Bonazzola, Rodrigo and Barbeira, Alvaro N and Hamel, Andrew R and Martinez-Perez, Angel and Soria, Jos{\'e} Manuel and Pierce, Brandon L and Stephens, Matthew and Eskin, Eleazar and Dermitzakis, Emmanouil T and Segr{\`e}, Ayellet V and Im, Hae Kyung and Engelhardt, Barbara E and Ardlie, Kristin G and Montgomery, Stephen B and Battle, Alexis J and Lappalainen, Tuuli and Guig{\'o}, Roderic and Stranger, Barbara E} } @article {903, title = {Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, abstract = {

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5\%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Asymptomatic Infections, Betacoronavirus, Child, Child, Preschool, Coronavirus Infections, COVID-19, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Infant, Interferon Regulatory Factor-7, Interferon Type I, Loss of Function Mutation, Male, Middle Aged, Pandemics, Pneumonia, Viral, Receptor, Interferon alpha-beta, SARS-CoV-2, Toll-Like Receptor 3, Young Adult}, issn = {1095-9203}, doi = {10.1126/science.abd4570}, author = {Zhang, Qian and Bastard, Paul and Liu, Zhiyong and Le Pen, J{\'e}r{\'e}mie and Moncada-Velez, Marcela and Chen, Jie and Ogishi, Masato and Sabli, Ira K D and Hodeib, Stephanie and Korol, Cecilia and Rosain, J{\'e}r{\'e}mie and Bilguvar, Kaya and Ye, Junqiang and Bolze, Alexandre and Bigio, Benedetta and Yang, Rui and Arias, Andr{\'e}s Augusto and Zhou, Qinhua and Zhang, Yu and Onodi, Fanny and Korniotis, Sarantis and Karpf, L{\'e}a and Philippot, Quentin and Chbihi, Marwa and Bonnet-Madin, Lucie and Dorgham, Karim and Smith, Nika{\"\i}a and Schneider, William M and Razooky, Brandon S and Hoffmann, Hans-Heinrich and Michailidis, Eleftherios and Moens, Leen and Han, Ji Eun and Lorenzo, Lazaro and Bizien, Lucy and Meade, Philip and Neehus, Anna-Lena and Ugurbil, Aileen Camille and Corneau, Aur{\'e}lien and Kerner, Gaspard and Zhang, Peng and Rapaport, Franck and Seeleuthner, Yoann and Manry, Jeremy and Masson, Cecile and Schmitt, Yohann and Schluter, Agatha and Le Voyer, Tom and Khan, Taushif and Li, Juan and Fellay, Jacques and Roussel, Lucie and Shahrooei, Mohammad and Alosaimi, Mohammed F and Mansouri, Davood and Al-Saud, Haya and Al-Mulla, Fahd and Almourfi, Feras and Al-Muhsen, Saleh Zaid and Alsohime, FAHd and Al Turki, Saeed and Hasanato, Rana and van de Beek, Diederik and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio{\textquoteright}, Mariella and Bonfanti, Paolo and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Oler, Andrew J and Tompkins, Miranda F and Alba, Camille and Vandernoot, Isabelle and Goffard, Jean-Christophe and Smits, Guillaume and Migeotte, Isabelle and Haerynck, Filomeen and Soler-Palacin, Pere and Martin-Nalda, Andrea and Colobran, Roger and Morange, Pierre-Emmanuel and Keles, Sevgi and {\c C}{\"o}lkesen, Fatma and Ozcelik, Tayfun and Yasar, Kadriye Kart and Senoglu, Sevtap and Karabela, {\c S}emsi Nur and Rodr{\'\i}guez-Gallego, Carlos and Novelli, Giuseppe and Hraiech, Sami and Tandjaoui-Lambiotte, Yacine and Duval, Xavier and Laou{\'e}nan, C{\'e}dric and Snow, Andrew L and Dalgard, Clifton L and Milner, Joshua D and Vinh, Donald C and Mogensen, Trine H and Marr, Nico and Spaan, Andr{\'a}s N and Boisson, Bertrand and Boisson-Dupuis, St{\'e}phanie and Bustamante, Jacinta and Puel, Anne and Ciancanelli, Michael J and Meyts, Isabelle and Maniatis, Tom and Soumelis, Vassili and Amara, Ali and Nussenzweig, Michel and Garc{\'\i}a-Sastre, Adolfo and Krammer, Florian and Pujol, Aurora and Duffy, Darragh and Lifton, Richard P and Zhang, Shen-Ying and Gorochov, Guy and B{\'e}ziat, Vivien and Jouanguy, Emmanuelle and Sancho-Shimizu, Vanessa and Rice, Charles M and Abel, Laurent and Notarangelo, Luigi D and Cobat, Aurelie and Su, Helen C and Casanova, Jean-Laurent} } @article {835, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {763-768}, abstract = {

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is~termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP~driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

}, keywords = {Adult, Africa, African Continental Ancestry Group, Aged, Aged, 80 and over, alpha Karyopherins, Cell Self Renewal, Clonal Hematopoiesis, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Hematopoietic Stem Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Precision Medicine, Proto-Oncogene Proteins, Tripartite Motif Proteins, United States, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2819-2}, author = {Bick, Alexander G and Weinstock, Joshua S and Nandakumar, Satish K and Fulco, Charles P and Bao, Erik L and Zekavat, Seyedeh M and Szeto, Mindy D and Liao, Xiaotian and Leventhal, Matthew J and Nasser, Joseph and Chang, Kyle and Laurie, Cecelia and Burugula, Bala Bharathi and Gibson, Christopher J and Lin, Amy E and Taub, Margaret A and Aguet, Francois and Ardlie, Kristin and Mitchell, Braxton D and Barnes, Kathleen C and Moscati, Arden and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Silverman, Edwin K and Weiss, Scott T and Palmer, Nicholette D and Vasan, Ramachandran S and Burchard, Esteban G and Kardia, Sharon L R and He, Jiang and Kaplan, Robert C and Smith, Nicholas L and Arnett, Donna K and Schwartz, David A and Correa, Adolfo and de Andrade, Mariza and Guo, Xiuqing and Konkle, Barbara A and Custer, Brian and Peralta, Juan M and Gui, Hongsheng and Meyers, Deborah A and McGarvey, Stephen T and Chen, Ida Yii-Der and Shoemaker, M Benjamin and Peyser, Patricia A and Broome, Jai G and Gogarten, Stephanie M and Wang, Fei Fei and Wong, Quenna and Montasser, May E and Daya, Michelle and Kenny, Eimear E and North, Kari E and Launer, Lenore J and Cade, Brian E and Bis, Joshua C and Cho, Michael H and Lasky-Su, Jessica and Bowden, Donald W and Cupples, L Adrienne and Mak, Angel C Y and Becker, Lewis C and Smith, Jennifer A and Kelly, Tanika N and Aslibekyan, Stella and Heckbert, Susan R and Tiwari, Hemant K and Yang, Ivana V and Heit, John A and Lubitz, Steven A and Johnsen, Jill M and Curran, Joanne E and Wenzel, Sally E and Weeks, Daniel E and Rao, Dabeeru C and Darbar, Dawood and Moon, Jee-Young and Tracy, Russell P and Buth, Erin J and Rafaels, Nicholas and Loos, Ruth J F and Durda, Peter and Liu, Yongmei and Hou, Lifang and Lee, Jiwon and Kachroo, Priyadarshini and Freedman, Barry I and Levy, Daniel and Bielak, Lawrence F and Hixson, James E and Floyd, James S and Whitsel, Eric A and Ellinor, Patrick T and Irvin, Marguerite R and Fingerlin, Tasha E and Raffield, Laura M and Armasu, Sebastian M and Wheeler, Marsha M and Sabino, Ester C and Blangero, John and Williams, L Keoki and Levy, Bruce D and Sheu, Wayne Huey-Herng and Roden, Dan M and Boerwinkle, Eric and Manson, JoAnn E and Mathias, Rasika A and Desai, Pinkal and Taylor, Kent D and Johnson, Andrew D and Auer, Paul L and Kooperberg, Charles and Laurie, Cathy C and Blackwell, Thomas W and Smith, Albert V and Zhao, Hongyu and Lange, Ethan and Lange, Leslie and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Scheet, Paul and Kitzman, Jacob O and Lander, Eric S and Engreitz, Jesse M and Ebert, Benjamin L and Reiner, Alexander P and Jaiswal, Siddhartha and Abecasis, Gon{\c c}alo and Sankaran, Vijay G and Kathiresan, Sekar and Natarajan, Pradeep} } @article {920, title = {KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 12 05}, pages = {3242-3261}, abstract = {

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden{\textquoteright}s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50\% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30\%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30\% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2\%) and cervical (50.5\%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9\% at 1 year to 16.2\% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9\%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Cohort Studies, Computer Simulation, Deep Brain Stimulation, Disease Progression, Dystonic Disorders, Endocrine System Diseases, Female, Fetal Growth Retardation, Gait Disorders, Neurologic, Histone-Lysine N-Methyltransferase, Humans, Laryngeal Diseases, Male, Mutation, Mutation, Missense, Phenotype, Quality of Life, Treatment Outcome, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awaa304}, author = {Cif, Laura and Demailly, Diane and Lin, Jean-Pierre and Barwick, Katy E and Sa, Mario and Abela, Lucia and Malhotra, Sony and Chong, Wui K and Steel, Dora and Sanchis-Juan, Alba and Ngoh, Adeline and Trump, Natalie and Meyer, Esther and Vasques, Xavier and Rankin, Julia and Allain, Meredith W and Applegate, Carolyn D and Attaripour IsfAHni, Sanaz and Baleine, Julien and Balint, Bettina and Bassetti, Jennifer A and Baple, Emma L and Bhatia, Kailash P and Blanchet, Catherine and Burglen, Lydie and Cambonie, Gilles and Seng, Emilie Chan and Bastaraud, Sandra Chantot and Cyprien, Fabienne and Coubes, Christine and d{\textquoteright}Hardemare, Vincent and Doja, Asif and Dorison, Nathalie and Doummar, Diane and Dy-Hollins, Marisela E and Farrelly, Ellyn and FitzPatrick, David R and Fearon, Conor and Fieg, Elizabeth L and Fogel, Brent L and Forman, Eva B and Fox, Rachel G and Gahl, William A and Galosi, Serena and Gonzalez, Victoria and Graves, Tracey D and Gregory, Allison and Hallett, Mark and Hasegawa, Harutomo and Hayflick, Susan J and Hamosh, Ada and Hully, Marie and Jansen, Sandra and Jeong, Suh Young and Krier, Joel B and Krystal, Sidney and Kumar, Kishore R and Laurencin, Chlo{\'e} and Lee, Hane and Lesca, Gaetan and Fran{\c c}ois, Laurence Lion and Lynch, Timothy and MAHnt, Neil and Martinez-Agosto, Julian A and Milesi, Christophe and Mills, Kelly A and Mondain, Michel and Morales-Briceno, Hugo and Ostergaard, John R and Pal, Swasti and Pallais, Juan C and Pavillard, Fr{\'e}d{\'e}rique and Perrigault, Pierre-Francois and Petersen, Andrea K and Polo, Gustavo and Poulen, Gaetan and Rinne, Tuula and Roujeau, Thomas and Rogers, Caleb and Roubertie, Agathe and SAHgian, Michelle and Schaefer, Elise and Selim, Laila and Selway, Richard and Sharma, Nutan and Signer, Rebecca and Soldatos, Ariane G and Stevenson, David A and Stewart, Fiona and Tchan, Michel and Verma, Ishwar C and de Vries, Bert B A and Wilson, Jenny L and Wong, Derek A and Zaitoun, Raghda and Zhen, Dolly and Znaczko, Anna and Dale, Russell C and de Gusm{\~a}o, Claudio M and Friedman, Jennifer and Fung, Victor S C and King, Mary D and Mohammad, Shekeeb S and Rohena, Luis and Waugh, Jeff L and Toro, Camilo and Raymond, F Lucy and Topf, Maya and Coubes, Philippe and Gorman, Kathleen M and Kurian, Manju A} } @article {785, title = {Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 05 27}, pages = {2539}, abstract = {

Multi-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs.

}, keywords = {CpG Islands, Databases, Genetic, DNA Mutational Analysis, Exome, Genetic Variation, Genome, Human, Humans, Mutation}, issn = {2041-1723}, doi = {10.1038/s41467-019-12438-5}, author = {Wang, Qingbo and Pierce-Hoffman, Emma and Cummings, Beryl B and Alf{\"o}ldi, Jessica and Francioli, Laurent C and Gauthier, Laura D and Hill, Andrew J and O{\textquoteright}Donnell-Luria, Anne H and Karczewski, Konrad J and MacArthur, Daniel G} } @article {830, title = {Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.}, journal = {Cell}, volume = {180}, year = {2020}, month = {2020 02 06}, pages = {568-584.e23}, abstract = {

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n~= 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

}, keywords = {Autistic Disorder, Case-Control Studies, Cell Lineage, Cerebral Cortex, Cohort Studies, Exome, Female, Gene Expression Regulation, Developmental, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Neurobiology, Neurons, Phenotype, Sex Factors, Single-Cell Analysis, Whole Exome Sequencing}, issn = {1097-4172}, doi = {10.1016/j.cell.2019.12.036}, author = {Satterstrom, F Kyle and Kosmicki, Jack A and Wang, Jiebiao and Breen, Michael S and De Rubeis, Silvia and An, Joon-Yong and Peng, Minshi and Collins, Ryan and Grove, Jakob and Klei, Lambertus and Stevens, Christine and Reichert, Jennifer and Mulhern, Maureen S and Artomov, Mykyta and Gerges, Sherif and Sheppard, Brooke and Xu, Xinyi and Bhaduri, Aparna and Norman, Utku and Brand, Harrison and Schwartz, Grace and Nguyen, Rachel and Guerrero, Elizabeth E and Dias, Caroline and Betancur, Catalina and Cook, Edwin H and Gallagher, Louise and Gill, Michael and Sutcliffe, James S and Thurm, Audrey and Zwick, Michael E and B{\o}rglum, Anders D and State, Matthew W and Cicek, A Ercument and Talkowski, Michael E and Cutler, David J and Devlin, Bernie and Sanders, Stephan J and Roeder, Kathryn and Daly, Mark J and Buxbaum, Joseph D} } @article {811, title = {Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 12}, pages = {2020-2028}, abstract = {

PURPOSE: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes.

METHODS: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups.

RESULTS: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 {\texttimes} 10). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 {\texttimes} 10). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12-17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases.

CONCLUSION: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

}, keywords = {Child, Hernias, Diaphragmatic, Congenital, Humans, Infant, Newborn, Retrospective Studies}, issn = {1530-0366}, doi = {10.1038/s41436-020-0908-0}, author = {Qiao, Lu and Wynn, Julia and Yu, Lan and Hernan, Rebecca and Zhou, Xueya and Duron, Vincent and Aspelund, Gudrun and Farkouh-Karoleski, Christiana and Zygumunt, Annette and Krishnan, Usha S and Nees, Shannon and Khlevner, Julie and Lim, Foong Yen and Crombleholme, Timothy and Cusick, Robert and Azarow, Kenneth and Danko, Melissa Ellen and Chung, Dai and Warner, Brad W and Mychaliska, George B and Potoka, Douglas and Wagner, Amy J and Soffer, Samuel and Schindel, David and McCulley, David J and Shen, Yufeng and Chung, Wendy K} } @article {926, title = {Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 12}, pages = {2179-2194}, abstract = {

Ciliopathies are clinically and genetically heterogeneous diseases. We studied three patients from two independent families presenting with features of Joubert syndrome: abnormal breathing pattern during infancy, developmental delay/intellectual disability, cerebellar ataxia, molar tooth sign on magnetic resonance imaging scans, and polydactyly. We identified biallelic loss-of-function (LOF) variants in CBY1, segregating with the clinical features of Joubert syndrome in the families. CBY1 localizes to the distal end of the mother centriole, contributing to the formation and function of cilia. In accordance with the clinical and mutational findings in the affected individuals, we demonstrated that depletion of Cby1 in zebrafish causes ciliopathy-related phenotypes. Levels of CBY1 transcript were found reduced in the patients compared with controls, suggesting degradation of the mutated transcript through nonsense-mediated messenger RNA decay. Accordingly, we could detect CBY1 protein in fibroblasts from controls, but not from patients by immunofluorescence. Furthermore, we observed reduced ability to ciliate, increased ciliary length, and reduced levels of the ciliary proteins AHI1 and ARL13B in patient fibroblasts. Our data show that CBY1 LOF-variants cause a ciliopathy with features of Joubert syndrome.

}, issn = {1098-1004}, doi = {10.1002/humu.24127}, author = {Epting, Daniel and Senaratne, Lokuliyange D S and Ott, Elisabeth and Holmgren, Asbj{\o}rn and Sumathipala, Dulika and Larsen, Selma M and Wallmeier, Julia and Bracht, Diana and Frikstad, Kari-Anne M and Crowley, Suzanne and Sikiric, Alma and Bar{\o}y, Tuva and K{\"a}smann-Kellner, Barbara and Decker, Eva and Decker, Christian and Bachmann, Nadine and Patzke, Sebastian and Phelps, Ian G and Katsanis, Nicholas and Giles, Rachel and Schmidts, Miriam and Zucknick, Manuela and Lienkamp, Soeren S and Omran, Heymut and Davis, Erica E and Doherty, Dan and Str{\o}mme, Petter and Frengen, Eirik and Bergmann, Carsten and Misceo, Doriana} } @article {915, title = {Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 11}, pages = {1768-1776}, abstract = {

PURPOSE: The goal of this study was to assess the scale of low-level parental mosaicism in exome sequencing (ES) databases.

METHODS: We analyzed approximately 2000 family trio ES data sets from the Baylor-Hopkins Center for Mendelian Genomics (BHCMG) and Baylor Genetics (BG). Among apparent de novo single-nucleotide variants identified in the affected probands, we selected rare unique variants with variant allele fraction (VAF) between 30\% and 70\% in the probands and lower than 10\% in one of the parents.

RESULTS: Of 102 candidate mosaic variants validated using amplicon-based next-generation sequencing, droplet digital polymerase chain reaction, or blocker displacement amplification, 27 (26.4\%) were confirmed to be low- (VAF between 1\% and 10\%) or very low (VAF <1\%) level mosaic. Detection precision in parental samples with two or more alternate reads was 63.6\% (BHCMG) and 43.6\% (BG). In nine investigated individuals, we observed variability of mosaic ratios among blood, saliva, fibroblast, buccal, hair, and urine samples.

CONCLUSION: Our computational pipeline enables robust discrimination between true and false positive candidate mosaic variants and efficient detection of low-level mosaicism in ES samples. We confirm that the presence of two or more alternate reads in the parental sample is a reliable predictor of low-level parental somatic mosaicism.

}, keywords = {Exome, High-Throughput Nucleotide Sequencing, Humans, Mosaicism, Parents, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-0897-z}, author = {Gambin, Tomasz and Liu, Qian and Karolak, Justyna A and Grochowski, Christopher M and Xie, Nina G and Wu, Lucia R and Yan, Yan Helen and Cao, Ye and Coban Akdemir, Zeynep H and Wilson, Theresa A and Jhangiani, Shalini N and Chen, Ed and Eng, Christine M and Muzny, Donna and Posey, Jennifer E and Yang, Yaping and Zhang, David Y and Shaw, Chad and Liu, Pengfei and Lupski, James R and Stankiewicz, Pawe{\l}} } @article {843, title = {Major Impacts of Widespread Structural Variation on Gene Expression and Crop Improvement in Tomato.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 07 09}, pages = {145-161.e23}, abstract = {

Structural variants (SVs) underlie important crop improvement and domestication traits. However, resolving the extent, diversity, and quantitative impact of SVs has been challenging. We used long-read nanopore sequencing to capture 238,490 SVs in 100 diverse tomato lines. This panSV genome, along with 14 new reference assemblies, revealed large-scale intermixing of diverse genotypes, as well as thousands of SVs intersecting genes and cis-regulatory regions. Hundreds of SV-gene pairs exhibit subtle and significant expression changes, which could broadly influence quantitative trait variation. By combining quantitative genetics with genome editing, we show how multiple SVs that changed gene dosage and expression levels modified fruit flavor, size, and production. In the last example, higher order epistasis among four SVs affecting three related transcription factors allowed introduction of an important harvesting trait in modern tomato. Our findings highlight the underexplored role of SVs in genotype-to-phenotype relationships and their widespread importance and utility in crop improvement.

}, keywords = {Alleles, Crops, Agricultural, Cytochrome P-450 Enzyme System, Ecotype, Epistasis, Genetic, Fruit, Gene Duplication, Gene Expression Regulation, Plant, Genome, Plant, Genomic Structural Variation, Genotype, Inbreeding, Lycopersicon esculentum, Molecular Sequence Annotation, Phenotype, Plant Breeding, Quantitative Trait Loci}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.05.021}, author = {Alonge, Michael and Wang, Xingang and Benoit, Matthias and Soyk, Sebastian and Pereira, Lara and Zhang, Lei and Suresh, Hamsini and Ramakrishnan, Srividya and Maumus, Florian and Ciren, Danielle and Levy, Yuval and Harel, Tom Hai and Shalev-Schlosser, Gili and Amsellem, Ziva and Razifard, Hamid and Caicedo, Ana L and Tieman, Denise M and Klee, Harry and Kirsche, Melanie and Aganezov, Sergey and Ranallo-Benavidez, T Rhyker and Lemmon, Zachary H and Kim, Jennifer and Robitaille, Gina and Kramer, Melissa and Goodwin, Sara and McCombie, W Richard and Hutton, Samuel and Van Eck, Joyce and Gillis, Jesse and Eshed, Yuval and Sedlazeck, Fritz J and van der Knaap, Esther and Schatz, Michael C and Lippman, Zachary B} } @article {810, title = {Missed diagnoses: Clinically relevant lessons learned through medical mysteries solved by the Undiagnosed Diseases Network.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 10}, pages = {e1397}, abstract = {

BACKGROUND: Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently difficult to access by clinical providers. While these resources do contribute to diagnoses in many cases, they are not always necessary to reach diagnostic resolution. The UDN experience has been that participants can also receive diagnoses through the thoughtful and customized application of approaches and resources that are readily available in clinical settings.

METHODS: The UDN Genetic Counseling and Testing Working Group collected case vignettes that illustrated how clinically available methods resulted in diagnoses. The case vignettes were classified into three themes; phenotypic considerations, selection of genetic testing, and evaluating exome/GS variants and data.

RESULTS: We present 12 participants that illustrate how clinical practices such as phenotype-driven genomic investigations, consideration of variable expressivity, selecting the relevant tissue of interest for testing, utilizing updated testing platforms, and recognition of alternate transcript nomenclature resulted in diagnoses.

CONCLUSION: These examples demonstrate that when a diagnosis is elusive, an iterative patient-specific approach utilizing assessment options available to clinical providers may solve a portion of cases. However, this does require increased provider time commitment, a particular challenge in the current practice of genomics.

}, keywords = {Adolescent, Child, Child, Preschool, Databases, Factual, Diagnosis, Computer-Assisted, Female, Genetic Diseases, Inborn, Genetic Testing, Humans, Information Dissemination, Male, Middle Aged, Missed Diagnosis, National Institutes of Health (U.S.), Phenotype, Precision Medicine, Undiagnosed Diseases, United States, Young Adult}, issn = {2324-9269}, doi = {10.1002/mgg3.1397}, author = {Cope, Heidi and Spillmann, Rebecca and Rosenfeld, Jill A and Brokamp, Elly and Signer, Rebecca and Schoch, Kelly and Kelley, Emily G and Sullivan, Jennifer A and Macnamara, Ellen and Lincoln, Sharyn and Golden-Grant, Katie and Orengo, James P and Clark, Gary and Burrage, Lindsay C and Posey, Jennifer E and Punetha, Jaya and Robertson, Amy and Cogan, Joy and Phillips, John A and Martinez-Agosto, Julian and Shashi, Vandana} } @article {749, title = {A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability.}, journal = {FEBS Lett}, volume = {594}, year = {2020}, month = {2020 02}, pages = {717-727}, abstract = {

X-linked intellectual disabilities (XLID) are common developmental disorders. The enzyme O-GlcNAc transferase encoded by OGT, a recently discovered XLID gene, attaches O-GlcNAc to nuclear and cytoplasmic proteins. As few missense mutations have been described, it is unclear what the aetiology of the patient phenotypes is. Here, we report the discovery of a missense mutation in the catalytic domain of OGT in an XLID patient. X-ray crystallography reveals that this variant leads to structural rearrangements in the catalytic domain. The mutation reduces in~vitro OGT activity on substrate peptides/protein. Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase (OGA) and global O-GlcNAc levels. These data suggest a direct link between changes in the O-GlcNAcome and intellectual disability observed in patients carrying OGT mutations.

}, keywords = {Animals, Catalytic Domain, Cell Line, Glycosylation, Humans, Intellectual Disability, Mice, Models, Molecular, Mutation, Missense, N-Acetylglucosaminyltransferases}, issn = {1873-3468}, doi = {10.1002/1873-3468.13640}, author = {Pravata, Veronica M and Gundogdu, Mehmet and Bartual, Sergio G and Ferenbach, Andrew T and Stavridis, Marios and {\~O}unap, Katrin and Pajusalu, Sander and {\v Z}ordania, Riina and Wojcik, Monica H and van Aalten, Daan M F} } @article {913, title = {Missense variant contribution to USP9X-female syndrome.}, journal = {NPJ Genom Med}, volume = {5}, year = {2020}, month = {2020 Dec 09}, pages = {53}, abstract = {

USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.

}, issn = {2056-7944}, doi = {10.1038/s41525-020-00162-9}, author = {Jolly, Lachlan A and Parnell, Euan and Gardner, Alison E and Corbett, Mark A and P{\'e}rez-Jurado, Luis A and Shaw, Marie and Lesca, Gaetan and Keegan, Catherine and Schneider, Michael C and Griffin, Emily and Maier, Felicitas and Kiss, Courtney and Guerin, Andrea and Crosby, Kathleen and Rosenbaum, Kenneth and Tanpaiboon, Pranoot and Whalen, Sandra and Keren, Boris and McCarrier, Julie and Basel, Donald and Sadedin, Simon and White, Susan M and Delatycki, Martin B and Kleefstra, Tjitske and K{\"u}ry, S{\'e}bastien and Brusco, Alfredo and Sukarova-Angelovska, Elena and Trajkova, Slavica and Yoon, Sehoun and Wood, Stephen A and Piper, Michael and Penzes, Peter and Gecz, Jozef} } @article {770, title = {MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 01 01}, pages = {55-68}, abstract = {

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3{\textquoteright} region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

}, keywords = {Abnormalities, Multiple, Adolescent, Basilar Artery, Carotid Arteries, Cerebellar Vermis, Cerebellum, Child, Child, Preschool, Cohort Studies, Comparative Genomic Hybridization, Craniofacial Abnormalities, Female, Fibroblasts, Humans, Imaging, Three-Dimensional, Infant, Intellectual Disability, Language Development Disorders, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Nervous System Malformations, Nonsense Mediated mRNA Decay, Polymicrogyria, Real-Time Polymerase Chain Reaction, RNA-Seq, Syndrome, Tomography, X-Ray Computed, Trans-Activators, Tumor Suppressor Proteins, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1460-2156}, doi = {10.1093/brain/awz379}, author = {Mak, Christopher C Y and Doherty, Dan and Lin, Angela E and Vegas, Nancy and Cho, Megan T and Viot, G{\'e}raldine and Dimartino, Cl{\'e}mantine and Weisfeld-Adams, James D and Lessel, Davor and Joss, Shelagh and Li, Chumei and Gonzaga-Jauregui, Claudia and Zarate, Yuri A and Ehmke, Nadja and Horn, Denise and Troyer, Caitlin and Kant, Sarina G and Lee, Youngha and Ishak, Gisele E and Leung, Gordon and Barone Pritchard, Amanda and Yang, Sandra and Bend, Eric G and Filippini, Francesca and Roadhouse, Chelsea and Lebrun, Nicolas and Mehaffey, Michele G and Martin, Pierre-Marie and Apple, Benjamin and Millan, Francisca and Puk, Oliver and Hoffer, Mariette J V and Henderson, Lindsay B and McGowan, Ruth and Wentzensen, Ingrid M and Pei, Steven and Zahir, Farah R and Yu, Mullin and Gibson, William T and Seman, Ann and Steeves, Marcie and Murrell, Jill R and Luettgen, Sabine and Francisco, Elizabeth and Strom, Tim M and Amlie-Wolf, Louise and Kaindl, Angela M and Wilson, William G and Halbach, Sara and Basel-Salmon, Lina and Lev-El, Noa and Denecke, Jonas and Vissers, Lisenka E L M and Radtke, Kelly and Chelly, Jamel and Zackai, Elaine and Friedman, Jan M and Bamshad, Michael J and Nickerson, Deborah A and Reid, Russell R and Devriendt, Koenraad and Chae, Jong-Hee and Stolerman, Elliot and McDougall, Carey and Powis, Z{\"o}e and Bienvenu, Thierry and Tan, Tiong Y and Orenstein, Naama and Dobyns, William B and Shieh, Joseph T and Choi, Murim and Waggoner, Darrel and Gripp, Karen W and Parker, Michael J and Stoler, Joan and Lyonnet, Stanislas and Cormier-Daire, Val{\'e}rie and Viskochil, David and Hoffman, Trevor L and Amiel, Jeanne and Chung, Brian H Y and Gordon, Christopher T} } @article {906, title = {Monogenic variants in dystonia: an exome-wide sequencing study.}, journal = {Lancet Neurol}, volume = {19}, year = {2020}, month = {2020 11}, pages = {908-918}, abstract = {

BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.

FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19\%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45\%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19\%] of 98) or isolated (16 [4\%] of 388) dystonia. Across all categories of dystonia, 104 (65\%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.

INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

FUNDING: Else Kr{\"o}ner-Fresenius-Stiftung, Technische Universit{\"a}t M{\"u}nchen, Helmholtz Zentrum M{\"u}nchen, Medizinische Universit{\"a}t Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

}, keywords = {Adolescent, Child, Child, Preschool, Dystonia, Exome, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Pedigree, Whole Exome Sequencing, Young Adult}, issn = {1474-4465}, doi = {10.1016/S1474-4422(20)30312-4}, author = {Zech, Michael and Jech, Robert and Boesch, Sylvia and {\v S}korv{\'a}nek, Matej and Weber, Sandrina and Wagner, Matias and Zhao, Chen and Jochim, Angela and Necp{\'a}l, J{\'a}n and Dincer, Yasemin and Vill, Katharina and Distelmaier, Felix and Stoklosa, Malgorzata and Krenn, Martin and Grunwald, Stephan and Bock-Bierbaum, Tobias and Fe{\v c}{\'\i}kov{\'a}, Anna and Havr{\'a}nkov{\'a}, Petra and Roth, Jan and P{\v r}{\'\i}hodov{\'a}, Iva and Adamovi{\v c}ov{\'a}, Miriam and Ulmanov{\'a}, Olga and Bechyn{\v e}, Karel and Danhofer, Pavl{\'\i}na and Vesel{\'y}, Branislav and Ha{\v n}, Vladim{\'\i}r and Pavelekova, Petra and Gdovinov{\'a}, Zuzana and Mantel, Tobias and Meindl, Tobias and Sitzberger, Alexandra and Schr{\"o}der, Sebastian and Blaschek, Astrid and Roser, Timo and Bonfert, Michaela V and Haberlandt, Edda and Plecko, Barbara and Leineweber, Birgit and Berweck, Steffen and Herberhold, Thomas and Langguth, Berthold and {\v S}vantnerov{\'a}, Jana and Min{\'a}r, Michal and Ramos-Rivera, Gonzalo Alonso and Wojcik, Monica H and Pajusalu, Sander and {\~O}unap, Katrin and Schatz, Ulrich A and P{\"o}lsler, Laura and Milenkovic, Ivan and Laccone, Franco and Pilshofer, Veronika and Colombo, Roberto and Patzer, Steffi and Iuso, Arcangela and Vera, Julia and Troncoso, Monica and Fang, Fang and Prokisch, Holger and Wilbert, Friederike and Eckenweiler, Matthias and Graf, Elisabeth and Westphal, Dominik S and Riedhammer, Korbinian M and Brunet, Theresa and Alhaddad, Bader and Berutti, Riccardo and Strom, Tim M and Hecht, Martin and Baumann, Matthias and Wolf, Marc and Telegrafi, Aida and Person, Richard E and Zamora, Francisca Millan and Henderson, Lindsay B and Weise, David and Musacchio, Thomas and Volkmann, Jens and Szuto, Anna and Becker, Jessica and Cremer, Kirsten and Sycha, Thomas and Zimprich, Fritz and Kraus, Verena and Makowski, Christine and Gonzalez-Alegre, Pedro and Bardakjian, Tanya M and Ozelius, Laurie J and Vetro, Annalisa and Guerrini, Renzo and Maier, Esther and Borggraefe, Ingo and Kuster, Alice and Wortmann, Saskia B and Hackenberg, Annette and Steinfeld, Robert and Assmann, Birgit and Staufner, Christian and Opladen, Thomas and R{\r u}{\v z}i{\v c}ka, Ev{\v z}en and Cohn, Ronald D and Dyment, David and Chung, Wendy K and Engels, Hartmut and Ceballos-Baumann, Andres and Ploski, Rafal and Daumke, Oliver and Haslinger, Bernhard and Mall, Volker and Oexle, Konrad and Winkelmann, Juliane} } @article {800, title = {Multi-omic studies on missense PLG variants in families with otitis media.}, journal = {Sci Rep}, volume = {10}, year = {2020}, month = {2020 09 14}, pages = {15035}, abstract = {

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045~T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045~T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

}, keywords = {Animals, Ear, Middle, Female, Genomics, Humans, Male, Mice, Microbiota, Mutation, Missense, Otitis Media, Pedigree, Plasminogen, Polymorphism, Single Nucleotide, Saliva}, issn = {2045-2322}, doi = {10.1038/s41598-020-70498-w}, author = {Bootpetch, Tori C and Hafr{\'e}n, Lena and Elling, Christina L and Baschal, Erin E and Manichaikul, Ani W and Pine, Harold S and Szeremeta, Wasyl and Scholes, Melissa A and Cass, Stephen P and Larson, Eric D and Chan, Kenny H and Ishaq, Rafaqat and Prager, Jeremy D and Shaikh, Rehan S and Gubbels, Samuel P and Yousaf, Ayesha and Wine, Todd M and Bamshad, Michael J and Yoon, Patricia J and Jenkins, Herman A and Nickerson, Deborah A and Streubel, Sven-Olrik and Friedman, Norman R and Frank, Daniel N and Einarsdottir, Elisabet and Kere, Juha and Riazuddin, Saima and Daly, Kathleen A and Leal, Suzanne M and Ryan, Allen F and Mattila, Petri S and Ahmed, Zubair M and Sale, Michele M and Chonmaitree, Tasnee and Santos-Cortez, Regie Lyn P} } @article {908, title = {Multiplexed Functional Assessment of Genetic Variants in CARD11.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 12 03}, pages = {1029-1043}, abstract = {

Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a "cloning-free" saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6\%) and specific (88.9\%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.

}, keywords = {Adenine, B-Cell CLL-Lymphoma 10 Protein, B-Lymphocytes, CARD Signaling Adaptor Proteins, Cell Line, Diploidy, Exons, Genes, Dominant, Genetic Variation, Guanylate Cyclase, Humans, Immunologic Deficiency Syndromes, Jurkat Cells, Lymphoma, NF-kappa B p50 Subunit, Piperidines, Polymorphism, Single Nucleotide, Primary Immunodeficiency Diseases, Sensitivity and Specificity}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.10.015}, author = {Meitlis, Iana and Allenspach, Eric J and Bauman, Bradly M and Phan, Isabelle Q and Dabbah, Gina and Schmitt, Erica G and Camp, Nathan D and Torgerson, Troy R and Nickerson, Deborah A and Bamshad, Michael J and Hagin, David and Luthers, Christopher R and Stinson, Jeffrey R and Gray, Jessica and Lundgren, Ingrid and Church, Joseph A and Butte, Manish J and Jordan, Mike B and Aceves, Seema S and Schwartz, Daniella M and Milner, Joshua D and Schuval, Susan and Skoda-Smith, Suzanne and Cooper, Megan A and Starita, Lea M and Rawlings, David J and Snow, Andrew L and James, Richard G} } @article {970, title = {A mutation affecting laminin alpha 5 polymerisation gives rise to a syndromic developmental disorder.}, journal = {Development}, volume = {147}, year = {2020}, month = {2020 06 22}, abstract = {

Laminin alpha 5 (LAMA5) is a member of a large family of proteins that trimerise and then polymerise to form a central component of all basement membranes. Consequently, the protein plays an instrumental role in shaping the normal development of the kidney, skin, neural tube, lung and limb, and many other organs and tissues. Pathogenic mutations in some laminins have been shown to cause a range of largely syndromic conditions affecting the competency of the basement membranes to which they contribute. We report the identification of a mutation in the polymerisation domain of LAMA5 in a patient with a complex syndromic disease characterised by defects in kidney, craniofacial and limb development, and by a range of other congenital defects. Using CRISPR-generated mouse models and biochemical assays, we demonstrate the pathogenicity of this variant, showing that the change results in a failure of the polymerisation of α/β/γ laminin trimers. Comparing these phenotypes with those apparent upon gene deletion in mice provides insights into the specific functional importance of laminin polymerisation during development and tissue homeostasis.

}, keywords = {Amino Acid Sequence, Animals, Animals, Newborn, Child, Preschool, Developmental Disabilities, Fetal Development, Fetus, Humans, Hydronephrosis, Infant, Newborn, Kidney, Laminin, Lung, Male, Mice, Mutation, Polymerization, Protein Domains, Syndrome}, issn = {1477-9129}, doi = {10.1242/dev.189183}, author = {Jones, Lynelle K and Lam, Rachel and McKee, Karen K and Aleksandrova, Maya and Dowling, John and Alexander, Stephen I and Mallawaarachchi, Amali and Cottle, Denny L and Short, Kieran M and Pais, Lynn and Miner, Jeffery H and Mallett, Andrew J and Simons, Cas and McCarthy, Hugh and Yurchenco, Peter D and Smyth, Ian M} } @article {784, title = {The mutational constraint spectrum quantified from variation in 141,456 humans.}, journal = {Nature}, volume = {581}, year = {2020}, month = {2020 05}, pages = {434-443}, abstract = {

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

}, keywords = {Adult, Brain, Cardiovascular Diseases, Cohort Studies, Databases, Genetic, Exome, Female, Genes, Essential, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Loss of Function Mutation, Male, Mutation Rate, Proprotein Convertase 9, Reproducibility of Results, RNA, Messenger, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2308-7}, author = {Karczewski, Konrad J and Francioli, Laurent C and Tiao, Grace and Cummings, Beryl B and Alf{\"o}ldi, Jessica and Wang, Qingbo and Collins, Ryan L and Laricchia, Kristen M and Ganna, Andrea and Birnbaum, Daniel P and Gauthier, Laura D and Brand, Harrison and Solomonson, Matthew and Watts, Nicholas A and Rhodes, Daniel and Singer-Berk, Moriel and England, Eleina M and Seaby, Eleanor G and Kosmicki, Jack A and Walters, Raymond K and Tashman, Katherine and Farjoun, Yossi and Banks, Eric and Poterba, Timothy and Wang, Arcturus and Seed, Cotton and Whiffin, Nicola and Chong, Jessica X and Samocha, Kaitlin E and Pierce-Hoffman, Emma and Zappala, Zachary and O{\textquoteright}Donnell-Luria, Anne H and Minikel, Eric Vallabh and Weisburd, Ben and Lek, Monkol and Ware, James S and Vittal, Christopher and Armean, Irina M and Bergelson, Louis and Cibulskis, Kristian and Connolly, Kristen M and Covarrubias, Miguel and Donnelly, Stacey and Ferriera, Steven and Gabriel, Stacey and Gentry, Jeff and Gupta, Namrata and Jeandet, Thibault and Kaplan, Diane and Llanwarne, Christopher and Munshi, Ruchi and Novod, Sam and Petrillo, Nikelle and Roazen, David and Ruano-Rubio, Valentin and Saltzman, Andrea and Schleicher, Molly and Soto, Jose and Tibbetts, Kathleen and Tolonen, Charlotte and Wade, Gordon and Talkowski, Michael E and Neale, Benjamin M and Daly, Mark J and MacArthur, Daniel G} } @article {794, title = {Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {2020 10}, pages = {1046-1056}, abstract = {

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14\% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

}, keywords = {Animals, beta Catenin, Cerebral Palsy, Cyclin D, Cytoskeleton, Drosophila, Exome, Extracellular Matrix, F-Box Proteins, Female, Focal Adhesions, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Mutation, Neurites, rhoB GTP-Binding Protein, Risk Factors, Sequence Analysis, DNA, Signal Transduction, Tubulin, Tumor Suppressor Proteins, Whole Exome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-020-0695-1}, author = {Jin, Sheng Chih and Lewis, Sara A and Bakhtiari, Somayeh and Zeng, Xue and Sierant, Michael C and Shetty, Sheetal and Nordlie, Sandra M and Elie, Aureliane and Corbett, Mark A and Norton, Bethany Y and van Eyk, Clare L and Haider, Shozeb and Guida, Brandon S and Magee, Helen and Liu, James and Pastore, Stephen and Vincent, John B and Brunstrom-Hernandez, Janice and Papavasileiou, Antigone and Fahey, Michael C and Berry, Jesia G and Harper, Kelly and Zhou, Chongchen and Zhang, Junhui and Li, Boyang and Zhao, Hongyu and Heim, Jennifer and Webber, Dani L and Frank, MAHlia S B and Xia, Lei and Xu, Yiran and Zhu, Dengna and Zhang, Bohao and Sheth, Amar H and Knight, James R and Castaldi, Christopher and Tikhonova, Irina R and L{\'o}pez-Gir{\'a}ldez, Francesc and Keren, Boris and Whalen, Sandra and Buratti, Julien and Doummar, Diane and Cho, Megan and Retterer, Kyle and Millan, Francisca and Wang, Yangong and Waugh, Jeff L and Rodan, Lance and Cohen, Julie S and Fatemi, Ali and Lin, Angela E and Phillips, John P and Feyma, Timothy and MacLennan, Suzanna C and Vaughan, Spencer and Crompton, Kylie E and Reid, Susan M and Reddihough, Dinah S and Shang, Qing and Gao, Chao and Novak, Iona and Badawi, Nadia and Wilson, Yana A and McIntyre, Sarah J and Mane, Shrikant M and Wang, Xiaoyang and Amor, David J and Zarnescu, Daniela C and Lu, Qiongshi and Xing, Qinghe and Zhu, Changlian and Bilguvar, Kaya and Padilla-Lopez, Sergio and Lifton, Richard P and Gecz, Jozef and MacLennan, Alastair H and Kruer, Michael C} } @article {921, title = {Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 07 02}, pages = {158-163}, abstract = {

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

}, keywords = {Aspartic Acid Endopeptidases, Heredity, Heterozygote, Humans, Ichthyosis, Lamellar, Intermediate Filament Proteins, Mutation, Missense, Phenotype, Skin Diseases, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.05.013}, author = {Boyden, Lynn M and Zhou, Jing and Hu, Ronghua and Zaki, Theodore and Loring, Erin and Scott, Jared and Traupe, Heiko and Paller, Amy S and Lifton, Richard P and Choate, Keith A} } @article {931, title = {Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling.}, journal = {EMBO Mol Med}, volume = {12}, year = {2020}, month = {2020 11 06}, pages = {e11739}, abstract = {

Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss-of-function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia-based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co-receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.

}, issn = {1757-4684}, doi = {10.15252/emmm.201911739}, author = {Bosakova, Michaela and AbrAHm, Sara P and Nita, Alexandru and Hruba, Eva and Buchtova, Marcela and Taylor, S Paige and Duran, Ivan and Martin, Jorge and Svozilova, Katerina and Barta, Tomas and Varecha, Miroslav and Balek, Lukas and Kohoutek, Jiri and Radaszkiewicz, Tomasz and Pusapati, Ganesh V and Bryja, Vitezslav and Rush, Eric T and Thiffault, Isabelle and Nickerson, Deborah A and Bamshad, Michael J and Rohatgi, Rajat and Cohn, Daniel H and Krakow, Deborah and Krejci, Pavel} } @article {814, title = {Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 08 06}, pages = {293-310}, abstract = {

We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

}, keywords = {Adolescent, Amino Acid Sequence, Animals, Arthrogryposis, Child, Contracture, Extremities, Female, Humans, Male, Muscle, Skeletal, Musculoskeletal Abnormalities, Mutation, Myosin Light Chains, Myosins, Pedigree, Young Adult, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.06.014}, author = {Chong, Jessica X and Talbot, Jared C and Teets, Emily M and Previs, Samantha and Martin, Brit L and Shively, Kathryn M and Marvin, Colby T and Aylsworth, Arthur S and Saadeh-Haddad, Reem and Schatz, Ulrich A and Inzana, Francesca and Ben-Omran, Tawfeg and Almusafri, Fatima and Al-Mulla, Mariam and Buckingham, Kati J and Harel, Tamar and Mor-Shaked, Hagar and Radhakrishnan, Periyasamy and Girisha, Katta M and Nayak, Shalini S and Shukla, Anju and Dieterich, Klaus and Faure, Julien and Rendu, John and Capri, Yline and Latypova, X{\'e}nia and Nickerson, Deborah A and Warshaw, David M and Janssen, Paul M L and Amacher, Sharon L and Bamshad, Michael J} } @article {907, title = {Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 10 01}, pages = {727-742}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X.~tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

}, keywords = {Amphibian Proteins, Animals, Case-Control Studies, Child, Child, Preschool, DNA-Binding Proteins, Epigenesis, Genetic, Family, Female, Forkhead Transcription Factors, Heterozygote, Humans, Infant, Larva, Male, Mice, Mice, Knockout, Morpholinos, Mutation, Pedigree, Protein Binding, Repressor Proteins, Transcription Factors, Urinary Tract, Urogenital Abnormalities, Whole Exome Sequencing, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.08.013}, author = {Connaughton, Dervla M and Dai, Rufeng and Owen, Danielle J and Marquez, Jonathan and Mann, Nina and GrAHm-Paquin, Adda L and Nakayama, Makiko and Coyaud, Etienne and Laurent, Estelle M N and St-Germain, Jonathan R and Blok, Lot Snijders and Vino, Arianna and Kl{\"a}mbt, Verena and Deutsch, Konstantin and Wu, Chen-Han Wilfred and Kolvenbach, Caroline M and Kause, Franziska and Ottlewski, Isabel and Schneider, Ronen and Kitzler, Thomas M and Majmundar, Amar J and Buerger, Florian and Onuchic-Whitford, Ana C and Youying, Mao and Kolb, Amy and Salmanullah, Daanya and Chen, Evan and van der Ven, Amelie T and Rao, Jia and Ityel, Hadas and Seltzsam, Steve and Rieke, Johanna M and Chen, Jing and Vivante, Asaf and Hwang, Daw-Yang and Kohl, Stefan and Dworschak, Gabriel C and Hermle, Tobias and Alders, Marielle and Bartolomaeus, Tobias and Bauer, Stuart B and Baum, Michelle A and Brilstra, Eva H and Challman, Thomas D and Zyskind, Jacob and Costin, Carrie E and Dipple, Katrina M and Duijkers, Floor A and Ferguson, Marcia and FitzPatrick, David R and Fick, Roger and Glass, Ian A and Hulick, Peter J and Kline, Antonie D and Krey, Ilona and Kumar, Selvin and Lu, Weining and Marco, Elysa J and Wentzensen, Ingrid M and Mefford, Heather C and Platzer, Konrad and Povolotskaya, Inna S and Savatt, Juliann M and Shcherbakova, Natalia V and Senguttuvan, Prabha and Squire, Audrey E and Stein, Deborah R and Thiffault, Isabelle and Voinova, Victoria Y and Somers, Michael J G and Ferguson, Michael A and Traum, Avram Z and Daouk, Ghaleb H and Daga, Ankana and Rodig, Nancy M and Terhal, Paulien A and van Binsbergen, Ellen and Eid, Loai A and Tasic, Velibor and Rasouly, Hila Milo and Lim, Tze Y and Ahram, Dina F and Gharavi, Ali G and Reutter, Heiko M and Rehm, Heidi L and MacArthur, Daniel G and Lek, Monkol and Laricchia, Kristen M and Lifton, Richard P and Xu, Hong and Mane, Shrikant M and Sanna-Cherchi, Simone and Sharrocks, Andrew D and Raught, Brian and Fisher, Simon E and Bouchard, Maxime and Khokha, Mustafa K and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {799, title = {NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 09 15}, pages = {4625}, abstract = {

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF{\textquoteright}s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

}, keywords = {Amino Acid Sequence, Animals, Female, Humans, Male, Mice, Mice, Knockout, Mutation, Neuromuscular Diseases, Proteolysis, Ribosomes, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Alignment}, issn = {2041-1723}, doi = {10.1038/s41467-020-18327-6}, author = {Martin, Paige B and Kigoshi-Tansho, Yu and Sher, Roger B and Ravenscroft, Gianina and Stauffer, Jennifer E and Kumar, Rajesh and Yonashiro, Ryo and M{\"u}ller, Tina and Griffith, Christopher and Allen, William and Pehlivan, Davut and Harel, Tamar and Zenker, Martin and Howting, Denise and Schanze, Denny and Faqeih, Eissa A and Almontashiri, Naif A M and Maroofian, Reza and Houlden, Henry and Mazaheri, Neda and Galehdari, Hamid and Douglas, Ganka and Posey, Jennifer E and Ryan, Monique and Lupski, James R and Laing, Nigel G and Joazeiro, Claudio A P and Cox, Gregory A} } @article {876, title = {Neurophysiological and Genetic Findings in Patients With Juvenile Myoclonic Epilepsy.}, journal = {Front Integr Neurosci}, volume = {14}, year = {2020}, month = {2020}, pages = {45}, abstract = {

Objective: Transcranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia.

Methods: 20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10-15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied.

Results: We identified increased polyphasia in patients (85\%) and relatives (70\%) compared to controls (47\%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in , in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia.

Conclusion: Polyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives.

}, issn = {1662-5145}, doi = {10.3389/fnint.2020.00045}, author = {Stefani, Stefani and Kousiappa, Ioanna and Nicolaou, Nicoletta and Papathanasiou, Eleftherios S and Oulas, Anastasis and Fanis, Pavlos and Neocleous, Vassos and Phylactou, Leonidas A and Spyrou, George M and Papacostas, Savvas S} } @article {852, title = {Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 07 25}, abstract = {

Approximately 30\% of individuals with autism spectrum disorder (ASD) experience developmental regression, the etiology of which remains largely unknown. We performed a complete literature search and identified 47 genes that had been implicated in such cases. We sequenced these genes in a preselected cohort of 134 individuals with regressive autism. In total, 16 variants in 12 genes with evidence supportive of pathogenicity were identified. They were classified as variants of uncertain significance based on ACMG standards and guidelines. Among these were recurring variants in and , variants in genes that were linked to syndromic forms of ASD (, , , , , and ), and variants in the form of oligogenic heterozygosity (, , and ).

}, keywords = {Autism Spectrum Disorder, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Gene Expression Regulation, Genetic Markers, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Mutation}, issn = {2073-4425}, doi = {10.3390/genes11080853}, author = {Yin, Jiani and Chun, Chun-An and Zavadenko, Nikolay N and Pechatnikova, Natalia L and Naumova, Oxana Yu and Doddapaneni, Harsha V and Hu, Jianhong and Muzny, Donna M and Schaaf, Christian P and Grigorenko, Elena L} } @article {875, title = {Non-parametric Polygenic Risk Prediction via Partitioned GWAS Summary Statistics.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 07 02}, pages = {46-59}, abstract = {

In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait{\textquoteright}s heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects. Now that predictive accuracies are improving, there is a growing interest in the practical utility of such methods for predicting risk of common diseases responsive to early therapeutic intervention. However, existing methods require individual-level genotypes or depend on accurately specifying the genetic architecture underlying each disease to be predicted. Here, we propose a polygenic risk prediction method that does not require explicitly modeling any underlying genetic architecture. We start with summary statistics in the form of SNP effect sizes from a large GWAS cohort. We then remove the correlation structure across summary statistics arising due to linkage disequilibrium and apply a piecewise linear interpolation on conditional mean effects. In both simulated and real datasets, this new non-parametric shrinkage (NPS) method can reliably allow for linkage disequilibrium in summary statistics of 5 million dense genome-wide markers and consistently improves prediction accuracy. We show that NPS improves the identification of groups at high risk for breast cancer, type 2 diabetes, inflammatory bowel disease, and coronary heart disease, all of which have available early intervention or prevention treatments.

}, keywords = {Aged, Cohort Studies, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Models, Genetic, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.05.004}, author = {Chun, Sung and Imakaev, Maxim and Hui, Daniel and Patsopoulos, Nikolaos A and Neale, Benjamin M and Kathiresan, Sekar and Stitziel, Nathan O and Sunyaev, Shamil R} } @article {928, title = {Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 04 01}, pages = {1114-1126}, abstract = {

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

}, keywords = {Adolescent, Animals, Apolipoprotein C-III, Child, Child, Preschool, Developmental Disabilities, Female, Glycosylation, Humans, Loss of Function Mutation, Male, Mice, N-Acetylgalactosaminyltransferases, Pedigree, Rats, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awaa063}, author = {Zilmer, Monica and Edmondson, Andrew C and Khetarpal, Sumeet A and Alesi, Viola and Zaki, MAH S and Rostasy, Kevin and Madsen, Camilla G and Lepri, Francesca R and Sinibaldi, Lorenzo and Cusmai, Raffaella and Novelli, Antonio and Issa, Mahmoud Y and Fenger, Christina D and Abou Jamra, Rami and Reutter, Heiko and Briuglia, Silvana and Agolini, Emanuele and Hansen, Lars and Pet{\"a}j{\"a}-Repo, Ulla E and Hintze, John and Raymond, Kimiyo M and Liedtke, Kristen and Stanley, Valentina and Musaev, Damir and Gleeson, Joseph G and Vitali, Cecilia and O{\textquoteright}Brien, W Timothy and Gardella, Elena and Rubboli, Guido and Rader, Daniel J and Schjoldager, Katrine T and M{\o}ller, Rikke S} } @article {813, title = {Otitis media susceptibility and shifts in the head and neck microbiome due to variants.}, journal = {J Med Genet}, year = {2020}, month = {2020 Jul 24}, abstract = {

BACKGROUND: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility.

METHODS: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues.

RESULTS: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare variants, a common variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within (LOD=4.09). Carriage of the missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel variants were identified in 12 families and individuals with OM. A role for in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased expression in human cholesteatoma.

CONCLUSION: variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2020-106844}, author = {Frank, Daniel N and Giese, Arnaud P J and Hafr{\'e}n, Lena and Bootpetch, Tori C and Yarza, Talitha Karisse L and Steritz, Matthew J and Pedro, Melquiadesa and Labra, Patrick John and Daly, Kathleen A and Tantoco, Ma Leah C and Szeremeta, Wasyl and Reyes-Quintos, Maria Rina T and AHnkoob, Niaz and Llanes, Erasmo Gonzalo D V and Pine, Harold S and Yousaf, Sairah and Ir, Diana and Einarsdottir, Elisabet and de la Cruz, Rhodieleen Anne R and Lee, Nanette R and Nonato, Rachelle Marie A and Robertson, Charles E and Ong, Kimberly Mae C and Magno, Jose Pedrito M and Chiong, Alessandra Nadine E and Espiritu-Chiong, Ma Carmina and San Agustin, Maria Luz and Cruz, Teresa Luisa G and Abes, Generoso T and Bamshad, Michael J and Cutiongco-de la Paz, Eva Maria and Kere, Juha and Nickerson, Deborah A and Mohlke, Karen L and Riazuddin, Saima and Chan, Abner and Mattila, Petri S and Leal, Suzanne M and Ryan, Allen F and Ahmed, Zubair M and Chonmaitree, Tasnee and Sale, Michele M and Chiong, Charlotte M and Santos-Cortez, Regie Lyn P} } @article {849, title = {The Parkinson{\textquoteright}s Disease Genome-Wide Association Study Locus Browser.}, journal = {Mov Disord}, volume = {35}, year = {2020}, month = {2020 11}, pages = {2056-2067}, abstract = {

BACKGROUND: Parkinson{\textquoteright}s disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome-wide association studies. The most recent large-scale PD genome-wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome-wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus.

METHODS: We included all significant genome-wide signals from multiple recent PD genome-wide association studies including themost recent PD risk genome-wide association study, age-at-onset genome-wide association study, progression genome-wide association study, and Asian population PD risk genome-wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Multiple databases were queried for each gene to collect additional causal data.

RESULTS: We created a PD genome-wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow-up functional studies to identify potential therapeutic targets.

CONCLUSIONS: Our PD genome-wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large-scale PD genome-wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. {\textcopyright} 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

}, keywords = {Age of Onset, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neurodegenerative Diseases, Parkinson Disease, Risk Factors}, issn = {1531-8257}, doi = {10.1002/mds.28197}, author = {Grenn, Francis P and Kim, Jonggeol J and Makarious, Mary B and Iwaki, Hirotaka and Illarionova, Anastasia and Brolin, Kajsa and Kluss, Jillian H and Schumacher-Schuh, Artur F and Leonard, Hampton and Faghri, Faraz and Billingsley, Kimberley and Krohn, Lynne and Hall, Ashley and Diez-Fairen, Monica and Peri{\~n}{\'a}n, Maria Teresa and Foo, Jia Nee and Sandor, Cynthia and Webber, Caleb and Fiske, Brian K and Gibbs, J Raphael and Nalls, Mike A and Singleton, Andrew B and Bandres-Ciga, Sara and Reed, Xylena and Blauwendraat, Cornelis} } @article {910, title = {Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.}, journal = {Neuron}, volume = {106}, year = {2020}, month = {2020 04 22}, pages = {237-245.e8}, abstract = {

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1~(also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of~posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

}, keywords = {Adolescent, Adult, Age of Onset, Animals, Centrosome, Child, Child, Preschool, Chromosome Aberrations, Classical Lissencephalies and Subcortical Band Heterotopias, Cytoskeletal Proteins, Female, Gene Knockdown Techniques, Genetic Variation, Heterozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Mice, Mutation, Oncogene Proteins, Fusion, Pedigree, Seizures, Young Adult}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.01.027}, author = {Tsai, Meng-Han and Muir, Alison M and Wang, Won-Jing and Kang, Yi-Ning and Yang, Kun-Chuan and Chao, Nian-Hsin and Wu, Mei-Feng and Chang, Ying-Chao and Porter, Brenda E and Jansen, Laura A and Sebire, Guillaume and Deconinck, Nicolas and Fan, Wen-Lang and Su, Shih-Chi and Chung, Wen-Hung and Almanza Fuerte, Edith P and Mehaffey, Michele G and Ng, Ching-Ching and Chan, Chung-Kin and Lim, Kheng-Seang and Leventer, Richard J and Lockhart, Paul J and Riney, Kate and Damiano, John A and Hildebrand, Michael S and Mirzaa, Ghayda M and Dobyns, William B and Berkovic, Samuel F and Scheffer, Ingrid E and Tsai, Jin-Wu and Mefford, Heather C} } @article {726, title = {PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.}, journal = {Eur J Med Genet}, volume = {63}, year = {2020}, month = {2020 Feb}, pages = {103660}, abstract = {

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.

}, keywords = {Brain Edema, Databases, Genetic, Edema, Epileptic Syndromes, Female, Finland, Heterozygote, Humans, Infant, Newborn, Mutation, Missense, Neurodegenerative Diseases, Nuclear Proteins, Optic Atrophy, Phenotype, Spasms, Infantile, Transcription Factors, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2019.04.017}, author = {{\~O}unap, Katrin and Muru, Kai and {\~O}iglane-Shlik, Eve and Ilves, Pilvi and Pajusalu, Sander and Kuus, Imbi and Wojcik, Monica H and Reimand, Tiia} } @article {854, title = {Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 12}, pages = {2094-2104}, abstract = {

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia~as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.

}, issn = {1098-1004}, doi = {10.1002/humu.24118}, author = {Montenegro-Garreaud, Ximena and Hansen, Adam W and Khayat, Michael M and Chander, Varuna and Grochowski, Christopher M and Jiang, Yunyun and Li, He and Mitani, Tadahiro and Kessler, Elena and Jayaseelan, Joy and Shen, Hua and Gezdirici, Alper and Pehlivan, Davut and Meng, Qingchang and Rosenfeld, Jill A and Jhangiani, Shalini N and Madan-Khetarpal, Suneeta and Scott, Daryl A and Abarca-Barriga, Hugo and Trubnykova, Milana and Gingras, Marie-Claude and Muzny, Donna M and Posey, Jennifer E and Liu, Pengfei and Lupski, James R and Gibbs, Richard A} } @article {707, title = {Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome).}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 01}, pages = {38-52}, abstract = {

White-Sutton syndrome (WHSUS) is a recently-identified genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ. Thus far, over 50 individuals have been reported worldwide, however phenotypic characterization and data regarding the natural history are still incomplete. Here we report the clinical features of 22 individuals with 21 unique loss of function POGZ variants. We observed a broad spectrum of intellectual disability and/or developmental delay with or without autism, and speech delay in all individuals. Other common problems included ocular abnormalities, hearing loss and gait abnormalities. A validated sleep disordered breathing questionnaire identified symptoms of obstructive sleep apnea in 4/12 (33\%) individuals. A higher-than-expected proportion of cases also had gastrointestinal phenotypes, both functional and anatomical, as well as genitourinary anomalies. In line with previous publications, we observed an increased body mass index (BMI) z-score compared to the general population (mean 0.59, median 0.9; p 0.0253). Common facial features included microcephaly, broad forehead, midface hypoplasia, triangular mouth, broad nasal root and flat nasal bridge. Analysis of the Baylor Genetics clinical laboratory database revealed that POGZ variants were implicated in approximately 0.14\% of cases who underwent clinical exome sequencing for neurological indications with or without involvement of other body systems. This study describes a greater allelic series and expands the phenotypic spectrum of this new syndromic form of intellectual disability and autism.

}, keywords = {Adolescent, Adult, Autistic Disorder, Child, Child, Preschool, Exome, Female, Heterozygote, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Microcephaly, Middle Aged, Mutation, Phenotype, Transposases, Whole Exome Sequencing, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61380}, author = {Assia Batzir, Nurit and Posey, Jennifer E and Song, Xiaofei and Akdemir, Zeynep Coban and Rosenfeld, Jill A and Brown, Chester W and Chen, Emily and Holtrop, Shannon G and Mizerik, Elizabeth and Nieto Moreno, Margarita and Payne, Katelyn and Raas-Rothschild, Annick and Scott, Richard and Vernon, Hilary J and Zadeh, Neda and Lupski, James R and Sutton, V Reid} } @article {912, title = {Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 07}, pages = {1215-1226}, abstract = {

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.

METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.

RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.

CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

}, keywords = {Exome, Germ Cells, Humans, Intellectual Disability, Mutation, Missense, Phenotype, Transcriptome, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins}, issn = {1530-0366}, doi = {10.1038/s41436-020-0792-7}, author = {Castilla-Vallmanya, Laura and Selmer, Kaja K and Dimartino, Cl{\'e}mantine and Rabionet, Raquel and Blanco-S{\'a}nchez, Bernardo and Yang, Sandra and Reijnders, Margot R F and van Essen, Antonie J and Oufadem, Myriam and Vigeland, Magnus D and Stadheim, Barbro and Houge, Gunnar and Cox, Helen and Kingston, Helen and Clayton-Smith, Jill and Innis, Jeffrey W and Iascone, Maria and Cereda, Anna and Gabbiadini, Sara and Chung, Wendy K and Sanders, Victoria and Charrow, Joel and Bryant, Emily and Millichap, John and Vitobello, Antonio and Thauvin, Christel and Mau-Them, Frederic Tran and Faivre, Laurence and Lesca, Gaetan and Labalme, Audrey and Rougeot, Christelle and Chatron, Nicolas and Sanlaville, Damien and Christensen, Katherine M and Kirby, Amelia and Lewandowski, Raymond and Gannaway, Rachel and Aly, MAH and Lehman, Anna and Clarke, Lorne and Graul-Neumann, Luitgard and Zweier, Christiane and Lessel, Davor and Lozic, Bernarda and Aukrust, Ingvild and Peretz, Ryan and Stratton, Robert and Smol, Thomas and Dieux-Co{\"e}slier, Anne and Meira, Joanna and Wohler, Elizabeth and Sobreira, Nara and Beaver, Erin M and Heeley, Jennifer and Briere, Lauren C and High, Frances A and Sweetser, David A and Walker, Melissa A and Keegan, Catherine E and Jayakar, Parul and Shinawi, Marwan and Kerstjens-Frederikse, Wilhelmina S and Earl, Dawn L and Siu, Victoria M and Reesor, Emma and Yao, Tony and Hegele, Robert A and Vaske, Olena M and Rego, Shannon and Shapiro, Kevin A and Wong, Brian and Gambello, Michael J and McDonald, Marie and Karlowicz, Danielle and Colombo, Roberto and Serretti, Alessandro and Pais, Lynn and O{\textquoteright}Donnell-Luria, Anne and Wray, Alison and Sadedin, Simon and Chong, Belinda and Tan, Tiong Y and Christodoulou, John and White, Susan M and Slavotinek, Anne and Barbouth, Deborah and Morel Swols, Dayna and Parisot, M{\'e}lanie and Bole-Feysot, Christine and Nitschk{\'e}, Patrick and Pingault, V{\'e}ronique and Munnich, Arnold and Cho, Megan T and Cormier-Daire, Val{\'e}rie and Balcells, Susanna and Lyonnet, Stanislas and Grinberg, Daniel and Amiel, Jeanne and Urreizti, Roser and Gordon, Christopher T} } @article {684, title = {The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 02}, pages = {427-431}, abstract = {

PURPOSE: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

METHODS: Exome sequencing from 39 trios were analyzed.

RESULTS: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

CONCLUSION: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.

}, keywords = {Adult, Cell Cycle Proteins, Cerebrovascular Disorders, Child, Child, Preschool, Developmental Disabilities, DNA Helicases, Exome, Female, Genetic Predisposition to Disease, Humans, Intellectual Disability, Male, Methyltransferases, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Middle Aged, Moyamoya Disease, Mutation, Nuclear Proteins, Transcription Factors, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-019-0639-2}, author = {Pinard, Amelie and Guey, St{\'e}phanie and Guo, Dongchuan and Cecchi, Alana C and Kharas, Natasha and Wallace, Stephanie and Regalado, Ellen S and Hostetler, Ellen M and Sharrief, Anjail Z and Bergametti, Fran{\c c}oise and Kossorotoff, Manoelle and Herv{\'e}, Dominique and Kraemer, Markus and Bamshad, Michael J and Nickerson, Deborah A and Smith, Edward R and Tournier-Lasserve, Elisabeth and Milewicz, Dianna M} } @article {978, title = {POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.}, journal = {Acta Neuropathol}, volume = {139}, year = {2020}, month = {2020 03}, pages = {565-582}, abstract = {

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM$\#$ 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients{\textquoteright} muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

}, keywords = {Animals, Animals, Genetically Modified, Drosophila melanogaster, Dystroglycans, Female, Genetic Association Studies, Glucosyltransferases, Glycosylation, Humans, Male, Muscle, Skeletal, Muscular Dystrophies, Limb-Girdle, Mutation, Pedigree, Satellite Cells, Skeletal Muscle}, issn = {1432-0533}, doi = {10.1007/s00401-019-02117-6}, author = {Servi{\'a}n-Morilla, E and Cabrera-Serrano, M and Johnson, K and Pandey, A and Ito, A and Rivas, E and Chamova, T and Muelas, N and Mongini, T and Nafissi, S and Claeys, K G and Grewal, R P and Takeuchi, M and Hao, H and B{\"o}nnemann, C and Lopes Abath Neto, O and Medne, L and Brandsema, J and T{\"o}pf, A and Taneva, A and Vilchez, J J and Tournev, I and Haltiwanger, R S and Takeuchi, H and Jafar-Nejad, H and Straub, V and Paradas, Carmen} } @article {848, title = {Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 20}, pages = {3635}, abstract = {

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17\% to 78\% for coronary artery disease, 13\% to 76\% for breast cancer, and 11\% to 80\% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

}, keywords = {Aged, Breast Neoplasms, Case-Control Studies, Colorectal Neoplasms, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Middle Aged, Multifactorial Inheritance, Odds Ratio, Penetrance, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-17374-3}, author = {Fahed, Akl C and Wang, Minxian and Homburger, Julian R and Patel, Aniruddh P and Bick, Alexander G and Neben, Cynthia L and Lai, Carmen and Brockman, Deanna and Philippakis, Anthony and Ellinor, Patrick T and Cassa, Christopher A and Lebo, Matthew and Ng, Kenney and Lander, Eric S and Zhou, Alicia Y and Kathiresan, Sekar and Khera, Amit V} } @article {940, title = {Polymicrogyria is Associated With Pathogenic Variants in PTEN.}, journal = {Ann Neurol}, volume = {88}, year = {2020}, month = {2020 12}, pages = {1153-1164}, abstract = {

OBJECTIVE: Congenital structural brain malformations have been described in patients with pathogenic phosphatase and tensin homologue (PTEN) variants, but the frequency of cortical malformations in patients with PTEN variants and their impact on clinical phenotype are not well understood. Our goal was to systematically characterize brain malformations in patients with PTEN variants and assess the relevance of their brain malformations to clinical presentation.

METHODS: We systematically searched a local radiology database for patients with PTEN variants who had available brain magnetic resonance imaging (MRI). The MRI scans were reviewed systematically for cortical abnormalities. We reviewed electroencephalogram (EEG) data and evaluated the electronic medical record for evidence of epilepsy and developmental delay.

RESULTS: In total, we identified 22 patients with PTEN pathogenic variants for which brain MRIs were available (age range 0.4-17 years). Twelve among these 22 patients (54\%) had polymicrogyria (PMG). Variants associated with PMG or atypical gyration encoded regions of the phosphatase or C2 domains of PTEN. Interestingly, epilepsy was present in only 2 of the 12 patients with PMG. We found a trend toward higher rates of global developmental delay (GDD), intellectual disability (ID), and motor delay in individuals with cortical abnormalities, although cohort size limited statistical significance.

INTERPRETATION: Malformations of cortical development, PMG in particular, represent an under-recognized phenotype associated with PTEN pathogenic variants and may have an association with cognitive and motor delays. Epilepsy was infrequent compared to the previously reported high risk of epilepsy in patients with PMG. ANN NEUROL 2020;88:1153-1164.

}, keywords = {Adolescent, Brain, Child, Child, Preschool, Comorbidity, Databases, Genetic, Developmental Disabilities, Electroencephalography, Female, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Massachusetts, Neuroimaging, Polymicrogyria, PTEN Phosphohydrolase}, issn = {1531-8249}, doi = {10.1002/ana.25904}, author = {Shao, Diane D and Achkar, Christelle M and Lai, Abbe and Srivastava, Siddharth and Doan, Ryan N and Rodan, Lance H and Chen, Allen Y and Poduri, Annapurna and Yang, Edward and Walsh, Christopher A} } @article {930, title = {Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.}, journal = {Neuron}, volume = {106}, year = {2020}, month = {2020 04 22}, pages = {246-255.e6}, abstract = {

Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L. We show that CEP85L is required cell autonomously in~vivo and in~vitro for migration, that it localizes to the maternal centriole, and that it forms a complex with many other proteins required for migration, including CDK5, LIS1, NDE1, KIF2A, and DYNC1H1. Loss of CEP85L disrupts CDK5 localization and activation, leading to centrosome disorganization and disrupted microtubule cytoskeleton organization. Together, our findings suggest that CEP85L highlights a complex that controls CDK5 activity to promote neuronal migration.

}, keywords = {Cell Movement, Centrioles, Child, Child, Preschool, Cyclin-Dependent Kinase 5, Cytoskeletal Proteins, Female, Humans, Lissencephaly, Male, Microtubules, Neocortex, Nerve Tissue Proteins, Neurons, Oncogene Proteins, Fusion, Young Adult}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.01.030}, author = {Kodani, Andrew and Kenny, Connor and Lai, Abbe and Gonzalez, Dilenny M and Stronge, Edward and Sejourne, Gabrielle M and Isacco, Laura and Partlow, Jennifer N and O{\textquoteright}Donnell, Anne and McWalter, Kirsty and Byrne, Alicia B and Barkovich, A James and Yang, Edward and Hill, R Sean and Gawlinski, Pawel and Wiszniewski, Wojciech and Cohen, Julie S and Fatemi, S Ali and Baranano, Kristin W and Sahin, Mustafa and Vossler, David G and Yuskaitis, Christopher J and Walsh, Christopher A} } @article {815, title = {Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.}, journal = {J Inherit Metab Dis}, volume = {43}, year = {2020}, month = {2020 11}, pages = {1333-1348}, abstract = {

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

}, issn = {1573-2665}, doi = {10.1002/jimd.12290}, author = {Ng, Bobby G and Eklund, Erik A and Shiryaev, Sergey A and Dong, Yin Y and Abbott, Mary-Alice and Asteggiano, Carla and Bamshad, Michael J and Barr, Eileen and Bernstein, Jonathan A and Chelakkadan, Shabeed and Christodoulou, John and Chung, Wendy K and Ciliberto, Michael A and Cousin, Janice and Gardiner, Fiona and Ghosh, Suman and Graf, William D and Grunewald, Stephanie and Hammond, Katherine and Hauser, Natalie S and Hoganson, George E and Houck, Kimberly M and Kohler, Jennefer N and Morava, Eva and Larson, Austin A and Liu, Pengfei and Madathil, Sujana and McCormack, Colleen and Meeks, Naomi J L and Miller, Rebecca and Monaghan, Kristin G and Nickerson, Deborah A and Palculict, Timothy Blake and Papazoglu, Gabriela Magali and Pletcher, Beth A and Scheffer, Ingrid E and Schenone, Andrea Beatriz and Schnur, Rhonda E and Si, Yue and Rowe, Leah J and Serrano Russi, Alvaro H and Russo, Rossana Sanchez and Thabet, Farouq and Tuite, Allysa and Villanueva, Mar{\'\i}a Mercedes and Wang, Raymond Y and Webster, Richard I and Wilson, Dorcas and Zalan, Alice and Wolfe, Lynne A and Rosenfeld, Jill A and Rhodes, Lindsay and Freeze, Hudson H} } @article {809, title = {Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 10}, pages = {e1406}, abstract = {

BACKGROUND: Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5\%-2\%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20\%. However, the contribution of causal BAV genes to TAD is not known. Therefore, we evaluated rare deleterious variants of GATA4, NOTCH1, SMAD6, or ROBO4 in patients with BAV who presented with TAD.

METHODS: Our cohort consisted of 487 probands with Heritable Thoracic Aortic Aneurysms or Dissections (HTAD, 12\% BAV, 29\% female) and 63 probands with Early onset complications of Bicuspid Aortic Valve disease (EBAV, 63\% TAD, 34\% female). After whole exome sequencing, we functionally annotated GATA4, NOTCH1, SMAD6, and ROBO4 variants and compared the prevalence of rare variants in these genes to controls without HTAD.

RESULTS: We identified 11 rare deleterious variants of GATA4, SMAD6, or ROBO4 in 12 (18\%) EBAV cases. The burden of rare SMAD6 and GATA4 variants was significantly enriched in EBAV but not in HTAD cases, even among HTAD cases with BAV (p~<~.003).

CONCLUSION: Rare variants of NOTCH1, ROBO4, SMAD6, or GATA4 do not significantly contribute to BAV in cohorts with HTAD. We conclude that BAV patients who present with HTAD are a genetically distinct subgroup with implications for genetic testing and prognosis.

}, keywords = {Adult, Aortic Aneurysm, Thoracic, Bicuspid Aortic Valve Disease, Female, GATA4 Transcription Factor, Gene Frequency, Humans, Male, Middle Aged, Mutation, Receptor, Notch1, Receptors, Cell Surface, Smad6 Protein}, issn = {2324-9269}, doi = {10.1002/mgg3.1406}, author = {Musfee, Fadi I and Guo, Dongchuan and Pinard, Am{\'e}lie C and Hostetler, Ellen M and Blue, Elizabeth E and Nickerson, Deborah A and Bamshad, Michael J and Milewicz, Dianna M and Prakash, Siddharth K} } @article {753, title = {Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 03}, pages = {641-654}, abstract = {

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64\% (34/53), of which 97\% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49\% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

}, issn = {1098-1004}, doi = {10.1002/humu.23960}, author = {Assia Batzir, Nurit and Kishor Bhagwat, Pranjali and Larson, Austin and Coban Akdemir, Zeynep and Bag{\l}aj, Maciej and Bofferding, Leon and Bosanko, Katherine B and Bouassida, Skander and Callewaert, Bert and Cannon, Ashley and Enchautegui Colon, Yazmin and Garnica, Adolfo D and Harr, Margaret H and Heck, Sandra and Hurst, Anna C E and Jhangiani, Shalini N and Isidor, Bertrand and Littlejohn, Rebecca O and Liu, Pengfei and Magoulas, Pilar and Mar Fan, Helen and Marom, Ronit and McLean, Scott and Nezarati, Marjan M and Nugent, Kimberly M and Petersen, Michael B and Rocha, Maria L and Roeder, Elizabeth and Smigiel, Robert and Tully, Ian and Weisfeld-Adams, James and Wells, Katerina O and Posey, Jennifer E and Lupski, James R and Beaudet, Arthur L and Wangler, Michael F} } @article {767, title = {Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 02 06}, pages = {272-279}, abstract = {

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.

}, keywords = {Amino Acid Sequence, ATPases Associated with Diverse Cellular Activities, Brain Diseases, Cardiomyopathies, Cholesterol, Corneal Opacity, DNA Copy Number Variations, Female, Gene Duplication, Gene Rearrangement, Homologous Recombination, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Diseases, Mitochondrial Proteins, Muscle Hypotonia, Mutation, Protein Conformation, Seizures, Sequence Homology}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.01.007}, author = {Gunning, Adam C and Strucinska, Klaudia and Mu{\~n}oz Oreja, Mikel and Parrish, Andrew and Caswell, Richard and Stals, Karen L and Durigon, Romina and Durlacher-Betzer, Karina and Cunningham, Mitchell H and Grochowski, Christopher M and Baptista, Julia and Tysoe, Carolyn and Baple, Emma and Lahiri, Nayana and Homfray, Tessa and Scurr, Ingrid and Armstrong, Catherine and Dean, John and Fernandez Pelayo, Uxoa and Jones, Aleck W E and Taylor, Robert W and Misra, Vinod K and Yoon, Wan Hee and Wright, Caroline F and Lupski, James R and Spinazzola, Antonella and Harel, Tamar and Holt, Ian J and Ellard, Sian} } @article {805, title = {Recurrent Rare Copy Number Variants Increase Risk for Esotropia.}, journal = {Invest Ophthalmol Vis Sci}, volume = {61}, year = {2020}, month = {2020 08 03}, pages = {22}, abstract = {

Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia.

Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints.

Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 {\texttimes} 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95\% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95\% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95\% CI 5.4-14.9). Overall, 114 cases (7\%) and only 28 controls (0.7\%) had one of the three rare duplications. No case nor control had more than one of these three duplications.

Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.

}, keywords = {Case-Control Studies, DNA Copy Number Variations, Esotropia, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Infant, Male, Markov Chains, Polymerase Chain Reaction, Risk Factors}, issn = {1552-5783}, doi = {10.1167/iovs.61.10.22}, author = {Whitman, Mary C and Di Gioia, Silvio Alessandro and Chan, Wai-Man and Gelber, Alon and Pratt, Brandon M and Bell, Jessica L and Collins, Thomas E and Knowles, James A and Armoskus, Christopher and Pato, Michele and Pato, Carlos and Shaaban, Sherin and Staffieri, Sandra and MacKinnon, Sarah and Maconachie, Gail D E and Elder, James E and Traboulsi, Elias I and Gottlob, Irene and Mackey, David A and Hunter, David G and Engle, Elizabeth C} } @article {713, title = {Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 02}, pages = {403-411}, abstract = {

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3{\textquoteright} splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56\% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate >=66\%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57\%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.

}, issn = {1098-1004}, doi = {10.1002/humu.23938}, author = {Bryen, Samantha J and Ewans, Lisa J and Pinner, Jason and MacLennan, Suzanna C and Donkervoort, Sandra and Castro, Diana and Topf, Ana and O{\textquoteright}Grady, Gina and Cummings, Beryl and Chao, Katherine R and Weisburd, Ben and Francioli, Laurent and Faiz, Fathimath and Bournazos, Adam M and Hu, Ying and Grosmann, Carla and Malicki, Denise M and Doyle, Helen and Witting, Nanna and Vissing, John and Claeys, Kristl G and Urankar, Kathryn and Beleza-Meireles, Ana and Baptista, Julia and Ellard, Sian and Savarese, Marco and Johari, Mridul and Vihola, Anna and Udd, Bjarne and Majumdar, Anirban and Straub, Volker and B{\"o}nnemann, Carsten G and MacArthur, Daniel G and Davis, Mark R and Cooper, Sandra T} } @article {746, title = {Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 06}, pages = {1040-1050}, abstract = {

PURPOSE: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown.

METHODS: We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout.

RESULTS: We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly.

CONCLUSION: Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.

}, keywords = {Animals, Brain Diseases, Cell Proliferation, Homozygote, Humans, Mice, Microcephaly, Zebrafish}, issn = {1530-0366}, doi = {10.1038/s41436-020-0758-9}, author = {Coulter, Michael E and Musaev, Damir and DeGennaro, Ellen M and Zhang, Xiaochang and Henke, Katrin and James, Kiely N and Smith, Richard S and Hill, R Sean and Partlow, Jennifer N and Kamumbu, A Stacy and Hatem, Nicole and Barkovich, A James and Aziza, Jacqueline and Chassaing, Nicolas and Zaki, MAH S and Sultan, Tipu and Burglen, Lydie and Rajab, Anna and Al-Gazali, Lihadh and Mochida, Ganeshwaran H and Harris, Matthew P and Gleeson, Joseph G and Walsh, Christopher A} } @article {765, title = {-related autosomal recessive encephalopathy in 2 Turkish children.}, journal = {Neurol Genet}, volume = {6}, year = {2020}, month = {2020 Feb}, pages = {e392}, abstract = {

Objective: This study presents the neurologic phenotypes of 2 brothers with a novel homozygous mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases.

Methods: Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents.

Results: We have identified a homozygous missense mutation in (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease.

Conclusions: has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that -related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.

}, issn = {2376-7839}, doi = {10.1212/NXG.0000000000000392}, author = {Yaramis, Ahmet and Lochm{\"u}ller, Hanns and Topf, Ana and Sonmezler, Ece and Yilmaz, Elmasnur and Hiz, Semra and Yis, Uluc and G{\"u}ng{\"o}r, Serdal and Ipek Polat, Ayse and Edem, Pinar and Beltran, Sergi and Laurie, Steven and Yaramis, Aysenur and Horvath, Rita and Oktay, Yavuz} } @article {834, title = {RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares.}, journal = {N Engl J Med}, volume = {383}, year = {2020}, month = {2020 07 16}, pages = {218-228}, abstract = {

BACKGROUND: Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown.

METHODS: We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings.

RESULTS: Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45-CD31-PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis.

CONCLUSIONS: Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.).

}, keywords = {Adult, Arthritis, Rheumatoid, B-Lymphocytes, Female, Fibroblasts, Flow Cytometry, Gene Expression, Humans, Male, Mesenchymal Stem Cells, Middle Aged, Patient Acuity, Sequence Analysis, RNA, Surveys and Questionnaires, Symptom Flare Up, Synovial Fluid}, issn = {1533-4406}, doi = {10.1056/NEJMoa2004114}, author = {Orange, Dana E and Yao, Vicky and Sawicka, Kirsty and Fak, John and Frank, Mayu O and Parveen, Salina and Blachere, Nathalie E and Hale, Caryn and Zhang, Fan and Raychaudhuri, Soumya and Troyanskaya, Olga G and Darnell, Robert B} } @article {911, title = {Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 09}, pages = {1478-1488}, abstract = {

PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology.

METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions.

RESULTS: We identified suspected pathogenic variants in 52\% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48\%) need further investigation.

CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

}, keywords = {Anoctamins, Exome, Glucosyltransferases, Humans, Muscular Dystrophies, Limb-Girdle, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-0840-3}, author = {Topf, Ana and Johnson, Katherine and Bates, Adam and Phillips, Lauren and Chao, Katherine R and England, Eleina M and Laricchia, Kristen M and Mullen, Thomas and Valkanas, Elise and Xu, Liwen and Bertoli, Marta and Blain, Alison and Casas{\'u}s, Ana B and Duff, Jennifer and Mroczek, Magdalena and Specht, Sabine and Lek, Monkol and Ensini, Monica and MacArthur, Daniel G and Straub, Volker} } @article {817, title = {Short stature and growth hormone deficiency in a subset of patients with Potocki-Lupski syndrome: Expanding the phenotype of PTLS.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 09}, pages = {2077-2084}, abstract = {

Potocki-Lupski Syndrome (PTLS, MIM 610883), or duplication of chromosome 17p11.2, is a clinically recognizable condition characterized by infantile hypotonia, failure to thrive, developmental delay, intellectual disability, and congenital anomalies. Short stature, classified as greater than two standard deviations below the mean, has not previously been considered a major feature of PTLS. Retrospective chart review on a cohort of 37 individuals with PTLS was performed to investigate the etiology of short stature. Relevant data included anthropometric measurements, insulin growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), growth hormone (GH) stimulation testing, blood glucose levels, brain MRI, and bone age. Approximately 25\% (9/37) of individuals with PTLS had short stature. Growth hormone deficiency (GHD) was definitively identified in two individuals. These two PTLS patients with growth hormone deficiency, as well as three others with short stature and no documented GHD, received growth hormone and obtained improvement in linear growth. One individual was identified to have pituitary abnormalities on MRI and had complications of hypoglycemia due to unrecognized GHD. Individuals with PTLS can benefit from undergoing evaluation for GHD should they present with short stature or hypoglycemia. Early identification of GHD could facilitate potential therapeutic benefit for individuals with PTLS, including linear growth, musculoskeletal, and in cases of hypoglycemia, potentially cognitive development as well.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61741}, author = {Franciskovich, Rachel and Soler-Alfonso, Claudia and Neira-Fresneda, Juanita and Lupski, James R and McCann-Crosby, Bonnie and Potocki, Lorraine} } @article {836, title = {A structural variation reference for medical and population genetics.}, journal = {Nature}, volume = {581}, year = {2020}, month = {2020 05}, pages = {444-451}, abstract = {

Structural variants (SVs) rearrange large segments of DNA and can have profound consequences in evolution and human disease. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral in the interpretation of single-nucleotide variants (SNVs). However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54\% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29\% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9\% of samples, and estimate that 0.13\% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings. This SV resource is freely distributed via the gnomAD browser and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

}, keywords = {Continental Population Groups, Disease, Female, Genetic Testing, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Reference Standards, Selection, Genetic, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2287-8}, author = {Collins, Ryan L and Brand, Harrison and Karczewski, Konrad J and Zhao, Xuefang and Alf{\"o}ldi, Jessica and Francioli, Laurent C and Khera, Amit V and Lowther, Chelsea and Gauthier, Laura D and Wang, Harold and Watts, Nicholas A and Solomonson, Matthew and O{\textquoteright}Donnell-Luria, Anne and Baumann, Alexander and Munshi, Ruchi and Walker, Mark and Whelan, Christopher W and Huang, Yongqing and Brookings, Ted and Sharpe, Ted and Stone, Matthew R and Valkanas, Elise and Fu, Jack and Tiao, Grace and Laricchia, Kristen M and Ruano-Rubio, Valentin and Stevens, Christine and Gupta, Namrata and Cusick, Caroline and Margolin, Lauren and Taylor, Kent D and Lin, Henry J and Rich, Stephen S and Post, Wendy S and Chen, Yii-Der Ida and Rotter, Jerome I and Nusbaum, Chad and Philippakis, Anthony and Lander, Eric and Gabriel, Stacey and Neale, Benjamin M and Kathiresan, Sekar and Daly, Mark J and Banks, Eric and MacArthur, Daniel G and Talkowski, Michael E} } @article {966, title = {Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3-CDG.}, journal = {Brain Dev}, volume = {42}, year = {2020}, month = {2020 Aug}, pages = {539-545}, abstract = {

BACKGROUND: Congenital disorders of glycosylation (CDG) is a heterogeneous group of congenital metabolic diseases with multisystem clinical involvement. ALG3-CDG is a very rare subtype with only 24 cases reported so far.

CASE: Here, we report two siblings with dysmorphic features, growth retardation, microcephaly, intractable epilepsy, and hemangioma in the frontal, occipital and lumbosacral regions.

RESULTS: We studied two siblings by whole exome sequencing. A pathogenic variant in ALG3 (NM_005787.6: c.165C~>~T; p.Gly55=) that had been previously associated with congenital glycolysis defect type 1d was identified. Their intractable seizures were controlled by ketogenic diet.

CONCLUSION: Although prominent findings of growth retardation and microcephaly seen in our patients have been extensively reported before, presence of hemangioma is a novel finding that may be used as an indication for ALG3-CDG diagnosis. Our patients are the first reported cases whose intractable seizures were controlled with ketogenic diet. This report adds ketogenic diet as an option for treatment of intractable epilepsy in ALG3-CDG.

}, keywords = {Central Nervous System Neoplasms, Congenital Disorders of Glycosylation, Craniofacial Abnormalities, Developmental Disabilities, Diet, Ketogenic, Drug Resistant Epilepsy, Female, Hemangioma, Humans, Infant, Male, Mannosyltransferases, Twins, Whole Exome Sequencing}, issn = {1872-7131}, doi = {10.1016/j.braindev.2020.04.008}, author = {Paketci, C and Edem, P and Hiz, S and Sonmezler, E and Soydemir, D and Sarikaya Uzan, G and Oktay, Y and O{\textquoteright}Heir, E and Beltran, S and Laurie, S and T{\"o}pf, A and Lochmuller, H and Horvath, R and Yis, U} } @article {953, title = {Systems Analysis Implicates WAVE2~Complex in the Pathogenesis of~Developmental Left-Sided Obstructive~Heart Defects.}, journal = {JACC Basic Transl Sci}, volume = {5}, year = {2020}, month = {2020 Apr}, pages = {376-386}, abstract = {

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins , , and and the regulators of small GTPase signaling and are critical to cardiac development.

}, issn = {2452-302X}, doi = {10.1016/j.jacbts.2020.01.012}, author = {Edwards, Jonathan J and Rouillard, Andrew D and Fernandez, Nicolas F and Wang, Zichen and Lachmann, Alexander and Shankaran, Sunita S and Bisgrove, Brent W and Demarest, Bradley and Turan, Nahid and Srivastava, Deepak and Bernstein, Daniel and Deanfield, John and Giardini, Alessandro and Porter, George and Kim, Richard and Roberts, Amy E and Newburger, Jane W and Goldmuntz, Elizabeth and Brueckner, Martina and Lifton, Richard P and Seidman, Christine E and Chung, Wendy K and Tristani-Firouzi, Martin and Yost, H Joseph and Ma{\textquoteright}ayan, Avi and Gelb, Bruce D} } @article {774, title = {TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 01}, pages = {182-195}, abstract = {

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10\% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

}, keywords = {Alleles, Cell Line, Female, Gene Expression, Genes, Reporter, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Inheritance Patterns, Male, Models, Molecular, Molecular Diagnostic Techniques, Mutation, Missense, Phenotype, Protein Conformation, Radiography, Sequence Analysis, DNA, Spine, Structure-Activity Relationship, T-Box Domain Proteins, Whole Exome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23907}, author = {Chen, Weisheng and Lin, Jiachen and Wang, Lianlei and Li, Xiaoxin and Zhao, Sen and Liu, Jiaqi and Akdemir, Zeynep C and Zhao, Yanxue and Du, Renqian and Ye, Yongyu and Song, Xiaofei and Zhang, Yuanqiang and Yan, Zihui and Yang, Xinzhuang and Lin, Mao and Shen, Jianxiong and Wang, Shengru and Gao, Na and Yang, Ying and Liu, Ying and Li, Wenli and Liu, Jia and Zhang, Na and Yang, Xu and Xu, Yuan and Zhang, Jianguo and Delgado, Mauricio R and Posey, Jennifer E and Qiu, Guixing and Rios, Jonathan J and Liu, Pengfei and Wise, Carol A and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan} } @article {797, title = {A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis.}, journal = {NPJ Genom Med}, volume = {5}, year = {2020}, month = {2020}, pages = {37}, abstract = {

Exome sequencing (ES) has become one of the important diagnostic tools in clinical genetics with a reported diagnostic rate of 25-58\%. Many studies have illustrated the diagnostic and immediate clinical impact of ES. However, up to 75\% of individuals remain undiagnosed and there is scarce evidence supporting clinical utility beyond a follow-up period of >1 year. This is a 3-year follow-up analysis to our previous publication by Mak et al. ( 3:19, 2018), to evaluate the long-term clinical utility of ES and the diagnostic potential of exome reanalysis. The diagnostic yield of the initial study was 41\% (43/104). Exome reanalysis in 46 undiagnosed individuals has achieved 12 new diagnoses. The additional yield compared with the initial analysis was at least 12\% (increased from 41\% to at least 53\%). After a median follow-up period of 3.4 years, change in clinical management was observed in 72.2\% of the individuals (26/36), leading to positive change in clinical outcome in four individuals (11\%). There was a minimum healthcare cost saving of HKD$152,078 (USD$19,497; {\texteuro}17,282) annually for these four individuals. There were a total of six pregnancies from five families within the period. Prenatal diagnosis was performed in four pregnancies; one fetus was affected and resulted in termination. None of the parents underwent preimplantation genetic diagnosis. This 3-year follow-up study demonstrated the long-term clinical utility of ES at individual, familial and health system level, and the promising diagnostic potential of subsequent reanalysis. This highlights the benefits of implementing ES and regular reanalysis in the clinical setting.

}, issn = {2056-7944}, doi = {10.1038/s41525-020-00144-x}, author = {Fung, Jasmine L F and Yu, Mullin H C and Huang, Shushu and Chung, Claudia C Y and Chan, Marcus C Y and Pajusalu, Sander and Mak, Christopher C Y and Hui, Vivian C C and Tsang, Mandy H Y and Yeung, Kit San and Lek, Monkol and Chung, Brian H Y} } @article {868, title = {Titin Truncating Variants in Adults Without Known Congestive Heart~Failure.}, journal = {J Am Coll Cardiol}, volume = {75}, year = {2020}, month = {2020 03 17}, pages = {1239-1241}, keywords = {Adult, Aged, Asymptomatic Diseases, Connectin, Female, Genetic Variation, Heart Failure, Humans, Male, Middle Aged}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.01.013}, author = {Pirruccello, James P and Bick, Alexander and Chaffin, Mark and Aragam, Krishna G and Choi, Seung Hoan and Lubitz, Steven A and Ho, Carolyn Y and Ng, Kenney and Philippakis, Anthony and Ellinor, Patrick T and Kathiresan, Sekar and Khera, Amit V} } @article {775, title = {Topical cholesterol/lovastatin for the treatment of porokeratosis: A pathogenesis-directed therapy.}, journal = {J Am Acad Dermatol}, volume = {82}, year = {2020}, month = {2020 Jan}, pages = {123-131}, abstract = {

BACKGROUND: Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy. We hypothesized that topical therapy that aims to replenish cholesterol, an essential mevalonate pathway end-product, and block the accumulation of mevalonate pathway toxic metabolites could alleviate porokeratosis.

OBJECTIVE: To study the efficacy of topical cholesterol/lovastatin in different variants of porokeratosis.

METHODS: We enrolled a series of 5 porokeratosis patients,1 with disseminated superficial actinic porokeratosis, 2 with porokeratosis palmaris et plantaris disseminata, and 2 with linear porokeratosis. Patients were genotyped before initiation of therapy. Patients then applied topical cholesterol/lovastatin twice daily to a unilaterally defined treatment area for up to 3~months. The response was evaluated and patients photographed at every visit.

RESULTS: Three patients had MVD mutations, and 2 patients had PMVK mutations. Treatment with topical cholesterol/lovastatin (but not cholesterol alone) resulted in near complete clearance of disseminated superficial actinic porokeratosis lesions after 4~weeks of therapy and moderate improvement of porokeratosis palmaris et plantaris disseminata lesions and linear porokeratosis lesions. There were no adverse events.

LIMITATIONS: Case series design with a small number of patients.

CONCLUSION: Topical cholesterol/lovastatin is an effective and well-tolerated therapy for porokeratosis that underscores the utility of a pathogenesis-based therapy that replaces deficient end products and prevents accumulation of potentially toxic precursors.

}, issn = {1097-6787}, doi = {10.1016/j.jaad.2019.08.043}, author = {Atzmony, Lihi and Lim, Young H and Hamilton, Claire and Leventhal, Jonathan S and Wagner, Annette and Paller, Amy S and Choate, Keith A} } @article {845, title = {Transcriptomic signatures across human tissues identify functional rare genetic variation.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.

}, keywords = {Genetic Variation, Genome, Human, Humans, Multifactorial Inheritance, Organ Specificity, Transcriptome}, issn = {1095-9203}, doi = {10.1126/science.aaz5900}, author = {Ferraro, Nicole M and Strober, Benjamin J and Einson, Jonah and Abell, Nathan S and Aguet, Francois and Barbeira, Alvaro N and Brandt, Margot and Bucan, Maja and Castel, Stephane E and Davis, Joe R and Greenwald, Emily and Hess, Gaelen T and Hilliard, Austin T and Kember, Rachel L and Kotis, Bence and Park, YoSon and Peloso, Gina and Ramdas, Shweta and Scott, Alexandra J and Smail, Craig and Tsang, Emily K and Zekavat, Seyedeh M and Ziosi, Marcello and Ardlie, Kristin G and Assimes, Themistocles L and Bassik, Michael C and Brown, Christopher D and Correa, Adolfo and Hall, Ira and Im, Hae Kyung and Li, Xin and Natarajan, Pradeep and Lappalainen, Tuuli and Mohammadi, Pejman and Montgomery, Stephen B and Battle, Alexis} } @article {844, title = {Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 10 12}, pages = {5139}, abstract = {

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

}, keywords = {Angiotensin-Converting Enzyme 2, Betacoronavirus, Child, Coronavirus Infections, COVID-19, Epithelial Cells, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Host-Pathogen Interactions, Humans, Inflammation, Interferons, Interleukin-13, Middle Aged, Nasal Mucosa, Pandemics, Peptidyl-Dipeptidase A, Pneumonia, Viral, SARS-CoV-2, Serine Endopeptidases, Virus Internalization}, issn = {2041-1723}, doi = {10.1038/s41467-020-18781-2}, author = {Sajuthi, Satria P and DeFord, Peter and Li, Yingchun and Jackson, Nathan D and Montgomery, Michael T and Everman, Jamie L and Rios, Cydney L and Pruesse, Elmar and Nolin, James D and Plender, Elizabeth G and Wechsler, Michael E and Mak, Angel C Y and Eng, Celeste and Salazar, Sandra and Medina, Vivian and Wohlford, Eric M and Huntsman, Scott and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Rice, Kenneth M and Kumar, Rajesh and Oh, Sam and Rodriguez-Santana, Jose and Burchard, Esteban G and Seibold, Max A} } @article {860, title = {Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium.}, journal = {bioRxiv}, year = {2020}, month = {2020 Apr 10}, abstract = {

Coronavirus disease 2019 (COVID-19) outcomes vary from asymptomatic infection to death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, ACE2, and the spike protein activator, TMPRSS2. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci (eQTL) for both and , that vary in frequency across world populations. Importantly, we find is part of a mucus secretory network, highly upregulated by T2 inflammation through the action of interleukin-13, and that interferon response to respiratory viruses highly upregulates expression. Finally, we define airway responses to coronavirus infections in children, finding that these infections upregulate while also stimulating a more pronounced cytotoxic immune response relative to other respiratory viruses. Our results reveal mechanisms likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

}, doi = {10.1101/2020.04.09.034454}, author = {Sajuthi, Satria P and DeFord, Peter and Jackson, Nathan D and Montgomery, Michael T and Everman, Jamie L and Rios, Cydney L and Pruesse, Elmar and Nolin, James D and Plender, Elizabeth G and Wechsler, Michael E and Mak, Angel Cy and Eng, Celeste and Salazar, Sandra and Medina, Vivian and Wohlford, Eric M and Huntsman, Scott and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Rice, Kenneth M and Kumar, Rajesh and Oh, Sam and Rodriguez-Santana, Jose and Burchard, Esteban G and Seibold, Max A} } @article {820, title = {Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines.}, journal = {JCI Insight}, volume = {5}, year = {2020}, month = {2020 08 06}, abstract = {

Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder that presents with cardio-cutaneous-craniofacial defects. Hypertrophic cardiomyopathy (HCM) represents the major life-threatening presentation in NSML. Mutations in the PTPN11 gene that encodes for the protein tyrosine phosphatase (PTP), SHP2, represents the predominant cause of HCM in NSML. NSML-associated PTPN11 mutations render SHP2 catalytically inactive with an "open" conformation. NSML-associated PTPN11 mutations cause hypertyrosyl phosphorylation of the transmembrane glycoprotein, protein zero-related (PZR), resulting in increased SHP2 binding. Here we show that NSML mice harboring a tyrosyl phosphorylation-defective mutant of PZR (NSML/PZRY242F) that is defective for SHP2 binding fail to develop HCM. Enhanced AKT/S6 kinase signaling in heart lysates of NSML mice was reversed in NSML/PZRY242F mice, demonstrating that PZR/SHP2 interactions promote aberrant AKT/S6 kinase activity in NSML. Enhanced PZR tyrosyl phosphorylation in the hearts of NSML mice was found to drive myocardial fibrosis by engaging an Src/NF-κB pathway, resulting in increased activation of IL-6. Increased expression of IL-6 in the hearts of NSML mice was reversed in NSML/PZRY242F mice, and PZRY242F mutant fibroblasts were defective for IL-6 secretion and STAT3-mediated fibrogenesis. These results demonstrate that NSML-associated PTPN11 mutations that induce PZR hypertyrosyl phosphorylation trigger pathophysiological signaling that promotes HCM and cardiac fibrosis.

}, keywords = {Animals, Cardiomyopathy, Hypertrophic, Disease Models, Animal, Female, Intracellular Signaling Peptides and Proteins, LEOPARD Syndrome, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Myocytes, Cardiac, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Tyrosine}, issn = {2379-3708}, doi = {10.1172/jci.insight.137753}, author = {Yi, Jae-Sung and Perla, Sravan and Enyenihi, Liz and Bennett, Anton M} } @article {853, title = {Validation of a Genome-Wide Polygenic~Score for Coronary Artery~Disease in~South Asians.}, journal = {J Am Coll Cardiol}, volume = {76}, year = {2020}, month = {2020 08 11}, pages = {703-714}, abstract = {

BACKGROUND: Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.

OBJECTIVES: This analysis used summary statistics from a prior genome-wide association study to derive a new GPS for South Asians.

METHODS: This GPS was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPS reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPS reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.

RESULTS: The GPS, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p~<~0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p~<~0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5\% of the GPS distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p~<~0.05 for each).

CONCLUSIONS: The new GPS has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.

}, keywords = {Adult, Aged, Bangladesh, Case-Control Studies, Coronary Artery Disease, Female, Genome-Wide Association Study, Humans, India, Male, Middle Aged, Multifactorial Inheritance}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.06.024}, author = {Wang, Minxian and Menon, Ramesh and Mishra, Sanghamitra and Patel, Aniruddh P and Chaffin, Mark and Tanneeru, Deepak and Deshmukh, Manjari and Mathew, Oshin and Apte, Sanika and Devanboo, Christina S and Sundaram, Sumathi and Lakshmipathy, Praveena and Murugan, Sakthivel and Sharma, Krishna Kumar and Rajendran, Karthikeyan and Santhosh, Sam and Thachathodiyl, Rajesh and Ahamed, Hisham and Balegadde, Aniketh Vijay and Alexander, Thomas and Swaminathan, Krishnan and Gupta, Rajeev and Mullasari, Ajit S and Sigamani, Alben and Kanchi, Muralidhar and Peterson, Andrew S and Butterworth, Adam S and Danesh, John and Di Angelantonio, Emanuele and Naheed, Aliya and Inouye, Michael and Chowdhury, Rajiv and Vedam, Ramprasad L and Kathiresan, Sekar and Gupta, Ravi and Khera, Amit V} } @article {961, title = {Variants in CAPZA2, a member of an F-actin capping complex, cause intellectual disability and developmental delay.}, journal = {Hum Mol Genet}, volume = {29}, year = {2020}, month = {2020 06 03}, pages = {1537-1546}, abstract = {

The actin cytoskeleton is regulated by many proteins including capping proteins that stabilize actin filaments (F-actin) by inhibiting actin polymerization and depolymerization. Here, we report two pediatric probands who carry damaging heterozygous de novo mutations in CAPZA2 (HGNC: 1490) and exhibit neurological symptoms with shared phenotypes including global motor development delay, speech delay, intellectual disability, hypotonia and a history of seizures. CAPZA2 encodes a subunit of an F-actin-capping protein complex (CapZ). CapZ is an obligate heterodimer consisting of α and β heterodimer conserved from yeast to human. Vertebrate genomes contain three α subunits encoded by three different genes and CAPZA2 encodes the α2 subunit. The single orthologue of CAPZA genes in Drosophila is cpa. Loss of cpa leads to lethality in early development and expression of the human reference; CAPZA2 rescues this lethality. However, the two CAPZA2 variants identified in the probands rescue this lethality at lower efficiency than the reference. Moreover, expression of the CAPZA2 variants affects bristle morphogenesis, a process that requires extensive actin polymerization and bundling during development. Taken together, our findings suggest that variants in CAPZA2 lead to a non-syndromic neurodevelopmental disorder in children.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddaa078}, author = {Huang, Yan and Mao, Xiao and van Jaarsveld, Richard H and Shu, Li and Terhal, Paulien A and Jia, Zhengjun and Xi, Hui and Peng, Ying and Yan, Huiming and Yuan, Shan and Li, Qibin and Wang, Hua and Bellen, Hugo J} } @article {752, title = {Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis.}, journal = {Kidney Int}, volume = {97}, year = {2020}, month = {2020 03}, pages = {567-579}, abstract = {

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70\% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59\%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2019.09.026}, author = {Jobst-Schwan, Tilman and Kl{\"a}mbt, Verena and Tarsio, Maureen and Heneghan, John F and Majmundar, Amar J and Shril, Shirlee and Buerger, Florian and Ottlewski, Isabel and Shmukler, Boris E and Topaloglu, Rezan and Hashmi, Seema and Hafeez, Farkhanda and Emma, Francesco and Greco, Marcella and Laube, Guido F and Fathy, Hanan M and Pohl, Martin and Gellermann, Jutta and Milosevic, Danko and Baum, Michelle A and Mane, Shrikant and Lifton, Richard P and Kane, Patricia M and Alper, Seth L and Hildebrandt, Friedhelm} } @article {858, title = {Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late.}, journal = {Clin Genet}, volume = {98}, year = {2020}, month = {2020 11}, pages = {477-485}, abstract = {

Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1\%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3\%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50\% of them.

}, issn = {1399-0004}, doi = {10.1111/cge.13823}, author = {Minardi, Raffaella and Licchetta, Laura and Baroni, Maria Chiara and Pippucci, Tommaso and Stipa, Carlotta and Mostacci, Barbara and Severi, Giulia and Toni, Francesco and Bergonzini, Luca and Carelli, Valerio and Seri, Marco and Tinuper, Paolo and Bisulli, Francesca} } @article {761, title = {Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 06}, pages = {1387-1399}, abstract = {

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population.

METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW.

RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6\% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF <= 0.005) with CADD score >= 25 in genes linked to AF in cases compared to controls (P = .0023).

CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

}, keywords = {Adolescent, Adult, AMP-Activated Protein Kinases, Ankyrins, Atrial Fibrillation, Carrier Proteins, Child, Cohort Studies, Cytoskeletal Proteins, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heart Atria, Homeodomain Proteins, Humans, LIM Domain Proteins, Male, Mutation, Transcription Factors, Whole Exome Sequencing, Wolff-Parkinson-White Syndrome, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61571}, author = {Coban-Akdemir, Zeynep H and Charng, Wu-Lin and Azamian, Mahshid and Paine, Ingrid S and Punetha, Jaya and Grochowski, Christopher M and Gambin, Tomasz and Valdes, Santiago O and Cannon, Bryan and Zapata, Gladys and Hernandez, Patricia P and Jhangiani, Shalini and Doddapaneni, Harsha and Hu, Jianhong and Boricha, Fatima and Muzny, Donna M and Boerwinkle, Eric and Yang, Yaping and Gibbs, Richard A and Posey, Jennifer E and Wehrens, Xander H T and Belmont, John W and Kim, Jeffrey J and Miyake, Christina Y and Lupski, James R and Lalani, Seema R} } @article {710, title = {X-chromosome association studies of congenital heart defects.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 01}, pages = {250-254}, keywords = {Chromosome Deletion, Chromosomes, Human, X, Female, Genes, X-Linked, Genetic Association Studies, Genetic Predisposition to Disease, Heart Defects, Congenital, Humans, Male}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61411}, author = {Agopian, A J and Hoang, Thanh T and Goldmuntz, Elizabeth and Hakonarson, Hakon and Musfee, Fadi I and Mitchell, Laura E} } @article {720, title = {Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 01}, pages = {150-168}, abstract = {

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM$\#$ 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization~and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65\%) and the clustering of ~47\% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

}, keywords = {Child, Child, Preschool, Chromosome Breakpoints, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, X, Comparative Genomic Hybridization, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Nervous System Diseases, Pedigree, Phenotype, Quantitative Trait, Heritable, Repetitive Sequences, Nucleic Acid, Sex Factors, Syndrome, X Chromosome Inactivation}, issn = {1098-1004}, doi = {10.1002/humu.23902}, author = {Hijazi, Hadia and Coelho, Fernanda S and Gonzaga-Jauregui, Claudia and Bernardini, Laura and Mar, Soe S and Manning, Melanie A and Hanson-Kahn, Andrea and Naidu, Sakkubai and Srivastava, Siddharth and Lee, Jennifer A and Jones, Julie R and Friez, Michael J and Alberico, Thomas and Torres, Barbara and Fang, Ping and Cheung, Sau Wai and Song, Xiaofei and Davis-Williams, Angelique and Jornlin, Carly and Wight, Patricia A and Patyal, Pankaj and Taube, Jennifer and Poretti, Andrea and Inoue, Ken and Zhang, Feng and Pehlivan, Davut and Carvalho, Claudia M B and Hobson, Grace M and Lupski, James R} } @article {699, title = {A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.}, journal = {Hum Mutat}, volume = {40}, year = {2019}, month = {2019 08}, pages = {1156-1171}, abstract = {

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular,~RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.

}, issn = {1098-1004}, doi = {10.1002/humu.23769}, author = {Larson, Eric D and Magno, Jose Pedrito M and Steritz, Matthew J and Llanes, Erasmo Gonzalo D V and Cardwell, Jonathan and Pedro, Melquiadesa and Roberts, Tori Bootpetch and Einarsdottir, Elisabet and Rosanes, Rose Anne Q and Greenlee, Christopher and Santos, Rachel Ann P and Yousaf, Ayesha and Streubel, Sven-Olrik and Santos, Aileen Trinidad R and Ruiz, Amanda G and Lagrana-Villagracia, Sheryl Mae and Ray, Dylan and Yarza, Talitha Karisse L and Scholes, Melissa A and Anderson, Catherine B and Acharya, Anushree and Gubbels, Samuel P and Bamshad, Michael J and Cass, Stephen P and Lee, Nanette R and Shaikh, Rehan S and Nickerson, Deborah A and Mohlke, Karen L and Prager, Jeremy D and Cruz, Teresa Luisa G and Yoon, Patricia J and Abes, Generoso T and Schwartz, David A and Chan, Abner L and Wine, Todd M and Cutiongco-de la Paz, Eva Maria and Friedman, Norman and Kechris, Katerina and Kere, Juha and Leal, Suzanne M and Yang, Ivana V and Patel, Janak A and Tantoco, Ma Leah C and Riazuddin, Saima and Chan, Kenny H and Mattila, Petri S and Reyes-Quintos, Maria Rina T and Ahmed, Zubair M and Jenkins, Herman A and Chonmaitree, Tasnee and Hafr{\'e}n, Lena and Chiong, Charlotte M and Santos-Cortez, Regie Lyn P} } @article {687, title = {Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Sep 05}, pages = {493-508}, abstract = {

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.07.007}, author = {Flex, Elisabetta and Martinelli, Simone and Van Dijck, Anke and Ciolfi, Andrea and Cecchetti, Serena and Coluzzi, Elisa and Pannone, Luca and Andreoli, Cristina and Radio, Francesca Clementina and Pizzi, Simone and Carpentieri, Giovanna and Bruselles, Alessandro and Catanzaro, Giuseppina and Pedace, Lucia and Miele, Evelina and Carcarino, Elena and Ge, Xiaoyan and Chijiwa, Chieko and Lewis, M E Suzanne and Meuwissen, Marije and Kenis, Sandra and Van der Aa, Nathalie and Larson, Austin and Brown, Kathleen and Wasserstein, Melissa P and Skotko, Brian G and Begtrup, Amber and Person, Richard and Karayiorgou, Maria and Roos, J Louw and Van Gassen, Koen L and Koopmans, Marije and Bijlsma, Emilia K and Santen, Gijs W E and Barge-Schaapveld, Daniela Q C M and Ruivenkamp, Claudia A L and Hoffer, Mariette J V and Lalani, Seema R and Streff, Haley and Craigen, William J and Graham, Brett H and van den Elzen, Annette P M and Kamphuis, Daan J and {\~O}unap, Katrin and Reinson, Karit and Pajusalu, Sander and Wojcik, Monica H and Viberti, Clara and Di Gaetano, Cornelia and Bertini, Enrico and Petrucci, Simona and De Luca, Alessandro and Rota, Rossella and Ferretti, Elisabetta and Matullo, Giuseppe and Dallapiccola, Bruno and Sgura, Antonella and Walkiewicz, Magdalena and Kooy, R Frank and Tartaglia, Marco} } @article {718, title = {Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.}, journal = {J Clin Invest}, volume = {129}, year = {2019}, month = {2019 Dec 02}, pages = {5568-5583}, abstract = {

Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.

}, issn = {1558-8238}, doi = {10.1172/JCI130600}, author = {Morelli, Kathryn H and Griffin, Laurie B and Pyne, Nettie K and Wallace, Lindsay M and Fowler, Allison M and Oprescu, Stephanie N and Takase, Ryuichi and Wei, Na and Meyer-Schuman, Rebecca and Mellacheruvu, Dattatreya and Kitzman, Jacob O and Kocen, Samuel G and Hines, Timothy J and Spaulding, Emily L and Lupski, James R and Nesvizhskii, Alexey and Mancias, Pedro and Butler, Ian J and Yang, Xiang-Lei and Hou, Ya-Ming and Antonellis, Anthony and Harper, Scott Q and Burgess, Robert W} } @article {691, title = {Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Oct}, pages = {2056-2066}, abstract = {

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61315}, author = {Karaca, Ender and Posey, Jennifer E and Bostwick, Bret and Liu, Pengfei and Gezdirici, Alper and Yesil, G{\"o}zde and Coban Akdemir, Zeynep and Bayram, Yavuz and Harms, Frederike L and Meinecke, Peter and Alawi, Malik and Bacino, Carlos A and Sutton, V Reid and Kort{\"u}m, Fanny and Lupski, James R} } @article {692, title = {Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy.}, journal = {Ann Clin Transl Neurol}, volume = {6}, year = {2019}, month = {2019 Aug}, pages = {1395-1406}, abstract = {

OBJECTIVE: To characterize the molecular and clinical phenotypic basis of developmental and epileptic encephalopathies caused by rare biallelic variants in CACNA2D2.

METHODS: Two affected individuals from a family with clinical features of early onset epileptic encephalopathy were recruited for exome sequencing at the Centers for Mendelian Genomics to identify their molecular diagnosis. GeneMatcher facilitated identification of a second family with a shared candidate disease gene identified through clinical gene panel-based testing.

RESULTS: Rare biallelic CACNA2D2 variants have been previously reported in three families with developmental and epileptic encephalopathy, and one family with congenital ataxia. We identified three individuals in two unrelated families with novel homozygous rare variants in CACNA2D2 with clinical features of developmental and epileptic encephalopathy and cerebellar atrophy. Family 1 includes two affected siblings with a likely damaging homozygous rare missense variant c.1778G>C; p.(Arg593Pro) in CACNA2D2. Family 2 includes a proband with a homozygous rare nonsense variant c.485_486del; p.(Tyr162Ter) in CACNA2D2. We compared clinical and molecular findings from all nine individuals reported to date and note that cerebellar atrophy is shared among all.

INTERPRETATION: Our study supports the candidacy of CACNA2D2 as a disease gene associated with a phenotypic spectrum of neurological disease that include features of developmental and epileptic encephalopathy, ataxia, and cerebellar atrophy. Age at presentation may affect apparent penetrance of neurogenetic trait manifestations and of a particular clinical neurological endophenotype, for example, seizures or ataxia.

}, issn = {2328-9503}, doi = {10.1002/acn3.50824}, author = {Punetha, Jaya and Karaca, Ender and Gezdirici, Alper and Lamont, Ryan E and Pehlivan, Davut and Marafi, Dana and Appendino, Juan P and Hunter, Jill V and Akdemir, Zeynep C and Fatih, Jawid M and Jhangiani, Shalini N and Gibbs, Richard A and Innes, A Micheil and Posey, Jennifer E and Lupski, James R} } @article {677, title = {Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 Jun 06}, pages = {1073-1087}, abstract = {

Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374~kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.04.002}, author = {Ansar, Muhammad and Ullah, Farid and Paracha, Sohail A and Adams, Darius J and Lai, Abbe and Pais, Lynn and Iwaszkiewicz, Justyna and Millan, Francisca and Sarwar, Muhammad T and Agha, Zehra and Shah, Sayyed Fahim and Qaisar, Azhar Ali and Falconnet, Emilie and Zoete, Vincent and Ranza, Emmanuelle and Makrythanasis, Periklis and Santoni, Federico A and Ahmed, Jawad and Katsanis, Nicholas and Walsh, Christopher and Davis, Erica E and Antonarakis, Stylianos E} } @article {593, title = {Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 03 07}, pages = {422-438}, abstract = {

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive~inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.01.007}, author = {Burrage, Lindsay C and Reynolds, John J and Baratang, Nissan Vida and Phillips, Jennifer B and Wegner, Jeremy and McFarquhar, Ashley and Higgs, Martin R and Christiansen, Audrey E and Lanza, Denise G and Seavitt, John R and Jain, Mahim and Li, Xiaohui and Parry, David A and Raman, Vandana and Chitayat, David and Chinn, Ivan K and Bertuch, Alison A and Karaviti, Lefkothea and Schlesinger, Alan E and Earl, Dawn and Bamshad, Michael and Savarirayan, Ravi and Doddapaneni, Harsha and Muzny, Donna and Jhangiani, Shalini N and Eng, Christine M and Gibbs, Richard A and Bi, Weimin and Emrick, Lisa and Rosenfeld, Jill A and Postlethwait, John and Westerfield, Monte and Dickinson, Mary E and Beaudet, Arthur L and Ranza, Emmanuelle and Huber, Celine and Cormier-Daire, Val{\'e}rie and Shen, Wei and Mao, Rong and Heaney, Jason D and Orange, Jordan S and Bertola, D{\'e}bora and Yamamoto, Guilherme L and Baratela, Wagner A R and Butler, Merlin G and Ali, Asim and Adeli, Mehdi and Cohn, Daniel H and Krakow, Deborah and Jackson, Andrew P and Lees, Melissa and Offiah, Amaka C and Carlston, Colleen M and Carey, John C and Stewart, Grant S and Bacino, Carlos A and Campeau, Philippe M and Lee, Brendan} } @article {573, title = {Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 12}, pages = {708}, abstract = {

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

}, keywords = {Alleles, Animals, Brain Diseases, Cell Line, Disease Models, Animal, Epilepsy, Female, Fibroblasts, Gene Knockout Techniques, Genetic Predisposition to Disease, Humans, Loss of Function Mutation, Male, Microcephaly, Models, Molecular, Neurodevelopmental Disorders, Pedigree, Prosencephalon, Valine-tRNA Ligase, Zebrafish}, issn = {2041-1723}, doi = {10.1038/s41467-018-07953-w}, author = {Siekierska, Aleksandra and Stamberger, Hannah and Deconinck, Tine and Oprescu, Stephanie N and Partoens, Mich{\`e}le and Zhang, Yifan and Sourbron, Jo and Adriaenssens, Elias and Mullen, Patrick and Wiencek, Patrick and Hardies, Katia and Lee, Jeong-Soo and Giong, Hoi-Khoanh and Distelmaier, Felix and Elpeleg, Orly and Helbig, Katherine L and Hersh, Joseph and Isikay, Sedat and Jordan, Elizabeth and Karaca, Ender and Kecskes, Angela and Lupski, James R and Kovacs-Nagy, Reka and May, Patrick and Narayanan, Vinodh and Pendziwiat, Manuela and Ramsey, Keri and Rangasamy, Sampathkumar and Shinde, Deepali N and Spiegel, Ronen and Timmerman, Vincent and von Spiczak, Sarah and Helbig, Ingo and Weckhuysen, Sarah and Francklyn, Christopher and Antonellis, Anthony and de Witte, Peter and De Jonghe, Peter} } @article {725, title = {Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Jul 03}, pages = {151-165}, abstract = {

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.05.016}, author = {Rafehi, Haloom and Szmulewicz, David J and Bennett, Mark F and Sobreira, Nara L M and Pope, Kate and Smith, Katherine R and Gillies, Greta and Diakumis, Peter and Dolzhenko, Egor and Eberle, Michael A and Barcina, Mar{\'\i}a Garc{\'\i}a and Breen, David P and Chancellor, Andrew M and Cremer, Phillip D and Delatycki, Martin B and Fogel, Brent L and Hackett, Anna and Halmagyi, G Michael and Kapetanovic, Solange and Lang, Anthony and Mossman, Stuart and Mu, Weiyi and Patrikios, Peter and Perlman, Susan L and Rosemergy, Ian and Storey, Elsdon and Watson, Shaun R D and Wilson, Michael A and Zee, David S and Valle, David and Amor, David J and Bahlo, Melanie and Lockhart, Paul J} } @article {515, title = {Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 03}, pages = {663-675}, abstract = {

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants~in known and candidate cohesinopathy genes from a clinical exome perspective.

METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

}, keywords = {Adolescent, Alleles, Antigens, Nuclear, Biological Variation, Population, Carrier Proteins, Cell Cycle Proteins, Child, Child, Preschool, Chromosomal Proteins, Non-Histone, Cohort Studies, De Lange Syndrome, Exome, Female, Gene Frequency, Genetic Heterogeneity, Humans, INDEL Mutation, Male, Mutation, Nuclear Proteins, Phenotype, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Retrospective Studies, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0085-6}, author = {Yuan, Bo and Neira, Juanita and Pehlivan, Davut and Santiago-Sim, Teresa and Song, Xiaofei and Rosenfeld, Jill and Posey, Jennifer E and Patel, Vipulkumar and Jin, Weihong and Adam, Margaret P and Baple, Emma L and Dean, John and Fong, Chin-To and Hickey, Scott E and Hudgins, Louanne and Leon, Eyby and Madan-Khetarpal, Suneeta and Rawlins, Lettie and Rustad, Cecilie F and Stray-Pedersen, Asbj{\o}rg and Tveten, Kristian and Wenger, Olivia and Diaz, Jullianne and Jenkins, Laura and Martin, Laura and McGuire, Marianne and Pietryga, Marguerite and Ramsdell, Linda and Slattery, Leah and Abid, Farida and Bertuch, Alison A and Grange, Dorothy and Immken, LaDonna and Schaaf, Christian P and Van Esch, Hilde and Bi, Weimin and Cheung, Sau Wai and Breman, Amy M and Smith, Janice L and Shaw, Chad and Crosby, Andrew H and Eng, Christine and Yang, Yaping and Lupski, James R and Xiao, Rui and Liu, Pengfei} } @article {731, title = {A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency.}, journal = {J Allergy Clin Immunol}, volume = {143}, year = {2019}, month = {2019 Jun}, pages = {2296-2299}, issn = {1097-6825}, doi = {10.1016/j.jaci.2019.02.003}, author = {Volpi, Stefano and Cicalese, Maria Pia and Tuijnenburg, Paul and Tool, Anton T J and Cuadrado, Eloy and Abu-Halaweh, Marwan and Ahanchian, Hamid and Alzyoud, Raed and Akdemir, Zeynep Coban and Barzaghi, Federica and Blank, Alexander and Boisson, Bertrand and Bottino, Cristina and Brigida, Immacolata and Caorsi, Roberta and Casanova, Jean-Laurent and Chiesa, Sabrina and Chinn, Ivan Kingyue and D{\"u}ckers, Gregor and Enders, Anselm and Erichsen, Hans Christian and Forbes, Lisa R and Gambin, Tomasz and Gattorno, Marco and Karimiani, Ehsan Ghayoor and Giliani, Silvia and Gold, Michael S and Jacobsen, Eva-Maria and Jansen, Machiel H and King, Jovanka R and Laxer, Ronald M and Lupski, James R and Mace, Emily and Marcenaro, Stefania and Maroofian, Reza and Meijer, Alexander B and Niehues, Tim and Notarangelo, Luigi D and Orange, Jordan and Pannicke, Ulrich and Pearson, Chris and Picco, Paolo and Quinn, Patrick J and Schulz, Ansgar and Seeborg, Filiz and Stray-Pedersen, Asbj{\o}rg and Tawamie, Hasan and van Leeuwen, Ester M M and Aiuti, Alessandro and Yeung, Rae and Schwarz, Klaus and Kuijpers, Taco W} } @article {576, title = {Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {213-228}, abstract = {

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61\%) individuals. In addition to TBX4, the overlapping \~{}2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

}, keywords = {DNA Copy Number Variations, Female, Fibroblast Growth Factor 10, Gene Expression Regulation, Gestational Age, Humans, Infant, Newborn, Infant, Newborn, Diseases, Lung, Lung Diseases, Male, Maternal Inheritance, Organogenesis, Paternal Inheritance, Pedigree, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 2, Signal Transduction, T-Box Domain Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.010}, author = {Karolak, Justyna A and Vincent, Marie and Deutsch, Gail and Gambin, Tomasz and Cogn{\'e}, Benjamin and Pichon, Olivier and Vetrini, Francesco and Mefford, Heather C and Dines, Jennifer N and Golden-Grant, Katie and Dipple, Katrina and Freed, Amanda S and Leppig, Kathleen A and Dishop, Megan and Mowat, David and Bennetts, Bruce and Gifford, Andrew J and Weber, Martin A and Lee, Anna F and Boerkoel, Cornelius F and Bartell, Tina M and Ward-Melver, Catherine and Besnard, Thomas and Petit, Florence and Bache, Iben and T{\"u}mer, Zeynep and Denis-Musquer, Marie and Joubert, Madeleine and Martinovic, Jelena and B{\'e}n{\'e}teau, Claire and Molin, Arnaud and Carles, Dominique and Andr{\'e}, Gwenaelle and Bieth, Eric and Chassaing, Nicolas and Devisme, Louise and Chalabreysse, Lara and Pasquier, Laurent and Secq, V{\'e}ronique and Don, Massimiliano and Orsaria, Maria and Missirian, Chantal and Mortreux, J{\'e}r{\'e}mie and Sanlaville, Damien and Pons, Linda and K{\"u}ry, S{\'e}bastien and B{\'e}zieau, St{\'e}phane and Liet, Jean-Michel and Joram, Nicolas and Bihou{\'e}e, Tiphaine and Scott, Daryl A and Brown, Chester W and Scaglia, Fernando and Tsai, Anne Chun-Hui and Grange, Dorothy K and Phillips, John A and Pfotenhauer, Jean P and Jhangiani, Shalini N and Gonzaga-Jauregui, Claudia G and Chung, Wendy K and Schauer, Galen M and Lipson, Mark H and Mercer, Catherine L and van Haeringen, Arie and Liu, Qian and Popek, Edwina and Coban Akdemir, Zeynep H and Lupski, James R and Szafranski, Przemyslaw and Isidor, Bertrand and Le Caignec, Cedric and Stankiewicz, Pawe{\l}} } @article {586, title = {Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 03}, pages = {694-704}, abstract = {

PURPOSE: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.

METHODS: IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.

RESULTS: Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.

CONCLUSION: Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.

}, keywords = {Adult, Chromosome Mapping, DNA Mutational Analysis, DNA, Intergenic, Female, HEK293 Cells, Humans, Male, Mutation, Pedigree, Proteins, Retinal Degeneration, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0104-7}, author = {Jamshidi, Farzad and Place, Emily M and Mehrotra, Sudeep and Navarro-Gomez, Daniel and Maher, Mathew and Branham, Kari E and Valkanas, Elise and Cherry, Timothy J and Lek, Monkol and Macarthur, Daniel and Pierce, Eric A and Bujakowska, Kinga M} } @article {663, title = {Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases.}, journal = {Genome Med}, volume = {11}, year = {2019}, month = {2019 05 17}, pages = {30}, abstract = {

BACKGROUND: Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.

METHODS: In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.

RESULTS: The QC array can detect ~ 70\% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9\% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2\% vs 4.6\%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4\%~(189/1089) of molecularly diagnosed ES cases with CMA and~were estimated to contribute in 10.6\% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions~(mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.

CONCLUSIONS: Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.

}, issn = {1756-994X}, doi = {10.1186/s13073-019-0639-5}, author = {Dharmadhikari, Avinash V and Ghosh, Rajarshi and Yuan, Bo and Liu, Pengfei and Dai, Hongzheng and Al Masri, Sami and Scull, Jennifer and Posey, Jennifer E and Jiang, Allen H and He, Weimin and Vetrini, Francesco and Braxton, Alicia A and Ward, Patricia and Chiang, Theodore and Qu, Chunjing and Gu, Shen and Shaw, Chad A and Smith, Janice L and Lalani, Seema and Stankiewicz, Pawel and Cheung, Sau-Wai and Bacino, Carlos A and Patel, Ankita and Breman, Amy M and Wang, Xia and Meng, Linyan and Xiao, Rui and Xia, Fan and Muzny, Donna and Gibbs, Richard A and Beaudet, Arthur L and Eng, Christine M and Lupski, James R and Yang, Yaping and Bi, Weimin} } @article {670, title = {CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 12}, pages = {2723-2733}, abstract = {

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD).

METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function.

RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits.

CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

}, issn = {1530-0366}, doi = {10.1038/s41436-019-0585-z}, author = {Konrad, Enrico D H and Nardini, Niels and Caliebe, Almuth and Nagel, Inga and Young, Dana and Horvath, Gabriella and Santoro, Stephanie L and Shuss, Christine and Ziegler, Alban and Bonneau, Dominique and Kempers, Marlies and Pfundt, Rolph and Legius, Eric and Bouman, Arjan and Stuurman, Kyra E and {\~O}unap, Katrin and Pajusalu, Sander and Wojcik, Monica H and Vasileiou, Georgia and Le Guyader, Gwena{\"e}l and Schnelle, Hege M and Berland, Siren and Zonneveld-Huijssoon, Evelien and Kersten, Simone and Gupta, Aditi and Blackburn, Patrick R and Ellingson, Marissa S and Ferber, Matthew J and Dhamija, Radhika and Klee, Eric W and McEntagart, Meriel and Lichtenbelt, Klaske D and Kenney, Amy and Vergano, Samantha A and Abou Jamra, Rami and Platzer, Konrad and Ella Pierpont, Mary and Khattar, Divya and Hopkin, Robert J and Martin, Richard J and Jongmans, Marjolijn C J and Chang, Vivian Y and Martinez-Agosto, Julian A and Kuismin, Outi and Kurki, Mitja I and Pietil{\"a}inen, Olli and Palotie, Aarno and Maarup, Timothy J and Johnson, Diana S and Venborg Pedersen, Katja and Laulund, Lone W and Lynch, Sally A and Blyth, Moira and Prescott, Katrina and Canham, Natalie and Ibitoye, Rita and Brilstra, Eva H and Shinawi, Marwan and Fassi, Emily and Sticht, Heinrich and Gregor, Anne and Van Esch, Hilde and Zweier, Christiane} } @article {580, title = {De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.}, journal = {Genome Med}, volume = {11}, year = {2019}, month = {2019 02 28}, pages = {12}, abstract = {

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).

METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.

RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

}, keywords = {Adolescent, Child, Child, Preschool, Craniofacial Abnormalities, Developmental Disabilities, Female, Humans, INDEL Mutation, Infant, Intellectual Disability, Male, Muscle Hypotonia, Smith-Magenis Syndrome, Transcription Factors, Young Adult}, issn = {1756-994X}, doi = {10.1186/s13073-019-0623-0}, author = {Vetrini, Francesco and McKee, Shane and Rosenfeld, Jill A and Suri, Mohnish and Lewis, Andrea M and Nugent, Kimberly Margaret and Roeder, Elizabeth and Littlejohn, Rebecca O and Holder, Sue and Zhu, Wenmiao and Alaimo, Joseph T and Graham, Brett and Harris, Jill M and Gibson, James B and Pastore, Matthew and McBride, Kim L and Komara, Makanko and Al-Gazali, Lihadh and Al Shamsi, Aisha and Fanning, Elizabeth A and Wierenga, Klaas J and Scott, Daryl A and Ben-Neriah, Ziva and Meiner, Vardiella and Cassuto, Hanoch and Elpeleg, Orly and Holder, J Lloyd and Burrage, Lindsay C and Seaver, Laurie H and Van Maldergem, Lionel and Mahida, Sonal and Soul, Janet S and Marlatt, Margaret and Matyakhina, Ludmila and Vogt, Julie and Gold, June-Anne and Park, Soo-Mi and Varghese, Vinod and Lampe, Anne K and Kumar, Ajith and Lees, Melissa and Holder-Espinasse, Muriel and McConnell, Vivienne and Bernhard, Birgitta and Blair, Ed and Harrison, Victoria and Muzny, Donna M and Gibbs, Richard A and Elsea, Sarah H and Posey, Jennifer E and Bi, Weimin and Lalani, Seema and Xia, Fan and Yang, Yaping and Eng, Christine M and Lupski, James R and Liu, Pengfei} } @article {717, title = {De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Oct 03}, pages = {854-868}, abstract = {

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs4]; c.2564_2567dupTGTT [p.Leu856Phefs5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.09.005}, author = {Accogli, Andrea and Calabretta, Sara and St-Onge, Judith and Boudrahem-Addour, Nassima and Dionne-Laporte, Alexandre and Joset, Pascal and Azzarello-Burri, Silvia and Rauch, Anita and Krier, Joel and Fieg, Elizabeth and Pallais, Juan C and McConkie-Rosell, Allyn and McDonald, Marie and Freedman, Sharon F and Rivi{\`e}re, Jean-Baptiste and Lafond-Lapalme, Jo{\"e}l and Simpson, Brittany N and Hopkin, Robert J and Trimouille, Aur{\'e}lien and Van-Gils, Julien and Begtrup, Amber and McWalter, Kirsty and Delphine, Heron and Keren, Boris and Genevi{\`e}ve, David and Argilli, Emanuela and Sherr, Elliott H and Severino, Mariasavina and Rouleau, Guy A and Yam, Patricia T and Charron, Fr{\'e}d{\'e}ric and Srour, Myriam} } @article {575, title = {De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {246-259}, abstract = {

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in~vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants~are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Child, Child, Preschool, Coffin-Lowry Syndrome, Cohort Studies, Conserved Sequence, DNA, Female, Heterozygote, HMG-Box Domains, Humans, Male, Mutation, Missense, Neurodevelopmental Disorders, SOXC Transcription Factors, Transcriptional Activation, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.014}, author = {Zawerton, Ash and Yao, Baojin and Yeager, J Paige and Pippucci, Tommaso and Haseeb, Abdul and Smith, Joshua D and Wischmann, Lisa and K{\"u}hl, Susanne J and Dean, John C S and Pilz, Daniela T and Holder, Susan E and McNeill, Alisdair and Graziano, Claudio and Lefebvre, V{\'e}ronique} } @article {697, title = {De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Aug 01}, pages = {403-412}, abstract = {

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.06.007}, author = {Snijders Blok, Lot and Kleefstra, Tjitske and Venselaar, Hanka and Maas, Saskia and Kroes, Hester Y and Lachmeijer, Augusta M A and van Gassen, Koen L I and Firth, Helen V and Tomkins, Susan and Bodek, Simon and {\~O}unap, Katrin and Wojcik, Monica H and Cunniff, Christopher and Bergstrom, Katherine and Powis, Z{\"o}e and Tang, Sha and Shinde, Deepali N and Au, Catherine and Iglesias, Alejandro D and Izumi, Kosuke and Leonard, Jacqueline and Abou Tayoun, Ahmad and Baker, Samuel W and Tartaglia, Marco and Niceta, Marcello and Dentici, Maria Lisa and Okamoto, Nobuhiko and Miyake, Noriko and Matsumoto, Naomichi and Vitobello, Antonio and Faivre, Laurence and Philippe, Christophe and Gilissen, Christian and Wiel, Laurens and Pfundt, Rolph and Deriziotis, Pelagia and Brunner, Han G and Fisher, Simon E} } @article {591, title = {De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Jul}, pages = {1081-1089}, abstract = {

Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Hexokinase activity in red blood cells of two patients was normal, suggesting that the disease mechanism is not due to loss of hexokinase enzymatic activity.

}, issn = {1476-5438}, doi = {10.1038/s41431-019-0366-9}, author = {Okur, Volkan and Cho, Megan T and van Wijk, Richard and van Oirschot, Brigitte and Picker, Jonathan and Coury, Stephanie A and Grange, Dorothy and Manwaring, Linda and Krantz, Ian and Muraresku, Colleen Clark and Hulick, Peter J and May, Holley and Pierce, Eric and Place, Emily and Bujakowska, Kinga and Telegrafi, Aida and Douglas, Ganka and Monaghan, Kristin G and Begtrup, Amber and Wilson, Ashley and Retterer, Kyle and Anyane-Yeboa, Kwame and Chung, Wendy K} } @article {735, title = {Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.}, journal = {Br J Ophthalmol}, volume = {103}, year = {2019}, month = {2019 03}, pages = {390-397}, abstract = {

BACKGROUND/AIMS: To describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease~1 (STGD1) studies (ProgStar) and to~determine geographic differences based on the allele frequency.

METHODS: 345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele.

RESULTS: 211 likely pathogenic variants were identified in the total cohort, including missense (63\%), splice site alteration (18\%), stop (9\%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50\%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15\%), p.G863A (7\%)~and~c.5461-10 T>C (5\%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants.

CONCLUSIONS: There is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

}, keywords = {Adolescent, Adult, Age of Onset, Aged, ATP-Binding Cassette Transporters, Child, Child, Preschool, Cohort Studies, Databases, Factual, DNA Mutational Analysis, Female, Gene Frequency, Genotyping Techniques, Geography, Humans, Internationality, Macular Degeneration, Male, Middle Aged, Mutation, Polymerase Chain Reaction}, issn = {1468-2079}, doi = {10.1136/bjophthalmol-2018-312064}, author = {Fujinami, Kaoru and Strauss, Rupert W and Chiang, John Pei-Wen and Audo, Isabelle S and Bernstein, Paul S and Birch, David G and Bomotti, Samantha M and Cideciyan, Artur V and Ervin, Ann-Margret and Marino, Meghan J and Sahel, Jos{\'e}-Alain and Mohand-Said, Saddek and Sunness, Janet S and Traboulsi, Elias I and West, Sheila and Wojciechowski, Robert and Zrenner, Eberhart and Michaelides, Michel and Scholl, Hendrik P N} } @article {651, title = {Dominant PAX2 mutations may cause steroid-resistant nephrotic syndrome and FSGS in children.}, journal = {Pediatr Nephrol}, volume = {34}, year = {2019}, month = {2019 Sep}, pages = {1607-1613}, abstract = {

BACKGROUND: Heterozygous PAX2 mutations cause renal coloboma syndrome (RCS) [OMIM no. 120330]. RCS is a renal syndromic disease encompassing retinal coloboma and sensorineural hearing loss. Recently, a causative role for PAX2 was reported in adult-onset nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS). However, the prevalence of PAX2 mutations among large cohort of children with steroid-resistant nephrotic syndrome (SRNS) and FSGS has not been systematically studied.

METHODS: We employed whole-exome sequencing (WES) to identify the percentage of SRNS cases explained by monogenic mutations in known genes of SRNS/FSGS. As PAX2 mutations are not an established cause of childhood FSGS, we evaluated a cohort of 215 unrelated families with SRNS, in whom no underlying genetic etiology had been previously established.

RESULTS: Using WES, we identified 3 novel causative heterozygous PAX2 mutations in 3 out of the 215 unrelated index cases studied (1.3\%). All three cases were detected in individuals from families with more than one affected and compatible with an autosomal dominant mode of inheritance (3/57 familial cases studied (5.2\%)). The clinical diagnosis in three out of four pediatric index patients was done during routine medical evaluation.

CONCLUSIONS: Our findings demonstrate high frequency of PAX2 mutations in familial form of SRNS (5.2\%) and further expand the phenotypic spectrum of PAX2 heterozygous mutations to include autosomal dominant childhood-onset FSGS. These results highlight the importance of including PAX2 in the list of genes known to cause FSGS in children.

}, issn = {1432-198X}, doi = {10.1007/s00467-019-04256-0}, author = {Vivante, Asaf and Chacham, Orna Staretz and Shril, Shirlee and Schreiber, Ruth and Mane, Shrikant M and Pode-Shakked, Ben and Soliman, Neveen A and Koneth, Irene and Schiffer, Mario and Anikster, Yair and Hildebrandt, Friedhelm} } @article {518, title = {DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients.}, journal = {JIMD Rep}, volume = {44}, year = {2019}, month = {2019}, pages = {85-92}, abstract = {

Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.

}, issn = {2192-8304}, doi = {10.1007/8904_2018_128}, author = {Ng, Bobby G and Underhill, Hunter R and Palm, Lars and Bengtson, Per and Rozet, Jean-Michel and Gerber, Sylvie and Munnich, Arnold and Zanlonghi, Xavier and Stevens, Cathy A and Kircher, Martin and Nickerson, Deborah A and Buckingham, Kati J and Josephson, Kevin D and Shendure, Jay and Bamshad, Michael J and Freeze, Hudson H and Eklund, Erik A} } @article {722, title = {Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative.}, journal = {Front Genet}, volume = {10}, year = {2019}, month = {2019}, pages = {611}, abstract = {

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

}, issn = {1664-8021}, doi = {10.3389/fgene.2019.00611}, author = {Nellaker, Christoffer and Alkuraya, Fowzan S and Baynam, Gareth and Bernier, Raphael A and Bernier, Francois P J and Boulanger, Vanessa and Brudno, Michael and Brunner, Han G and Clayton-Smith, Jill and Cogn{\'e}, Benjamin and Dawkins, Hugh J S and deVries, Bert B A and Douzgou, Sofia and Dudding-Byth, Tracy and Eichler, Evan E and Ferlaino, Michael and Fieggen, Karen and Firth, Helen V and FitzPatrick, David R and Gration, Dylan and Groza, Tudor and Haendel, Melissa and Hallowell, Nina and Hamosh, Ada and Hehir-Kwa, Jayne and Hitz, Marc-Phillip and Hughes, Mark and Kini, Usha and Kleefstra, Tjitske and Kooy, R Frank and Krawitz, Peter and K{\"u}ry, S{\'e}bastien and Lees, Melissa and Lyon, Gholson J and Lyonnet, Stanislas and Marcadier, Julien L and Meyn, Stephen and Moslerov{\'a}, Veronika and Politei, Juan M and Poulton, Cathryn C and Raymond, F Lucy and Reijnders, Margot R F and Robinson, Peter N and Romano, Corrado and Rose, Catherine M and Sainsbury, David C G and Schofield, Lyn and Sutton, Vernon R and Turnovec, Marek and Van Dijck, Anke and Van Esch, Hilde and Wilkie, Andrew O M} } @article {680, title = {Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.}, journal = {J Clin Endocrinol Metab}, volume = {104}, year = {2019}, month = {2019 Aug 01}, pages = {3049-3067}, abstract = {

CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75\% to 90\% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait.

OBJECTIVE: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI.

DESIGN, SETTING, AND PARTICIPANTS: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity.

RESULTS: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44\%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13\%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94\%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds.

CONCLUSIONS: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.

}, issn = {1945-7197}, doi = {10.1210/jc.2019-00248}, author = {Jolly, Angad and Bayram, Yavuz and Turan, Serap and Aycan, Zehra and Tos, Tulay and Abali, Zehra Yavas and Hacihamdioglu, Bulent and Coban Akdemir, Zeynep Hande and Hijazi, Hadia and Bas, Serpil and Atay, Zeynep and Guran, Tulay and Abali, Saygin and Bas, Firdevs and Darendeliler, Feyza and Colombo, Roberto and Barakat, Tahsin Stefan and Rinne, Tuula and White, Janson J and Yesil, G{\"o}zde and Gezdirici, Alper and Gulec, Elif Yilmaz and Karaca, Ender and Pehlivan, Davut and Jhangiani, Shalini N and Muzny, Donna M and Poyrazoglu, Sukran and Bereket, Abdullah and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R} } @article {666, title = {Exome sequencing of family trios from the National Birth Defects Prevention Study: Tapping into a rich resource of genetic and environmental data.}, journal = {Birth Defects Res}, volume = {111}, year = {2019}, month = {2019 Dec 01}, pages = {1618-1632}, abstract = {

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child{\textquoteright}s father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens.

METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA.

RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol.

CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.

}, issn = {2472-1727}, doi = {10.1002/bdr2.1554}, author = {Jenkins, Mary M and Almli, Lynn M and Pangilinan, Faith and Chong, Jessica X and Blue, Elizabeth E and Shapira, Stuart K and White, Janson and McGoldrick, Daniel and Smith, Joshua D and Mullikin, James C and Bean, Christopher J and Nembhard, Wendy N and Lou, Xiang-Yang and Shaw, Gary M and Romitti, Paul A and Keppler-Noreuil, Kim and Yazdy, Mahsa M and Kay, Denise M and Carter, Tonia C and Olshan, Andrew F and Moore, Kristin J and Nascone-Yoder, Nanette and Finnell, Richard H and Lupo, Philip J and Feldkamp, Marcia L and Nickerson, Deborah A and Bamshad, Michael J and Brody, Lawrence C and Reefhuis, Jennita} } @article {656, title = {Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Mar}, pages = {257-269}, abstract = {

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60\%) or its homologous EP300 (~ 10\%). No causative mutation is identified in up to 30\% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring-Opitz, Kabuki and Wiedemann-Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.

}, keywords = {Child, Child, Preschool, Comparative Genomic Hybridization, CREB-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Genetic, Facies, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Male, Mutation, Phenotype, Rubinstein-Taybi Syndrome, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-01985-y}, author = {Negri, Gloria and Magini, Pamela and Milani, Donatella and Crippa, Milena and Biamino, Elisa and Piccione, Maria and Sotgiu, Stefano and Perr{\`\i}a, Chiara and Vitiello, Giuseppina and Frontali, Marina and Boni, Antonella and Di Fede, Elisabetta and Gandini, Maria Chiara and Colombo, Elisa Adele and Bamshad, Michael J and Nickerson, Deborah A and Smith, Joshua D and Loddo, Italia and Finelli, Palma and Seri, Marco and Pippucci, Tommaso and Larizza, Lidia and Gervasini, Cristina} } @article {563, title = {Genetic architecture of laterality defects revealed by whole exome sequencing.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Apr}, pages = {563-573}, abstract = {

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20\% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1\% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.

}, issn = {1476-5438}, doi = {10.1038/s41431-018-0307-z}, author = {Li, Alexander H and Hanchard, Neil A and Azamian, Mahshid and D{\textquoteright}Alessandro, Lisa C A and Coban-Akdemir, Zeynep and Lopez, Keila N and Hall, Nancy J and Dickerson, Heather and Nicosia, Annarita and Fernbach, Susan and Boone, Philip M and Gambin, Tomaz and Karaca, Ender and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Doddapaneni, HarshaVardhan and Hu, Jianhong and Dinh, Huyen and Jayaseelan, Joy and Muzny, Donna and Lalani, Seema and Towbin, Jeffrey and Penny, Daniel and Fraser, Charles and Martin, James and Lupski, James R and Gibbs, Richard A and Boerwinkle, Eric and Ware, Stephanie M and Belmont, John W} } @article {672, title = {The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Jul 03}, pages = {132-150}, abstract = {

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2\% (58/89) of families. Eleven out of 58 families (19.0\%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.05.015}, author = {Pehlivan, Davut and Bayram, Yavuz and Gunes, Nilay and Coban Akdemir, Zeynep and Shukla, Anju and Bierhals, Tatjana and Tabakci, Burcu and Sahin, Yavuz and Gezdirici, Alper and Fatih, Jawid M and Gulec, Elif Yilmaz and Yesil, G{\"o}zde and Punetha, Jaya and Ocak, Zeynep and Grochowski, Christopher M and Karaca, Ender and Albayrak, Hatice Mutlu and Radhakrishnan, Periyasamy and Erdem, Haktan Bagis and Sahin, Ibrahim and Yildirim, Timur and Bayhan, Ilhan A and Bursali, Aysegul and Elmas, Muhsin and Yuksel, Zafer and Ozdemir, Ozturk and Silan, Fatma and Yildiz, Onur and Yesilbas, Osman and Isikay, Sedat and Balta, Burhan and Gu, Shen and Jhangiani, Shalini N and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Tsiakas, Konstantinos and Hempel, Maja and Girisha, Katta Mohan and Gul, Davut and Posey, Jennifer E and Elcioglu, Nursel H and Tuysuz, Beyhan and Lupski, James R} } @article {730, title = {Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Jun}, pages = {869-878}, abstract = {

Roma are a socially and culturally distinct isolated population with genetically divergent subisolates, residing mainly across Central, Southern, and Eastern Europe. We evaluated the genetic etiology of hearing impairment (HI) in 15 Hungarian Roma families through exome sequencing. A family with autosomal dominant non-syndromic HI segregating a rare variant in the Calponin-homology 2 domain of PLS1, or Plastin 1 [p.(Leu363Phe)] was identified. Young adult Pls1 knockout mice have progressive HI and show morphological defects to their inner hair cells. There is evidence that PLS1 is important in the preservation of adult stereocilia and normal hearing. Four families segregated the European ancestral variant c.35delG [p.(Gly12fs)] in GJB2, and one family was homozygous for p.(Trp24*), an Indian subcontinent ancestral variant which is common amongst Roma from Slovakia, Czech Republic, and Spain. We also observed variants in known HI genes USH1G, USH2A, MYH9, MYO7A, and a splice site variant in MANBA (c.2158-2A>G) in a family with HI, intellectual disability, behavioral problems, and respiratory inflammation, which was previously reported in a Czech Roma family with similar features. Lastly, using multidimensional scaling and ADMIXTURE analyses, we delineate the degree of Asian/European admixture in the HI families understudy, and show that Roma individuals carrying the GJB2 p.(Trp24*) and MANBA c.2158-2A>G variants have a more pronounced South Asian background, whereas the other hearing-impaired Roma display an ancestral background similar to Europeans. We demonstrate a diverse genetic HI etiology in the Hungarian Roma and identify a new gene PLS1, for autosomal dominant human non-syndromic HI.

}, issn = {1476-5438}, doi = {10.1038/s41431-019-0372-y}, author = {Schrauwen, Isabelle and Melegh, B{\'e}la I and Chakchouk, Imen and Acharya, Anushree and Nasir, Abdul and Poston, Alexis and Cornejo-Sanchez, Diana M and Szabo, Zsolt and Karosi, Tam{\'a}s and Bene, Judit and Melegh, B{\'e}la and Leal, Suzanne M} } @article {667, title = {Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity.}, journal = {Clin Genet}, volume = {96}, year = {2019}, month = {2019 Oct}, pages = {366-370}, abstract = {

The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.

}, issn = {1399-0004}, doi = {10.1111/cge.13605}, author = {Karolak, Justyna A and Szafranski, Przemyslaw and Kilner, David and Patel, Chirag and Scurry, Bonnie and Kinning, Esther and Chandler, Kate and Jhangiani, Shalini N and Coban Akdemir, Zeynep H and Lupski, James R and Popek, Edwina and Stankiewicz, Pawe{\l}} } @article {678, title = {Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 Jun 06}, pages = {1210-1222}, abstract = {

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70\% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.03.021}, author = {O{\textquoteright}Donnell-Luria, Anne H and Pais, Lynn S and Faundes, V{\'\i}ctor and Wood, Jordan C and Sveden, Abigail and Luria, Victor and Abou Jamra, Rami and Accogli, Andrea and Amburgey, Kimberly and Anderlid, Britt Marie and Azzarello-Burri, Silvia and Basinger, Alice A and Bianchini, Claudia and Bird, Lynne M and Buchert, Rebecca and Carr{\'e}, Wilfrid and Ceulemans, Sophia and Charles, Perrine and Cox, Helen and Culliton, Lisa and Curr{\`o}, Aurora and Demurger, Florence and Dowling, James J and Duban-Bedu, Benedicte and Dubourg, Christ{\`e}le and Eiset, Saga Elise and Escobar, Luis F and Ferrarini, Alessandra and Haack, Tobias B and Hashim, Mona and Heide, Solveig and Helbig, Katherine L and Helbig, Ingo and Heredia, Raul and H{\'e}ron, Delphine and Isidor, Bertrand and Jonasson, Amy R and Joset, Pascal and Keren, Boris and Kok, Fernando and Kroes, Hester Y and Lavillaureix, Alino{\"e} and Lu, Xin and Maas, Saskia M and Maegawa, Gustavo H B and Marcelis, Carlo L M and Mark, Paul R and Masruha, Marcelo R and McLaughlin, Heather M and McWalter, Kirsty and Melchinger, Esther U and Mercimek-Andrews, Saadet and Nava, Caroline and Pendziwiat, Manuela and Person, Richard and Ramelli, Gian Paolo and Ramos, Luiza L P and Rauch, Anita and Reavey, Caitlin and Renieri, Alessandra and Rie{\ss}, Angelika and Sanchez-Valle, Amarilis and Sattar, Shifteh and Saunders, Carol and Schwarz, Niklas and Smol, Thomas and Srour, Myriam and Steindl, Katharina and Syrbe, Steffen and Taylor, Jenny C and Telegrafi, Aida and Thiffault, Isabelle and Trauner, Doris A and van der Linden, Helio and van Koningsbruggen, Silvana and Villard, Laurent and Vogel, Ida and Vogt, Julie and Weber, Yvonne G and Wentzensen, Ingrid M and Widjaja, Elysa and Zak, Jaroslav and Baxter, Samantha and Banka, Siddharth and Rodan, Lance H} } @article {716, title = {Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Nov 07}, pages = {1048-1056}, abstract = {

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in~vitro assessment of cell surface expression, and in~vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.09.025}, author = {Dias, Caroline M and Punetha, Jaya and Zheng, C{\'e}line and Mazaheri, Neda and Rad, Abolfazl and Efthymiou, Stephanie and Petersen, Andrea and Dehghani, Mohammadreza and Pehlivan, Davut and Partlow, Jennifer N and Posey, Jennifer E and Salpietro, Vincenzo and Gezdirici, Alper and Malamiri, Reza Azizi and Al Menabawy, Nihal M and Selim, Laila A and Vahidi Mehrjardi, Mohammad Yahya and Banu, Selina and Polla, Daniel L and Yang, Edward and Rezazadeh Varaghchi, Jamileh and Mitani, Tadahiro and van Beusekom, Ellen and Najafi, Maryam and Sedaghat, Alireza and Keller-Ramey, Jennifer and Durham, Leslie and Coban-Akdemir, Zeynep and Karaca, Ender and Orlova, Valeria and Schaeken, Lieke L M and Sherafat, Amir and Jhangiani, Shalini N and Stanley, Valentina and Shariati, Gholamreza and Galehdari, Hamid and Gleeson, Joseph G and Walsh, Christopher A and Lupski, James R and Seiradake, Elena and Houlden, Henry and van Bokhoven, Hans and Maroofian, Reza} } @article {607, title = {Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease.}, journal = {J Allergy Clin Immunol}, volume = {143}, year = {2019}, month = {2019 Apr}, pages = {1482-1495}, abstract = {

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing.

OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles.

METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants.

RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein.

CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

}, issn = {1097-6825}, doi = {10.1016/j.jaci.2018.08.013}, author = {Dorjbal, Batsukh and Stinson, Jeffrey R and Ma, Chi A and Weinreich, Michael A and Miraghazadeh, Bahar and Hartberger, Julia M and Frey-Jakobs, Stefanie and Weidinger, Stephan and Moebus, Lena and Franke, Andre and Sch{\"a}ffer, Alejandro A and Bulashevska, Alla and Fuchs, Sebastian and Ehl, Stephan and Limaye, Sandhya and Arkwright, Peter D and Briggs, Tracy A and Langley, Claire and Bethune, Claire and Whyte, Andrew F and Alachkar, Hana and Nejentsev, Sergey and DiMaggio, Thomas and Nelson, Celeste G and Stone, Kelly D and Nason, Martha and Brittain, Erica H and Oler, Andrew J and Veltri, Daniel P and Leahy, T Ronan and Conlon, Niall and Poli, Maria C and Borzutzky, Arturo and Cohen, Jeffrey I and Davis, Joie and Lambert, Michele P and Romberg, Neil and Sullivan, Kathleen E and Paris, Kenneth and Freeman, Alexandra F and Lucas, Laura and Chandrakasan, Shanmuganathan and Savic, Sinisa and Hambleton, Sophie and Patel, Smita Y and Jordan, Michael B and Theos, Amy and Lebensburger, Jeffrey and Atkinson, T Prescott and Torgerson, Troy R and Chinn, Ivan K and Milner, Joshua D and Grimbacher, Bodo and Cook, Matthew C and Snow, Andrew L} } @article {694, title = {Infant mortality: the contribution of genetic disorders.}, journal = {J Perinatol}, volume = {39}, year = {2019}, month = {2019 Dec}, pages = {1611-1619}, abstract = {

OBJECTIVE: To determine the proportion of infant deaths occurring in the setting of a confirmed genetic disorder.

STUDY DESIGN: A retrospective analysis of the electronic medical records of infants born from 1 January, 2011 to 1 June, 2017, who died prior to 1 year of age.

RESULTS: Five hundred and seventy three deceased infants were identified. One hundred and seventeen were confirmed to have a molecular or cytogenetic diagnosis in a clinical diagnostic laboratory and an additional seven were diagnosed by research testing for a total of 124/573 (22\%) diagnosed infants. A total of 67/124 (54\%) had chromosomal disorders and 58/124 (47\%) had single gene disorders (one infant had both). The proportion of diagnoses made by sequencing technologies, such as exome sequencing, increased over the years.

CONCLUSIONS: The prevalence of confirmed genetic disorders within our cohort of infant deaths is higher than that previously reported. Increased efforts are needed to further understand the mortality burden of genetic disorders in infancy.

}, issn = {1476-5543}, doi = {10.1038/s41372-019-0451-5}, author = {Wojcik, Monica H and Schwartz, Talia S and Thiele, Katri E and Paterson, Heather and Stadelmaier, Rachel and Mullen, Thomas E and VanNoy, Grace E and Genetti, Casie A and Madden, Jill A and Gubbels, Cynthia S and Yu, Timothy W and Tan, Wen-Hann and Agrawal, Pankaj B} } @article {595, title = {Insights into genetics, human biology and disease gleaned from family based genomic studies.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 04}, pages = {798-812}, abstract = {

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75\% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in~novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

}, keywords = {Databases, Genetic, Genetic Diseases, Inborn, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome, Human, Genomics, Humans, National Institutes of Health (U.S.), Pedigree, United States, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0408-7}, author = {Posey, Jennifer E and O{\textquoteright}Donnell-Luria, Anne H and Chong, Jessica X and Harel, Tamar and Jhangiani, Shalini N and Coban Akdemir, Zeynep H and Buyske, Steven and Pehlivan, Davut and Carvalho, Claudia M B and Baxter, Samantha and Sobreira, Nara and Liu, Pengfei and Wu, Nan and Rosenfeld, Jill A and Kumar, Sushant and Avramopoulos, Dimitri and White, Janson J and Doheny, Kimberly F and Witmer, P Dane and Boehm, Corinne and Sutton, V Reid and Muzny, Donna M and Boerwinkle, Eric and G{\"u}nel, Murat and Nickerson, Deborah A and Mane, Shrikant and MacArthur, Daniel G and Gibbs, Richard A and Hamosh, Ada and Lifton, Richard P and Matise, Tara C and Rehm, Heidi L and Gerstein, Mark and Bamshad, Michael J and Valle, David and Lupski, James R} } @article {650, title = {Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome.}, journal = {Genome Med}, volume = {11}, year = {2019}, month = {2019 04 23}, pages = {25}, abstract = {

BACKGROUND: Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases.

METHODS: Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD~(UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology.

RESULTS: We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay.

CONCLUSIONS: These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.

}, issn = {1756-994X}, doi = {10.1186/s13073-019-0633-y}, author = {Carvalho, Claudia M B and Coban-Akdemir, Zeynep and Hijazi, Hadia and Yuan, Bo and Pendleton, Matthew and Harrington, Eoghan and Beaulaurier, John and Juul, Sissel and Turner, Daniel J and Kanchi, Rupa S and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Stankiewicz, Pawel and Belmont, John W and Shaw, Chad A and Cheung, Sau Wai and Hanchard, Neil A and Sutton, V Reid and Bader, Patricia I and Lupski, James R} } @article {557, title = {Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts.}, journal = {Genet Epidemiol}, volume = {43}, year = {2019}, month = {2019 03}, pages = {215-226}, abstract = {

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6\% of individuals. Rare or low-frequency missense variants were found in 16\% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.

}, keywords = {Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Heart Defects, Congenital, Humans, Introns, Loss of Function Mutation, Male, Mutation, Missense, Pedigree, Receptor, Notch1, Risk Factors, Ventricular Outflow Obstruction, Whole Exome Sequencing}, issn = {1098-2272}, doi = {10.1002/gepi.22176}, author = {Helle, Emmi and C{\'o}rdova-Palomera, Aldo and Ojala, Tiina and Saha, Priyanka and Potiny, Praneetha and Gustafsson, Stefan and Ingelsson, Erik and Bamshad, Michael and Nickerson, Deborah and Chong, Jessica X and Ashley, Euan and Priest, James R} } @article {719, title = {Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Oct 03}, pages = {689-705}, abstract = {

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.08.006}, author = {Magini, Pamela and Smits, Daphne J and Vandervore, Laura and Schot, Rachel and Columbaro, Marta and Kasteleijn, Esmee and van der Ent, Mees and Palombo, Flavia and Lequin, Maarten H and Dremmen, Marjolein and de Wit, Marie Claire Y and Severino, Mariasavina and Divizia, Maria Teresa and Striano, Pasquale and Ordonez-Herrera, Natalia and Alhashem, Amal and Al Fares, Ahmed and Al Ghamdi, Malak and Rolfs, Arndt and Bauer, Peter and Demmers, Jeroen and Verheijen, Frans W and Wilke, Martina and van Slegtenhorst, Marjon and van der Spek, Peter J and Seri, Marco and Jansen, Anna C and Stottmann, Rolf W and Hufnagel, Robert B and Hopkin, Robert J and Aljeaid, Deema and Wiszniewski, Wojciech and Gawlinski, Pawel and Laure-Kamionowska, Milena and Alkuraya, Fowzan S and Akleh, Hanah and Stanley, Valentina and Musaev, Damir and Gleeson, Joseph G and Zaki, Maha S and Brunetti-Pierri, Nicola and Cappuccio, Gerarda and Davidov, Bella and Basel-Salmon, Lina and Bazak, Lily and Shahar, Noa Ruhrman and Bertoli-Avella, Aida and Mirzaa, Ghayda M and Dobyns, William B and Pippucci, Tommaso and Fornerod, Maarten and Mancini, Grazia M S} } @article {585, title = {Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.}, journal = {J Clin Invest}, volume = {129}, year = {2019}, month = {2019 Mar 01}, pages = {1240-1256}, abstract = {

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients{\textquoteright} fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

}, issn = {1558-8238}, doi = {10.1172/JCI123959}, author = {Pant, Devesh C and Dorboz, Imen and Schluter, Agatha and Fourcade, St{\'e}phane and Launay, Nathalie and Joya, Javier and Aguilera-Albesa, Sergio and Yoldi, Maria Eugenia and Casasnovas, Carlos and Willis, Mary J and Ruiz, Montserrat and Ville, Doroth{\'e}e and Lesca, Gaetan and Siquier-Pernet, Karine and Desguerre, Isabelle and Yan, Huifang and Wang, Jingmin and Burmeister, Margit and Brady, Lauren and Tarnopolsky, Mark and Cornet, Carles and Rubbini, Davide and Terriente, Javier and James, Kiely N and Musaev, Damir and Zaki, Maha S and Patterson, Marc C and Lanpher, Brendan C and Klee, Eric W and Pinto E Vairo, Filippo and Wohler, Elizabeth and Sobreira, Nara Lygia de M and Cohen, Julie S and Maroofian, Reza and Galehdari, Hamid and Mazaheri, Neda and Shariati, Gholamreza and Colleaux, Laurence and Rodriguez, Diana and Gleeson, Joseph G and Pujades, Cristina and Fatemi, Ali and Boespflug-Tanguy, Odile and Pujol, Aurora} } @article {693, title = {MAGEL2-related disorders: A study and case series.}, journal = {Clin Genet}, volume = {96}, year = {2019}, month = {2019 Dec}, pages = {493-505}, abstract = {

Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders.

}, issn = {1399-0004}, doi = {10.1111/cge.13620}, author = {Patak, Jameson and Gilfert, James and Byler, Melissa and Neerukonda, Vamsee and Thiffault, Isabelle and Cross, Laura and Amudhavalli, Shivarajan and Pacio-Miguez, Marta and Palomares-Bralo, Maria and Garcia-Minaur, Sixto and Santos-Simarro, Fernando and Powis, Z{\"o}e and Alcaraz, Wendy and Tang, Sha and Jurgens, Julie and Barry, Brenda and England, Eleina and Engle, Elizabeth and Hess, Jonathon and Lebel, Robert R} } @article {589, title = {Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 03 07}, pages = {530-541}, abstract = {

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.01.010}, author = {Cogn{\'e}, Benjamin and Ehresmann, Sophie and Beauregard-Lacroix, Eliane and Rousseau, Justine and Besnard, Thomas and Garcia, Thomas and Petrovski, Slav{\'e} and Avni, Shiri and McWalter, Kirsty and Blackburn, Patrick R and Sanders, Stephan J and Uguen, K{\'e}vin and Harris, Jacqueline and Cohen, Julie S and Blyth, Moira and Lehman, Anna and Berg, Jonathan and Li, Mindy H and Kini, Usha and Joss, Shelagh and von der Lippe, Charlotte and Gordon, Christopher T and Humberson, Jennifer B and Robak, Laurie and Scott, Daryl A and Sutton, Vernon R and Skraban, Cara M and Johnston, Jennifer J and Poduri, Annapurna and Nordenskj{\"o}ld, Magnus and Shashi, Vandana and Gerkes, Erica H and Bongers, Ernie M H F and Gilissen, Christian and Zarate, Yuri A and Kvarnung, Malin and Lally, Kevin P and Kulch, Peggy A and Daniels, Brina and Hernandez-Garcia, Andres and Stong, Nicholas and McGaughran, Julie and Retterer, Kyle and Tveten, Kristian and Sullivan, Jennifer and Geisheker, Madeleine R and Stray-Pedersen, Asbjorg and Tarpinian, Jennifer M and Klee, Eric W and Sapp, Julie C and Zyskind, Jacob and Holla, {\O}ystein L and Bedoukian, Emma and Filippini, Francesca and Guimier, Anne and Picard, Arnaud and Busk, {\O}yvind L and Punetha, Jaya and Pfundt, Rolph and Lindstrand, Anna and Nordgren, Ann and Kalb, Fayth and Desai, Megha and Ebanks, Ashley Harmon and Jhangiani, Shalini N and Dewan, Tammie and Coban Akdemir, Zeynep H and Telegrafi, Aida and Zackai, Elaine H and Begtrup, Amber and Song, Xiaofei and Toutain, Annick and Wentzensen, Ingrid M and Odent, Sylvie and Bonneau, Dominique and Latypova, X{\'e}nia and Deb, Wallid and Redon, Sylvia and Bilan, Fr{\'e}d{\'e}ric and Legendre, Marine and Troyer, Caitlin and Whitlock, Kerri and Caluseriu, Oana and Murphree, Marine I and Pichurin, Pavel N and Agre, Katherine and Gavrilova, Ralitza and Rinne, Tuula and Park, Meredith and Shain, Catherine and Heinzen, Erin L and Xiao, Rui and Amiel, Jeanne and Lyonnet, Stanislas and Isidor, Bertrand and Biesecker, Leslie G and Lowenstein, Dan and Posey, Jennifer E and Denomm{\'e}-Pichon, Anne-Sophie and F{\'e}rec, Claude and Yang, Xiang-Jiao and Rosenfeld, Jill A and Gilbert-Dussardier, Brigitte and Audebert-Bellanger, S{\'e}verine and Redon, Richard and Stessman, Holly A F and Nellaker, Christoffer and Yang, Yaping and Lupski, James R and Goldstein, David B and Eichler, Evan E and Bolduc, Francois and B{\'e}zieau, St{\'e}phane and K{\"u}ry, S{\'e}bastien and Campeau, Philippe M} } @article {592, title = {Monogenic causes of chronic kidney disease in adults.}, journal = {Kidney Int}, volume = {95}, year = {2019}, month = {2019 04}, pages = {914-928}, abstract = {

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37\%). A monogenic cause was identified in 36\% of affected families with a positive family history of CKD, 69\% of those with extra-renal features, and only 15\% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40\%), corrected the clinical diagnosis in 9 (22\%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38\%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2018.10.031}, author = {Connaughton, Dervla M and Kennedy, Claire and Shril, Shirlee and Mann, Nina and Murray, Susan L and Williams, Patrick A and Conlon, Eoin and Nakayama, Makiko and van der Ven, Amelie T and Ityel, Hadas and Kause, Franziska and Kolvenbach, Caroline M and Dai, Rufeng and Vivante, Asaf and Braun, Daniela A and Schneider, Ronen and Kitzler, Thomas M and Moloney, Brona and Moran, Conor P and Smyth, John S and Kennedy, Alan and Benson, Katherine and Stapleton, Caragh and Denton, Mark and Magee, Colm and O{\textquoteright}Seaghdha, Conall M and Plant, William D and Griffin, Matthew D and Awan, Atif and Sweeney, Clodagh and Mane, Shrikant M and Lifton, Richard P and Griffin, Brenda and Leavey, Sean and Casserly, Liam and de Freitas, Declan G and Holian, John and Dorman, Anthony and Doyle, Brendan and Lavin, Peter J and Little, Mark A and Conlon, Peter J and Hildebrandt, Friedhelm} } @article {686, title = {MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.}, journal = {Acta Neuropathol}, volume = {138}, year = {2019}, month = {2019 Dec}, pages = {1013-1031}, abstract = {

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70\% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

}, issn = {1432-0533}, doi = {10.1007/s00401-019-02059-z}, author = {Donkervoort, S and Sabouny, R and Yun, P and Gauquelin, L and Chao, K R and Hu, Y and Al Khatib, I and T{\"o}pf, A and Mohassel, P and Cummings, B B and Kaur, R and Saade, D and Moore, S A and Waddell, L B and Farrar, M A and Goodrich, J K and Uapinyoying, P and Chan, S H S and Javed, A and Leach, M E and Karachunski, P and Dalton, J and Medne, L and Harper, A and Thompson, C and Thiffault, I and Specht, S and Lamont, R E and Saunders, C and Racher, H and Bernier, F P and Mowat, D and Witting, N and Vissing, J and Hanson, R and Coffman, K A and Hainlen, M and Parboosingh, J S and Carnevale, A and Yoon, G and Schnur, R E and Boycott, K M and Mah, J K and Straub, V and Foley, A Reghan and Innes, A M and B{\"o}nnemann, C G and Shutt, T E} } @article {724, title = {Mutations in and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis.}, journal = {Proc Natl Acad Sci U S A}, volume = {116}, year = {2019}, month = {2019 Jul 23}, pages = {15116-15121}, abstract = {

Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15\% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation ( = 4.0 {\texttimes} 10); additionally, a rare damaging mutation in , which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in , a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant ( = 8.2 {\texttimes} 10). Three probands had rare damaging mutations in , , or , which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier , and , encoding catenin α-1. These findings establish as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.

}, issn = {1091-6490}, doi = {10.1073/pnas.1902041116}, author = {Timberlake, Andrew T and Jin, Sheng Chih and Nelson-Williams, Carol and Wu, Robin and Furey, Charuta G and Islam, Barira and Haider, Shozeb and Loring, Erin and Galm, Amy and Steinbacher, Derek M and Larysz, Dawid and Staffenberg, David A and Flores, Roberto L and Rodriguez, Eduardo D and Boggon, Titus J and Persing, John A and Lifton, Richard P} } @article {721, title = {Novel Heterozygous Mutation in Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome.}, journal = {Front Pediatr}, volume = {7}, year = {2019}, month = {2019}, pages = {303}, abstract = {

Nuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by (MIM: 164012) belongs to the NF-κB family of transcription factors that play a critical role in inflammation, immunity, cell proliferation, differentiation and survival. Heterozygous C-terminal mutations in have been associated with early-onset common variable immunodeficiency (CVID), central adrenal insufficiency and ectodermal dysplasia. Only two previously reported cases have documented decreased natural killer (NK) cell cytotoxicity, and little is known about the role of NF-κB2 in NK cell maturation and function. Here we report a 13-year-old female that presented at 6 years of age with a history of early onset recurrent sinopulmonary infections, progressive hair loss, and hypogamaglobulinemia consistent with a clinical diagnosis of CVID. At 9 years of age she had cytomegalovirus (CMV) pneumonia that responded to ganciclovir treatment. Functional NK cell testing demonstrated decreased NK cell cytotoxicity despite normal NK cell numbers, consistent with a greater susceptibility to systemic CMV infection. Research exome sequencing (ES) was performed and revealed a novel heterozygous nonsense mutation in (c.2611C>T, p.Gln871) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be in the patient. At age 12, she presented with a reactivation of the systemic CMV infection that was associated with severe and progressive nephrotic syndrome with histologic evidence of pedicellar effacement and negative immunofluorescence. To our knowledge, this is the third NF-κB2 deficient patient in which an abnormal NK cell function has been observed, suggesting a role for non-canonical NF-κB2 signaling in NK cell cytotoxicity. NK cell function should be assessed in patients with mutations in the non-canonical NF-κB pathway to explore the risk for systemic viral infections that may lead to severe complications and impact patient survival. Similarly NF-κB2 should be considered in patients with combined immunodeficiency who have aberrant NK cell function. Further studies are needed to characterize the role of NF-κB2 in NK cell cytotoxic function.

}, issn = {2296-2360}, doi = {10.3389/fped.2019.00303}, author = {Aird, Alejandra and Lagos, Macarena and Vargas-Hernandez, Alexander and Posey, Jennifer E and Coban-Akdemir, Zeynep and Jhangiani, Shalini and Mace, Emily M and Reyes, Anaid and King, Alejandra and Cavagnaro, Felipe and Forbes, Lisa R and Chinn, Ivan K and Lupski, James R and Orange, Jordan S and Poli, Maria Cecilia} } @article {689, title = {Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Oct}, pages = {2112-2118}, abstract = {

Generalized arterial calcifications of infancy (GACI) is caused by mutations in ENPP1. Other ENPP1-related phenotypes include pseudoxanthoma elasticum, hypophosphatemic rickets, and Cole disease. We studied four children from two Bedouin consanguineous families who presented with severe clinical phenotype including thrombocytopenia, hypoglycemia, hepatic, and neurologic manifestations. Initial working diagnosis included congenital infection; however, patients remained without a definitive diagnosis despite extensive workup. Consequently, we investigated a potential genetic etiology. Whole exome sequencing (WES) was performed for affected children and their parents. Following the identification of a novel mutation in the ENPP1 gene, we characterized this novel multisystemic presentation and revised relevant imaging studies. Using WES, we identified a novel homozygous mutation (c.556G > C; p.Gly186Arg) in ENPP1 which affects a highly conserved protein domain (somatomedin B2). ENPP1-associated genetic diseases exhibit phenotypic heterogeneity depending on mutation type and location. Follow-up clinical characterization of these families allowed us to revise and detect new features of systemic calcifications, which established the diagnosis of GACI, expanding the phenotypic spectrum associated with ENPP1 mutations. Our findings demonstrate that this novel ENPP1 founder mutation can cause a fatal multisystemic phenotype, mimicking severe congenital infection. This also represents the first reported mutation affecting the SMB2 domain, associated with GACI.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61334}, author = {Staretz-Chacham, Orna and Shukrun, Rachel and Barel, Ortal and Pode-Shakked, Ben and Pleniceanu, Oren and Anikster, Yair and Shalva, Nechama and Ferreira, Carlos R and Ben-Haim Kadosh, Admit and Richardson, Justin and Mane, Shrikant M and Hildebrandt, Friedhelm and Vivante, Asaf} } @article {665, title = {Objective measures of sleep disturbances in children with Potocki-Lupski syndrome.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Oct}, pages = {1982-1986}, abstract = {

Potocki-Lupski syndrome (PTLS; MIM 610883) is a neurodevelopmental disorder caused by a microduplication, a 3.7 Mb copy number variant, mapping within chromosome 17p11.2, encompassing the dosage-sensitive RAI1 gene. Whereas RAI1 triplosensitivity causes PTLS, haploinsufficiency of RAI1 due to 17p11.2 microdeletion causes the clinically distinct Smith-Magenis syndrome (SMS; MIM 182290). Most individuals with SMS have an inversion of the melatonin cycle. Subjects with PTLS have mild sleep disturbances such as sleep apnea with no melatonin abnormalities described. Sleep patterns and potential disturbances in subjects with PTLS have not been objectively characterized. We delineated sleep characteristics in 23 subjects with PTLS who underwent a polysomnogram at Texas Children{\textquoteright}s Hospital. Eleven of these subjects (58\%) completed the Child{\textquoteright}s Sleep Habits Questionnaire (CSHQ). Urinary melatonin was measured in one patient and published previously. While the circadian rhythm of melatonin in PTLS appears not to be disrupted, we identified significant differences in sleep efficiency, percentage of rapid eye movement sleep, oxygen nadir, obstructive apnea hypopnea index, and periodic limb movements between prepubertal subjects with PTLS and previously published normative data. Data from the CSHQ indicate that 64\% (7/11) of parents do not identify a sleep disturbance in their children. Our data indicate that younger individuals, <10 years, with PTLS have statistically significant abnormalities in five components of sleep despite lack of recognition of substantial sleep disturbances by parents. Our data support the contention that patients with PTLS should undergo clinical evaluations for sleep disordered breathing and periodic limb movement disorder, both of which are treatable conditions.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61307}, author = {Kaplan, Kevin and McCool, Caroline and Lupski, James R and Glaze, Daniel and Potocki, Lorraine} } @article {733, title = {Oral therapy for riboflavin transporter deficiency - What is the regimen of choice?}, journal = {Parkinsonism Relat Disord}, volume = {61}, year = {2019}, month = {2019 04}, pages = {245-247}, issn = {1873-5126}, doi = {10.1016/j.parkreldis.2018.10.017}, author = {Gorcenco, Sorina and Vaz, Fr{\'e}d{\'e}ric M and Tracewska-Siemi{\k a}tkowska, Anna and Tranebj{\ae}rg, Lisbeth and Cremers, Frans P M and Ygland, Emil and Kicsi, Jen{\H o} and Rendtorff, Nanna Dahl and M{\"o}ller, Claes and Kjellstr{\"o}m, Ulrika and Andr{\'e}asson, Sten and Puschmann, Andreas} } @article {698, title = {Paralog Studies Augment Gene Discovery: DDX and DHX Genes.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Aug 01}, pages = {302-316}, abstract = {

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four~individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.06.001}, author = {Paine, Ingrid and Posey, Jennifer E and Grochowski, Christopher M and Jhangiani, Shalini N and Rosenheck, Sarah and Kleyner, Robert and Marmorale, Taylor and Yoon, Margaret and Wang, Kai and Robison, Reid and Cappuccio, Gerarda and Pinelli, Michele and Magli, Adriano and Coban Akdemir, Zeynep and Hui, Joannie and Yeung, Wai Lan and Wong, Bibiana K Y and Ortega, Lucia and Bekheirnia, Mir Reza and Bierhals, Tatjana and Hempel, Maja and Johannsen, Jessika and Santer, Ren{\'e} and Aktas, Dilek and Alika{\c s}ifo{\u g}lu, Mehmet and Bozdogan, Sevcan and Aydin, Hatip and Karaca, Ender and Bayram, Yavuz and Ityel, Hadas and Dorschner, Michael and White, Janson J and Wilichowski, Ekkehard and Wortmann, Saskia B and Casella, Erasmo B and Kitajima, Joao Paulo and Kok, Fernando and Monteiro, Fabiola and Muzny, Donna M and Bamshad, Michael and Gibbs, Richard A and Sutton, V Reid and Van Esch, Hilde and Brunetti-Pierri, Nicola and Hildebrandt, Friedhelm and Brautbar, Ariel and Van den Veyver, Ignatia B and Glass, Ian and Lessel, Davor and Lyon, Gholson J and Lupski, James R} } @article {728, title = {Pathogenic Variants in GPC4 Cause Keipert Syndrome.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 May 02}, pages = {914-924}, abstract = {

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506 and p.Glu496 were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.02.026}, author = {Amor, David J and Stephenson, Sarah E M and Mustapha, Mirna and Mensah, Martin A and Ockeloen, Charlotte W and Lee, Wei Shern and Tankard, Rick M and Phelan, Dean G and Shinawi, Marwan and de Brouwer, Arjan P M and Pfundt, Rolph and Dowling, Cari and Toler, Tomi L and Sutton, V Reid and Agolini, Emanuele and Rinelli, Martina and Capolino, Rossella and Martinelli, Diego and Zampino, Giuseppe and Dumi{\'c}, Miroslav and Reardon, William and Shaw-Smith, Charles and Leventer, Richard J and Delatycki, Martin B and Kleefstra, Tjitske and Mundlos, Stefan and Mortier, Geert and Bahlo, Melanie and Allen, Nicola J and Lockhart, Paul J} } @article {676, title = {Pathogenic Variants in NUP214 Cause "Plugged" Nuclear Pore Channels and Acute Febrile Encephalopathy.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Jul 03}, pages = {48-64}, abstract = {

We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as "plugs") in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.05.003}, author = {Fichtman, Boris and Harel, Tamar and Biran, Nitzan and Zagairy, Fadia and Applegate, Carolyn D and Salzberg, Yuval and Gilboa, Tal and Salah, Somaya and Shaag, Avraham and Simanovsky, Natalia and Ayoubieh, Houriya and Sobreira, Nara and Punzi, Giuseppe and Pierri, Ciro Leonardo and Hamosh, Ada and Elpeleg, Orly and Harel, Amnon and Edvardson, Simon} } @article {608, title = {Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype.}, journal = {Am J Respir Crit Care Med}, volume = {199}, year = {2019}, month = {2019 01 15}, pages = {190-198}, abstract = {

RATIONALE: In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood.

OBJECTIVES: To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype.

METHODS: This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEV and weight and height z-scores).

MEASUREMENTS AND MAIN RESULTS: A total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV and weight and height z-scores than the isolated outer dynein arm defect (n = 55) group. Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV and weight and height z-scores than those with DNAH5 mutations (n = 36). For the entire cohort, percent predicted FEV decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr. Rate of decline was different from zero only in the IDA/MTD/CA group (mean [SE], -1.11 [0.48] percent predicted/yr; P = 0.02).

CONCLUSIONS: Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.

}, keywords = {Child, Cilia, Cohort Studies, Female, Genotype, Humans, Kartagener Syndrome, Longitudinal Studies, Lung, Male, Mutation, Phenotype, Prospective Studies, Respiratory Function Tests}, issn = {1535-4970}, doi = {10.1164/rccm.201803-0548OC}, author = {Davis, Stephanie D and Rosenfeld, Margaret and Lee, Hye-Seung and Ferkol, Thomas W and Sagel, Scott D and Dell, Sharon D and Milla, Carlos and Pittman, Jessica E and Shapiro, Adam J and Sullivan, Kelli M and Nykamp, Keith R and Krischer, Jeffrey P and Zariwala, Maimoona A and Knowles, Michael R and Leigh, Margaret W} } @article {673, title = {Reanalysis of Clinical Exome Sequencing Data.}, journal = {N Engl J Med}, volume = {380}, year = {2019}, month = {2019 06 20}, pages = {2478-2480}, keywords = {Exome, Genetic Diseases, Inborn, Genetic Testing, Humans, Mutation, Phenotype, Sequence Analysis, DNA, Whole Exome Sequencing}, issn = {1533-4406}, doi = {10.1056/NEJMc1812033}, author = {Liu, Pengfei and Meng, Linyan and Normand, Elizabeth A and Xia, Fan and Song, Xiaofei and Ghazi, Andrew and Rosenfeld, Jill and Magoulas, Pilar L and Braxton, Alicia and Ward, Patricia and Dai, Hongzheng and Yuan, Bo and Bi, Weimin and Xiao, Rui and Wang, Xia and Chiang, Theodore and Vetrini, Francesco and He, Weimin and Cheng, Hanyin and Dong, Jie and Gijavanekar, Charul and Benke, Paul J and Bernstein, Jonathan A and Eble, Tanya and Eroglu, Yasemen and Erwin, Deanna and Escobar, Luis and Gibson, James B and Gripp, Karen and Kleppe, Soledad and Koenig, Mary K and Lewis, Andrea M and Natowicz, Marvin and Mancias, Pedro and Minor, LaKeesha and Scaglia, Fernando and Schaaf, Christian P and Streff, Haley and Vernon, Hilary and Uhles, Crescenda L and Zackai, Elaine H and Wu, Nan and Sutton, V Reid and Beaudet, Arthur L and Muzny, Donna and Gibbs, Richard A and Posey, Jennifer E and Lalani, Seema and Shaw, Chad and Eng, Christine M and Lupski, James R and Yang, Yaping} } @article {685, title = {Redefining the Etiologic Landscape of Cerebellar Malformations.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Sep 05}, pages = {606-615}, abstract = {

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51\%) than for DWM (16\%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19\%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85\%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47\%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.07.019}, author = {Aldinger, Kimberly A and Timms, Andrew E and Thomson, Zachary and Mirzaa, Ghayda M and Bennett, James T and Rosenberg, Alexander B and Roco, Charles M and Hirano, Matthew and Abidi, Fatima and Haldipur, Parthiv and Cheng, Chi V and Collins, Sarah and Park, Kaylee and Zeiger, Jordan and Overmann, Lynne M and Alkuraya, Fowzan S and Biesecker, Leslie G and Braddock, Stephen R and Cathey, Sara and Cho, Megan T and Chung, Brian H Y and Everman, David B and Zarate, Yuri A and Jones, Julie R and Schwartz, Charles E and Goldstein, Amy and Hopkin, Robert J and Krantz, Ian D and Ladda, Roger L and Leppig, Kathleen A and McGillivray, Barbara C and Sell, Susan and Wusik, Katherine and Gleeson, Joseph G and Nickerson, Deborah A and Bamshad, Michael J and Gerrelli, Dianne and Lisgo, Steven N and Seelig, Georg and Ishak, Gisele E and Barkovich, A James and Curry, Cynthia J and Glass, Ian A and Millen, Kathleen J and Doherty, Dan and Dobyns, William B} } @article {675, title = {A retrospective analysis of the prevalence of imprinting disorders in Estonia from 1998 to 2016.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Nov}, pages = {1649-1658}, abstract = {

Imprinting disorders (ImpDis) represent a small group of rare congenital diseases primarily affecting growth, development, and the hormonal and metabolic systems. The aim of present study was to identify the prevalence of the ImpDis in Estonia, to describe trends in the live birth prevalence of these disorders between 1998 and 2016, and to compare the results with previously published data. We retrospectively reviewed the records of all Estonian patients since 1998 with both molecularly and clinically diagnosed ImpDis. A prospective study was also conducted, in which all patients with clinical suspicion for an ImpDis were molecularly analyzed. Eighty-seven individuals with ImpDis were identified. Twenty-seven (31\%) of them had Prader-Willi syndrome (PWS), 15 (17\%) had Angelman syndrome (AS), 15 (17\%) had Silver-Russell syndrome (SRS), 12 (14\%) had Beckwith-Wiedemann syndrome (BWS), 10 (11\%) had pseudo- or pseudopseudohypoparathyroidism, four had central precocious puberty, two had Temple syndrome, one had transient neonatal diabetes mellitus, and one had myoclonus-dystonia syndrome. One third of SRS and BWS cases fulfilled the diagnostic criteria for these disorders, but tested negative for genetic abnormalities. Seventy-six individuals were alive as of January 1, 2018, indicating the total prevalence of ImpDis in Estonia is 5.8/100,000 (95\% CI 4.6/100,000-7.2/100,000). The minimum live birth prevalence of all ImpDis in Estonia in 2004-2016 was 1/3,462, PWS 1/13,599, AS 1/27,198, BWS 1/21,154, SRS 1/15,866, and PHP/PPHP 1/27,198. Our results are only partially consistent with previously published data. The worldwide prevalence of SRS and GNAS-gene-related ImpDis is likely underestimated and may be at least three times higher than expected.

}, issn = {1476-5438}, doi = {10.1038/s41431-019-0446-x}, author = {Yakoreva, Maria and Kahre, Tiina and {\v Z}ordania, Riina and Reinson, Karit and Teek, Rita and Tillmann, Vallo and Peet, Aleksandr and {\~O}iglane-Shlik, Eve and Pajusalu, Sander and Murumets, {\"U}lle and Vals, Mari-Anne and Mee, Pille and Wojcik, Monica H and {\~O}unap, Katrin} } @article {566, title = {ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 01}, pages = {42-50}, abstract = {

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2\%) that frequently presents with ascending aortic aneurysm (AscAA). BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for <=1\% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Aortic Valve, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Female, Heart Valve Diseases, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Receptors, Cell Surface, Zebrafish}, issn = {1546-1718}, doi = {10.1038/s41588-018-0265-y}, author = {Gould, Russell A and Aziz, Hamza and Woods, Courtney E and Seman-Senderos, Manuel Alejandro and Sparks, Elizabeth and Preuss, Christoph and W{\"u}nnemann, Florian and Bedja, Djahida and Moats, Cassandra R and McClymont, Sarah A and Rose, Rebecca and Sobreira, Nara and Ling, Hua and MacCarrick, Gretchen and Kumar, Ajay Anand and Luyckx, Ilse and Cannaerts, Elyssa and Verstraeten, Aline and Bj{\"o}rk, Hanna M and Lehsau, Ann-Cathrin and Jaskula-Ranga, Vinod and Lauridsen, Henrik and Shah, Asad A and Bennett, Christopher L and Ellinor, Patrick T and Lin, Honghuang and Isselbacher, Eric M and Lino Cardenas, Christian Lacks and Butcher, Jonathan T and Hughes, G Chad and Lindsay, Mark E and Mertens, Luc and Franco-Cereceda, Anders and Verhagen, Judith M A and Wessels, Marja and Mohamed, Salah A and Eriksson, Per and Mital, Seema and Van Laer, Lut and Loeys, Bart L and Andelfinger, Gregor and McCallion, Andrew S and Dietz, Harry C} } @article {594, title = {Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 May}, pages = {747-759}, abstract = {

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. We here report 12 independent patients harboring a variety of de novo variants in CYFIP2 broadening the molecular and clinical spectrum of a novel CYFIP2-related neurodevelopmental disorder. Using trio whole-exome or -genome sequencing, we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2 with a shared phenotype of intellectual disability, seizures, and muscular hypotonia. We detected seven different missense variants, of which two occurred recurrently (p.(Arg87Cys) and p.(Ile664Met)), and a splice donor variant in the last intron for which we showed exon skipping in the transcript. The latter is expected to escape nonsense-mediated mRNA decay resulting in a truncated protein. Despite the large spacing in the primary structure, the variants spatially cluster in the tertiary structure and are all predicted to weaken the interaction with WAVE1 or NCKAP1 of the actin polymerization regulating WRC-complex. Preliminary genotype-phenotype correlation indicates a profound phenotype in p.Arg87 substitutions and a more variable phenotype in other alterations. This study evidenced a variety of de novo variants in CYFIP2 as a novel cause of mostly severe intellectual disability with seizures and muscular hypotonia.

}, issn = {1476-5438}, doi = {10.1038/s41431-018-0331-z}, author = {Zweier, Markus and Begemann, Ana{\"\i}s and McWalter, Kirsty and Cho, Megan T and Abela, Lucia and Banka, Siddharth and Behring, Bettina and Berger, Andrea and Brown, Chester W and Carneiro, Maryline and Chen, Jiani and Cooper, Gregory M and Finnila, Candice R and Guillen Sacoto, Maria J and Henderson, Alex and H{\"u}ffmeier, Ulrike and Joset, Pascal and Kerr, Bronwyn and Lesca, Gaetan and Leszinski, Gloria S and McDermott, John Henry and Meltzer, Meira R and Monaghan, Kristin G and Mostafavi, Roya and {\~O}unap, Katrin and Plecko, Barbara and Powis, Z{\"o}e and Purcarin, Gabriela and Reimand, Tiia and Riedhammer, Korbinian M and Schreiber, John M and Sirsi, Deepa and Wierenga, Klaas J and Wojcik, Monica H and Papuc, Sorina M and Steindl, Katharina and Sticht, Heinrich and Rauch, Anita} } @article {682, title = {TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 07}, pages = {1548-1558}, abstract = {

PURPOSE: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model.

METHODS: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS).

RESULTS: In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 {\texttimes} 10), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 {\texttimes} 10); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 {\texttimes} 10), while intraspinal anomalies were uncommon (P = 7.0 {\texttimes} 10). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 {\texttimes} 10). A Tbx6 mouse model supported that a~gene dosage effect underlies the TACS phenotype.

CONCLUSION: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10\% of CS.

}, issn = {1530-0366}, doi = {10.1038/s41436-018-0377-x}, author = {Liu, Jiaqi and Wu, Nan and Yang, Nan and Takeda, Kazuki and Chen, Weisheng and Li, Weiyu and Du, Renqian and Liu, Sen and Zhou, Yangzhong and Zhang, Ling and Liu, Zhenlei and Zuo, Yuzhi and Zhao, Sen and Blank, Robert and Pehlivan, Davut and Dong, Shuangshuang and Zhang, Jianguo and Shen, Jianxiong and Si, Nuo and Wang, Yipeng and Liu, Gang and Li, Shugang and Zhao, Yanxue and Zhao, Hong and Chen, Yixin and Zhao, Yu and Song, Xiaofei and Hu, Jianhua and Lin, Mao and Tian, Ye and Yuan, Bo and Yu, Keyi and Niu, Yuchen and Yu, Bin and Li, Xiaoxin and Chen, Jia and Yan, Zihui and Zhu, Qiankun and Meng, Xiaolu and Chen, Xiaoli and Su, Jianzhong and Zhao, Xiuli and Wang, Xiaoyue and Ming, Yue and Li, Xiao and Raggio, Cathleen L and Zhang, Baozhong and Weng, Xisheng and Zhang, Shuyang and Zhang, Xue and Watanabe, Kota and Matsumoto, Morio and Jin, Li and Shen, Yiping and Sobreira, Nara L and Posey, Jennifer E and Giampietro, Philip F and Valle, David and Liu, Pengfei and Wu, Zhihong and Ikegawa, Shiro and Lupski, James R and Zhang, Feng and Qiu, Guixing} } @article {653, title = {Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes.}, journal = {Eur J Hum Genet}, year = {2019}, month = {2019 Apr 12}, abstract = {

Clinical exome sequencing (CES) is increasingly being utilized; however, a large proportion of patients remain undiagnosed, creating a need for a systematic approach to increase the diagnostic yield. We have reanalyzed CES data for a clinically heterogeneous cohort of 102 probands with likely Mendelian conditions, including 74 negative cases and 28 cases with candidate variants, but reanalysis requested by clinicians. Reanalysis was performed by an interdisciplinary team using a validated custom-built pipeline, "Variant Explorer Pipeline" (VExP). This reanalysis approach and results were compared with existing literature. Reanalysis of candidate variants from CES in 28 cases revealed 1 interpretation that needed to be reclassified. A confirmed or potential genetic diagnosis was identified in 24 of 75 CES-negative/reclassified cases (32.0\%), including variants in known disease-causing genes (n = 6) or candidate genes (n = 18). This yield was higher compared with similar studies demonstrating the utility of this approach. In summary, reanalysis of negative CES in a research setting enhances diagnostic yield by about a third. This study suggests the need for comprehensive, continued reanalysis of exome data when molecular diagnosis is elusive.

}, issn = {1476-5438}, doi = {10.1038/s41431-019-0401-x}, author = {Schmitz-Abe, Klaus and Li, Qifei and Rosen, Samantha M and Nori, Neeharika and Madden, Jill A and Genetti, Casie A and Wojcik, Monica H and Ponnaluri, Sadhana and Gubbels, Cynthia S and Picker, Jonathan D and O{\textquoteright}Donnell-Luria, Anne H and Yu, Timothy W and Bodamer, Olaf and Brownstein, Catherine A and Beggs, Alan H and Agrawal, Pankaj B} } @article {577, title = {ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {319-330}, abstract = {

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de~novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In~vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In~vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

}, keywords = {Alleles, Animals, Child, Child, Preschool, Developmental Disabilities, Female, Humans, Infant, Intellectual Disability, Male, Mice, Point Mutation, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.007}, author = {Carapito, Raphael and Ivanova, Ekaterina L and Morlon, Aurore and Meng, Linyan and Molitor, Anne and Erdmann, Eva and Kieffer, Bruno and Pichot, Ang{\'e}lique and Naegely, Lydie and Kolmer, Aline and Paul, Nicod{\`e}me and Hanauer, Antoine and Tran Mau-Them, Fr{\'e}d{\'e}ric and Jean-Mar{\c c}ais, Nolwenn and Hiatt, Susan M and Cooper, Gregory M and Tvrdik, Tatiana and Muir, Alison M and Dimartino, Cl{\'e}mantine and Chopra, Maya and Amiel, Jeanne and Gordon, Christopher T and Dutreux, Fabien and Garde, Aurore and Thauvin-Robinet, Christel and Wang, Xia and Leduc, Magalie S and Phillips, Meredith and Crawford, Heather P and Kukolich, Mary K and Hunt, David and Harrison, Victoria and Kharbanda, Mira and Smigiel, Robert and Gold, Nina and Hung, Christina Y and Viskochil, David H and Dugan, Sarah L and Bayrak-Toydemir, Pinar and Joly-Helas, G{\'e}raldine and Guerrot, Anne-Marie and Schluth-Bolard, Caroline and Rio, Marl{\`e}ne and Wentzensen, Ingrid M and McWalter, Kirsty and Schnur, Rhonda E and Lewis, Andrea M and Lalani, Seema R and Mensah-Bonsu, No{\"e}l and C{\'e}raline, Jocelyn and Sun, Zijie and Ploski, Rafal and Bacino, Carlos A and Mefford, Heather C and Faivre, Laurence and Bodamer, Olaf and Chelly, Jamel and Isidor, Bertrand and Bahram, Seiamak} } @article {548, title = {Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Dec}, pages = {921-939}, abstract = {

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson-Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79\%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann-Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

}, keywords = {Adolescent, Alternative Splicing, Child, Female, Fetal Growth Retardation, Genetic Predisposition to Disease, Humans, Infant, Lamin Type A, Male, Mutation, Phenotype, Progeria, Pyrroline Carboxylate Reductases, RNA Polymerase III}, issn = {1432-1203}, doi = {10.1007/s00439-018-1957-1}, author = {Lessel, Davor and Ozel, Ayse Bilge and Campbell, Susan E and Saadi, Abdelkrim and Arlt, Martin F and McSweeney, Keisha Melodi and Plaiasu, Vasilica and Szakszon, Katalin and Sz{\H o}ll{\H o}s, Anna and Rusu, Cristina and Rojas, Armando J and Lopez-Valdez, Jaime and Thiele, Holger and N{\"u}rnberg, Peter and Nickerson, Deborah A and Bamshad, Michael J and Li, Jun Z and Kubisch, Christian and Glover, Thomas W and Gordon, Leslie B} } @article {614, title = {Analysis of 17 genes detects mutations in 81\% of 811 patients with lissencephaly.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 11}, pages = {1354-1364}, abstract = {

PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.

METHODS: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort.

RESULTS: The overall mutation frequency in the entire cohort was 81\%. LIS1 accounted for 40\% of patients, followed by DCX (23\%), TUBA1A (5\%), and DYNC1H1 (3\%). Other genes accounted for 1\% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria.

CONCLUSION: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

}, keywords = {Brain, Classical Lissencephalies and Subcortical Band Heterotopias, DNA Mutational Analysis, Female, Genetic Association Studies, Humans, Lissencephaly, Male, Mutation, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/gim.2018.8}, author = {Di Donato, Nataliya and Timms, Andrew E and Aldinger, Kimberly A and Mirzaa, Ghayda M and Bennett, James T and Collins, Sarah and Olds, Carissa and Mei, Davide and Chiari, Sara and Carvill, Gemma and Myers, Candace T and Rivi{\`e}re, Jean-Baptiste and Zaki, Maha S and Gleeson, Joseph G and Rump, Andreas and Conti, Valerio and Parrini, Elena and Ross, M Elizabeth and Ledbetter, David H and Guerrini, Renzo and Dobyns, William B} } @article {466, title = {A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 04}, pages = {1015-1022}, abstract = {

Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.

}, keywords = {Alleles, Amino Acid Substitution, Animals, Anodontia, Child, Consanguinity, Facies, Genetic Association Studies, Genotype, Humans, Male, Mice, Mutation, Neoplasm Proteins, Pedigree, Phenotype, Radiography, Receptors, Cell Surface, Whole Exome Sequencing}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38625}, author = {Dinckan, Nuriye and Du, Renqian and Akdemir, Zeynep C and Bayram, Yavuz and Jhangiani, Shalini N and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Boerwinkle, Eric and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Uyguner, Zehra O and Letra, Ariadne} } @article {562, title = {Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 11 01}, pages = {794-807}, abstract = {

Ca signaling is vital for various cellular processes including synaptic vesicle exocytosis, muscle contraction, regulation of secretion, gene transcription, and cellular proliferation. The endoplasmic reticulum (ER) is the largest intracellular Ca store, and dysregulation of ER Ca signaling and homeostasis contributes to the pathogenesis of various complex disorders and Mendelian disease traits. We describe four unrelated individuals with a complex multisystem disorder characterized by woolly hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and global developmental delay. Through whole-exome sequencing and family-based genomics, we identified bi-allelic variants in CCDC47 that encodes the Ca-binding ER transmembrane protein CCDC47. CCDC47, also known as calumin, has been shown to bind Ca with low affinity and high capacity. In mice, loss of Ccdc47 leads to embryonic lethality, suggesting that Ccdc47 is essential for early development. Characterization of cells from individuals with predicted likely damaging alleles showed decreased CCDC47 mRNA expression and protein levels. In~vitro cellular experiments showed decreased total ER Ca storage, impaired Ca signaling mediated by the IPR Ca release channel, and reduced ER Ca refilling via store-operated Ca entry. These results, together with the previously described role of CCDC47 in Ca signaling and development, suggest that bi-allelic loss-of-function variants in CCDC47 underlie the pathogenesis of this multisystem disorder.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.014}, author = {Morimoto, Marie and Waller-Evans, Helen and Ammous, Zineb and Song, Xiaofei and Strauss, Kevin A and Pehlivan, Davut and Gonzaga-Jauregui, Claudia and Puffenberger, Erik G and Holst, Charles R and Karaca, Ender and Brigatti, Karlla W and Maguire, Emily and Coban-Akdemir, Zeynep H and Amagata, Akiko and Lau, C Christopher and Chepa-Lotrea, Xenia and Macnamara, Ellen and Tos, Tulay and Isikay, Sedat and Nehrebecky, Michele and Overton, John D and Klein, Matthew and Markello, Thomas C and Posey, Jennifer E and Adams, David R and Lloyd-Evans, Emyr and Lupski, James R and Gahl, William A and Malicdan, May Christine V} } @article {520, title = {Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 09 06}, pages = {431-439}, abstract = {

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.07.010}, author = {Ghosh, Shereen G and Becker, Kerstin and Huang, He and Dixon-Salazar, Tracy and Chai, Guoliang and Salpietro, Vincenzo and Al-Gazali, Lihadh and Waisfisz, Quinten and Wang, Haicui and Vaux, Keith K and Stanley, Valentina and Manole, Andreea and Akpulat, Ugur and Weiss, Marjan M and Efthymiou, Stephanie and Hanna, Michael G and Minetti, Carlo and Striano, Pasquale and Pisciotta, Livia and De Grandis, Elisa and Altm{\"u}ller, Janine and N{\"u}rnberg, Peter and Thiele, Holger and Yis, Uluc and Okur, Tuncay Derya and Polat, Ayse Ipek and Amiri, Nafise and Doosti, Mohammad and Karimani, Ehsan Ghayoor and Toosi, Mehran B and Haddad, Gabriel and Karakaya, Mert and Wirth, Brunhilde and van Hagen, Johanna M and Wolf, Nicole I and Maroofian, Reza and Houlden, Henry and Cirak, Sebahattin and Gleeson, Joseph G} } @article {579, title = {Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 12 06}, pages = {968-975}, abstract = {

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.10.010}, author = {Wambach, Jennifer A and Wegner, Daniel J and Patni, Nivedita and Kircher, Martin and Willing, Marcia C and Baldridge, Dustin and Xing, Chao and Agarwal, Anil K and Vergano, Samantha A Schrier and Patel, Chirag and Grange, Dorothy K and Kenney, Amy and Najaf, Tasnim and Nickerson, Deborah A and Bamshad, Michael J and Cole, F Sessions and Garg, Abhimanyu} } @article {504, title = {CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris.}, journal = {J Am Acad Dermatol}, volume = {79}, year = {2018}, month = {2018 Sep}, pages = {487-494}, abstract = {

BACKGROUND: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors.

OBJECTIVE: We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14.

METHODS: Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed.

RESULTS: We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab.

LIMITATIONS: Relatively small sample size.

CONCLUSIONS: Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.

}, keywords = {Age of Onset, CARD Signaling Adaptor Proteins, Child, Child, Preschool, Dermatologic Agents, Facial Dermatoses, Genetic Testing, Guanylate Cyclase, Humans, Infant, Infant, Newborn, Membrane Proteins, Phenotype, Pityriasis Rubra Pilaris, Psoriasis, Retreatment, Skin Diseases, Papulosquamous, Ustekinumab}, issn = {1097-6787}, doi = {10.1016/j.jaad.2018.02.034}, author = {Craiglow, Brittany G and Boyden, Lynn M and Hu, Ronghua and Virtanen, Marie and Su, John and Rodriguez, Gabriela and McCarthy, Catherine and Luna, Paula and Larralde, Margarita and Humphrey, Stephen and Holland, Kristen E and Hogeling, Marcia and Hidalgo-Matlock, Benjamin and Ferrari, Bruno and Fernandez-Faith, Esteban and Drolet, Beth and Cordoro, Kelly M and Bowcock, Anne M and Antaya, Richard J and Ashack, Kurt and Ashack, Richard J and Lifton, Richard P and Milstone, Leonard M and Paller, Amy S and Choate, Keith A} } @article {508, title = {ClinGen advancing genomic data-sharing standards as a GA4GH driver project.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 11}, pages = {1686-1689}, abstract = {

The Clinical Genome Resource (ClinGen){\textquoteright}s work to develop a knowledge base to support the understanding of genes and variants for use in precision medicine and research depends on robust, broadly applicable, and adaptable technical standards for sharing data and information. To forward this goal, ClinGen has joined with the Global Alliance for Genomics and Health (GA4GH) to support the development of open, freely-available technical standards and regulatory frameworks for secure and responsible sharing of genomic and health-related data. In its capacity as one of the 15 inaugural GA4GH "Driver Projects," ClinGen is providing input on the key standards needs of the global genomics community, and has committed to participate on GA4GH Work Streams to support the development of: (1) a standard model for computer-readable variant representation; (2) a data model for linking variant data to annotations; (3) a specification to enable sharing of genomic variant knowledge and associated clinical interpretations; and (4) a set of best practices for use of phenotype and disease ontologies. ClinGen{\textquoteright}s participation as a GA4GH Driver Project will provide a robust environment to test drive emerging genomic knowledge sharing standards and prove their utility among the community, while accelerating the construction of the ClinGen evidence base.

}, issn = {1098-1004}, doi = {10.1002/humu.23625}, author = {Dolman, Lena and Page, Angela and Babb, Lawrence and Freimuth, Robert R and Arachchi, Harindra and Bizon, Chris and Brush, Matthew and Fiume, Marc and Haendel, Melissa and Hansen, David P and Milosavljevic, Aleksandar and Patel, Ronak Y and Pawliczek, Piotr and Yates, Andrew D and Rehm, Heidi L} } @article {526, title = {The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Jul}, pages = {553-567}, abstract = {

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be {\textquoteright}induced{\textquoteright} by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10\%) and pathogenic/likely pathogenic CNVs (overlap 99.69\%) was significantly higher than the random distribution (p < 1 {\texttimes} 10 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.

}, keywords = {Adolescent, Congenital Abnormalities, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genomics, Genotype, Haplotypes, Humans, Phenotype, Polymorphism, Single Nucleotide, Scoliosis}, issn = {1432-1203}, doi = {10.1007/s00439-018-1910-3}, author = {Liu, Jiaqi and Zhou, Yangzhong and Liu, Sen and Song, Xiaofei and Yang, Xin-Zhuang and Fan, Yanhui and Chen, Weisheng and Akdemir, Zeynep Coban and Yan, Zihui and Zuo, Yuzhi and Du, Renqian and Liu, Zhenlei and Yuan, Bo and Zhao, Sen and Liu, Gang and Chen, Yixin and Zhao, Yanxue and Lin, Mao and Zhu, Qiankun and Niu, Yuchen and Liu, Pengfei and Ikegawa, Shiro and Song, You-Qiang and Posey, Jennifer E and Qiu, Guixing and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan} } @article {521, title = {A comprehensive clinical and genetic study in 127 patients with ID in Kinshasa, DR Congo.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 09}, pages = {1897-1909}, abstract = {

Pathogenic variants account for 4 to 41\% of patients with intellectual disability (ID) or developmental delay (DD). In Sub-Saharan Africa, the prevalence of ID is thought to be higher, but data in Central Africa are limited to some case reports. In addition, clinical descriptions of some syndromes are not available for this population. This study aimed at providing an estimate for the fraction of ID/DD for which an underlying etiological genetic cause may be elucidated and provide insights into their clinical presentation in special institutions in a Central African country. A total of 127 patients (33 females and 94 males, mean age 10.03 {\textpm} 4.68 years), were recruited from six institutions across Kinshasa. A clinical diagnosis was achieved in 44 but molecular confirmation was achieved in 21 of the 22 patients with expected genetic defect (95\% clinical sensitivity). Identified diseases included Down syndrome (15\%), submicroscopic copy number variants (9\%), aminoacylase deficiency (0.8\%), Partington syndrome in one patient (0.8\%) and his similarly affected brother, X-linked syndromic Mental Retardation type 33 (0.8\%), and two conditions without clear underlying molecular genetic etiologies (Oculo-Auriculo-Vertebral and Amniotic Bands Sequence). We have shown that genetic etiologies, similar to those reported in Caucasian subjects, are a common etiologic cause of ID in African patients from Africa. We have confirmed the diagnostic utility of clinical characterization prior to genetic testing. Finally, our clinical descriptions provide insights into the presentation of these genetic diseases in African patients.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.40382}, author = {Lumaka, Aim{\'e} and Race, Valerie and Peeters, Hilde and Corveleyn, Anniek and Coban-Akdemir, Zeynep and Jhangiani, Shalini N and Song, Xiaofei and Mubungu, Gerrye and Posey, Jennifer and Lupski, James R and Vermeesch, Joris R and Lukusa, Prosper and Devriendt, Koenraad} } @article {460, title = {Comprehensive genomic analysis of patients with disorders of cerebral cortical development.}, journal = {Eur J Hum Genet}, volume = {26}, year = {2018}, month = {2018 08}, pages = {1121-1131}, abstract = {

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes~ and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

}, keywords = {Cadherins, DNA Copy Number Variations, Exome, Female, Genetic Heterogeneity, Humans, Male, Malformations of Cortical Development, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Receptors, Cell Surface}, issn = {1476-5438}, doi = {10.1038/s41431-018-0137-z}, author = {Wiszniewski, Wojciech and Gawlinski, Pawel and Gambin, Tomasz and Bekiesinska-Figatowska, Monika and Obersztyn, Ewa and Antczak-Marach, Dorota and Akdemir, Zeynep Hande Coban and Harel, Tamar and Karaca, Ender and Jurek, Marta and Sobecka, Katarzyna and Nowakowska, Beata and Kruk, Malgorzata and Terczynska, Iwona and Goszczanska-Ciuchta, Alicja and Rudzka-Dybala, Mariola and Jamroz, Ewa and Pyrkosz, Antoni and Jakubiuk-Tomaszuk, Anna and Iwanowski, Piotr and Gieruszczak-Bialek, Dorota and Piotrowicz, Malgorzata and Sasiadek, Maria and Kochanowska, Iwona and Gurda, Barbara and Steinborn, Barbara and Dawidziuk, Mateusz and Castaneda, Jennifer and Wlasienko, Pawel and Bezniakow, Natalia and Jhangiani, Shalini N and Hoffman-Zacharska, Dorota and Bal, Jerzy and Szczepanik, Elzbieta and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R} } @article {445, title = {The Congenital Heart Disease Genetic Network Study: Cohort description.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0191319}, abstract = {

The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40\%) or left ventricular outflow tract obstruction (21\%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.

}, keywords = {Adult, Cohort Studies, Female, Gene Regulatory Networks, Heart Defects, Congenital, Humans, Male, Phenotype}, issn = {1932-6203}, doi = {10.1371/journal.pone.0191319}, author = {Hoang, Thanh T and Goldmuntz, Elizabeth and Roberts, Amy E and Chung, Wendy K and Kline, Jennie K and Deanfield, John E and Giardini, Alessandro and Aleman, Adolfo and Gelb, Bruce D and Mac Neal, Meghan and Porter, George A and Kim, Richard and Brueckner, Martina and Lifton, Richard P and Edman, Sharon and Woyciechowski, Stacy and Mitchell, Laura E and Agopian, A J} } @article {451, title = {Congenital Titinopathy: Comprehensive characterization and pathogenic insights.}, journal = {Ann Neurol}, volume = {83}, year = {2018}, month = {2018 Jun}, pages = {1105-1124}, abstract = {

OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.

METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients.

RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46\% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder.

INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

}, issn = {1531-8249}, doi = {10.1002/ana.25241}, author = {Oates, Emily C and Jones, Kristi J and Donkervoort, Sandra and Charlton, Amanda and Brammah, Susan and Smith, John E and Ware, James S and Yau, Kyle S and Swanson, Lindsay C and Whiffin, Nicola and Peduto, Anthony J and Bournazos, Adam and Waddell, Leigh B and Farrar, Michelle A and Sampaio, Hugo A and Teoh, Hooi Ling and Lamont, Phillipa J and Mowat, David and Fitzsimons, Robin B and Corbett, Alastair J and Ryan, Monique M and O{\textquoteright}Grady, Gina L and Sandaradura, Sarah A and Ghaoui, Roula and Joshi, Himanshu and Marshall, Jamie L and Nolan, Melinda A and Kaur, Simranpreet and Punetha, Jaya and Topf, Ana and Harris, Elizabeth and Bakshi, Madhura and Genetti, Casie A and Marttila, Minttu and Werlauff, Ulla and Streichenberger, Nathalie and Pestronk, Alan and Mazanti, Ingrid and Pinner, Jason R and Vuillerot, Carole and Grosmann, Carla and Camacho, Ana and Mohassel, Payam and Leach, Meganne E and Foley, A Reghan and Bharucha-Goebel, Diana and Collins, James and Connolly, Anne M and Gilbreath, Heather R and Iannaccone, Susan T and Castro, Diana and Cummings, Beryl B and Webster, Richard I and Lazaro, Le{\"\i}la and Vissing, John and Coppens, Sandra and Deconinck, Nicolas and Luk, Ho-Ming and Thomas, Neil H and Foulds, Nicola C and Illingworth, Marjorie A and Ellard, Sian and McLean, Catriona A and Phadke, Rahul and Ravenscroft, Gianina and Witting, Nanna and Hackman, Peter and Richard, Isabelle and Cooper, Sandra T and Kamsteeg, Erik-Jan and Hoffman, Eric P and Bushby, Kate and Straub, Volker and Udd, Bjarne and Ferreiro, Ana and North, Kathryn N and Clarke, Nigel F and Lek, Monkol and Beggs, Alan H and B{\"o}nnemann, Carsten G and MacArthur, Daniel G and Granzier, Henk and Davis, Mark R and Laing, Nigel G} } @article {495, title = {Co-occurrence of frameshift mutations in and in a child with complex craniosynostosis.}, journal = {Hum Genome Var}, volume = {5}, year = {2018}, month = {2018}, pages = {14}, abstract = {

Non-syndromic craniosynostosis (CS) affects 1 in 2350 live births. Recent studies have shown that a significant fraction of cases are caused by de novo or rare transmitted mutations that promote premature osteoblast differentiation in cranial sutures. Rare heterozygous loss-of-function (LOF) mutations in and are highly enriched in patients with non-syndromic sagittal and coronal CS, respectively. Interestingly, both mutations show striking incomplete penetrance, suggesting a role for modifying alleles; in the case of , a common variant near drastically increases penetrance of sagittal CS. Here, we report a proband presenting with both sagittal and coronal craniosynostosis with the highly unusual recurrence of CS within two months of initial surgery, requiring a second operation to re-establish suture patency at six months of age. Exome sequencing revealed a rare transmitted frameshift mutation in (p. 152 fs*27) inherited from an unaffected parent, absence of the common risk variant, and a de novo frameshift mutation in (p.E548fs*14). and independently inhibit transcriptional targets of BMP signaling. The findings are consistent with epistasis of these mutations, increasing penetrance and severity of CS in this proband. They also add to the list of composite phenotypes resulting from two Mendelian mutations, and support the utility of exome sequencing in atypical CS cases.

}, issn = {2054-345X}, doi = {10.1038/s41439-018-0014-x}, author = {Timberlake, Andrew T and Wu, Robin and Nelson-Williams, Carol and Furey, Charuta G and Hildebrand, Kristi I and Elton, Scott W and Wood, Jeyhan S and Persing, John A and Lifton, Richard P} } @article {550, title = {De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.}, journal = {Cell Rep}, volume = {24}, year = {2018}, month = {2018 Sep 25}, pages = {3441-3454.e12}, abstract = {

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2018.08.082}, author = {Wang, Sheng and Mandell, Jeffrey D and Kumar, Yogesh and Sun, Nawei and Morris, Montana T and Arbelaez, Juan and Nasello, Cara and Dong, Shan and Duhn, Clif and Zhao, Xin and Yang, Zhiyu and Padmanabhuni, Shanmukha S and Yu, Dongmei and King, Robert A and Dietrich, Andrea and Khalifa, Najah and Dahl, Niklas and Huang, Alden Y and Neale, Benjamin M and Coppola, Giovanni and Mathews, Carol A and Scharf, Jeremiah M and Fernandez, Thomas V and Buxbaum, Joseph D and De Rubeis, Silvia and Grice, Dorothy E and Xing, Jinchuan and Heiman, Gary A and Tischfield, Jay A and Paschou, Peristera and Willsey, A Jeremy and State, Matthew W} } @article {658, title = {De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.}, journal = {PLoS Genet}, volume = {14}, year = {2018}, month = {2018 12}, pages = {e1007822}, abstract = {

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.

}, keywords = {Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Female, Genetic Variation, Heart Defects, Congenital, Hernias, Diaphragmatic, Congenital, Humans, Infant, Newborn, Longitudinal Studies, Male, Membrane Proteins, Mutation, Mutation, Missense, Phenotype, Sequence Analysis, RNA, Syndrome, Transcription Factors, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1007822}, author = {Qi, Hongjian and Yu, Lan and Zhou, Xueya and Wynn, Julia and Zhao, Haoquan and Guo, Yicheng and Zhu, Na and Kitaygorodsky, Alexander and Hernan, Rebecca and Aspelund, Gudrun and Lim, Foong-Yen and Crombleholme, Timothy and Cusick, Robert and Azarow, Kenneth and Danko, Melissa E and Chung, Dai and Warner, Brad W and Mychaliska, George B and Potoka, Douglas and Wagner, Amy J and ElFiky, Mahmoud and Wilson, Jay M and Nickerson, Debbie and Bamshad, Michael and High, Frances A and Longoni, Mauro and Donahoe, Patricia K and Chung, Wendy K and Shen, Yufeng} } @article {487, title = {Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness.}, journal = {Skelet Muscle}, volume = {8}, year = {2018}, month = {2018 07 30}, pages = {23}, abstract = {

BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration.

METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250~ng DNA was completed using an Illumina exome capture and a 38~Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants.

RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7\% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase.

CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Dystroglycans, Female, Genetic Predisposition to Disease, Genetic Variation, Glycosylation, Heterozygote, Homozygote, Humans, Male, Middle Aged, Muscle Proteins, Muscular Dystrophies, Limb-Girdle, Mutation, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {2044-5040}, doi = {10.1186/s13395-018-0170-1}, author = {Johnson, Katherine and Bertoli, Marta and Phillips, Lauren and Topf, Ana and Van den Bergh, Peter and Vissing, John and Witting, Nanna and Nafissi, Shahriar and Jamal-Omidi, Shirin and {\L}usakowska, Anna and Kostera-Pruszczyk, Anna and Potulska-Chromik, Anna and Deconinck, Nicolas and Wallgren-Pettersson, Carina and Strang-Karlsson, Sonja and Colomer, Jaume and Claeys, Kristl G and De Ridder, Willem and Baets, Jonathan and von der Hagen, Maja and Fern{\'a}ndez-Torr{\'o}n, Roberto and Zulaica Ijurco, Miren and Espinal Valencia, Juan Bautista and Hahn, Andreas and Durmus, Hacer and Willis, Tracey and Xu, Liwen and Valkanas, Elise and Mullen, Thomas E and Lek, Monkol and MacArthur, Daniel G and Straub, Volker} } @article {541, title = {Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence.}, journal = {J Clin Endocrinol Metab}, volume = {103}, year = {2018}, month = {2018 04 01}, pages = {1273-1276}, abstract = {

Context: Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders.

Case Description: A missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism. This variant has been reported to reduce, but not abolish, postreceptor signaling in vitro. Biochemical evaluation during the neonatal period revealed low testosterone levels. By 11 years and 8 months, the boy began demonstrating increases in testicular volume. By 17 years and 3 months, his testicular volume was 20 mL; his penile length was 7.3 cm; and he had adult levels of circulating gonadotropins and testosterone.

Conclusion: This case report associates biallelic loss-of-function mutations in KISS1R with normal timing of adolescent puberty. Because these coding sequence variants occurred in a patient with microphallus and cryptorchidism, they demonstrate different levels of dependence of the hypothalamic-pituitary-gonadal cascade on kisspeptin signaling at distinct times in the reproductive life span. The suppression of the hypothalamic-pituitary-gonadal cascade during early life but not adolescence suggests that the mini puberty of infancy depends more on kisspeptin-induced, gonadotropin-releasing hormone-induced luteinizing hormone secretion than does adolescent puberty.

}, keywords = {Cryptorchidism, Follicle Stimulating Hormone, Follow-Up Studies, Humans, Infant, Kisspeptins, Luteinizing Hormone, Male, Mutation, Missense, Penis, Receptors, Kisspeptin-1, Sexual Maturation, Signal Transduction, Testosterone}, issn = {1945-7197}, doi = {10.1210/jc.2017-02636}, author = {Shahab, Muhammad and Lippincott, Margaret and Chan, Yee-Ming and Davies, Addie and Merino, Paulina M and Plummer, Lacey and Mericq, Veronica and Seminara, Stephanie} } @article {628, title = {Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.}, journal = {Cell}, volume = {172}, year = {2018}, month = {2018 02 22}, pages = {897-909.e21}, abstract = {

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian~neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly~across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific~transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.

}, keywords = {Alternative Splicing, Alu Elements, Base Sequence, Cohort Studies, CRISPR-Cas Systems, Dystonic Disorders, Family, Female, Genetic Diseases, X-Linked, Genetic Loci, Genome, Human, Haplotypes, High-Throughput Nucleotide Sequencing, Histone Acetyltransferases, Humans, Induced Pluripotent Stem Cells, Introns, Male, Minisatellite Repeats, Models, Genetic, Nerve Degeneration, Neural Stem Cells, Neurons, RNA, Messenger, Short Interspersed Nucleotide Elements, TATA-Binding Protein Associated Factors, Transcription Factor TFIID, Transcriptome}, issn = {1097-4172}, doi = {10.1016/j.cell.2018.02.011}, author = {Aneichyk, Tatsiana and Hendriks, William T and Yadav, Rachita and Shin, David and Gao, Dadi and Vaine, Christine A and Collins, Ryan L and Domingo, Aloysius and Currall, Benjamin and Stortchevoi, Alexei and Multhaupt-Buell, Trisha and Penney, Ellen B and Cruz, Lilian and Dhakal, Jyotsna and Brand, Harrison and Hanscom, Carrie and Antolik, Caroline and Dy, Marisela and Ragavendran, Ashok and Underwood, Jason and Cantsilieris, Stuart and Munson, Katherine M and Eichler, Evan E and Acu{\~n}a, Patrick and Go, Criscely and Jamora, R Dominic G and Rosales, Raymond L and Church, Deanna M and Williams, Stephen R and Garcia, Sarah and Klein, Christine and M{\"u}ller, Ulrich and Wilhelmsen, Kirk C and Timmers, H T Marc and Sapir, Yechiam and Wainger, Brian J and Henderson, Daniel and Ito, Naoto and Weisenfeld, Neil and Jaffe, David and Sharma, Nutan and Breakefield, Xandra O and Ozelius, Laurie J and Bragg, D Cristopher and Talkowski, Michael E} } @article {491, title = {Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {744-759}, abstract = {

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D.~rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in~vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

}, keywords = {Adolescent, Adult, Aged, 80 and over, Alleles, Animals, Autistic Disorder, Brain, Cerebellar Ataxia, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Female, Genes, Dominant, Genetic Complementation Test, Humans, Intellectual Disability, Larva, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense, Nuclear Receptor Subfamily 1, Group F, Member 1, Purkinje Cells, Syndrome, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.02.021}, author = {Guissart, Claire and Latypova, X{\'e}nia and Rollier, Paul and Khan, Tahir N and Stamberger, Hannah and McWalter, Kirsty and Cho, Megan T and Kjaergaard, Susanne and Weckhuysen, Sarah and Lesca, Gaetan and Besnard, Thomas and {\~O}unap, Katrin and Schema, Lynn and Chiocchetti, Andreas G and McDonald, Marie and de Bellescize, Julitta and Vincent, Marie and Van Esch, Hilde and Sattler, Shannon and Forghani, Irman and Thiffault, Isabelle and Freitag, Christine M and Barbouth, Deborah Sara and Cadieux-Dion, Maxime and Willaert, Rebecca and Guillen Sacoto, Maria J and Safina, Nicole P and Dubourg, Christ{\`e}le and Grote, Lauren and Carr{\'e}, Wilfrid and Saunders, Carol and Pajusalu, Sander and Farrow, Emily and Boland, Anne and Karlowicz, Danielle Hays and Deleuze, Jean-Fran{\c c}ois and Wojcik, Monica H and Pressman, Rena and Isidor, Bertrand and Vogels, Annick and Van Paesschen, Wim and Al-Gazali, Lihadh and Al Shamsi, Aisha Mohamed and Claustres, Mireille and Pujol, Aurora and Sanders, Stephan J and Rivier, Fran{\c c}ois and Leboucq, Nicolas and Cogn{\'e}, Benjamin and Sasorith, Souphatta and Sanlaville, Damien and Retterer, Kyle and Odent, Sylvie and Katsanis, Nicholas and B{\'e}zieau, St{\'e}phane and Koenig, Michel and Davis, Erica E and Pasquier, Laurent and K{\"u}ry, S{\'e}bastien} } @article {435, title = {FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.}, journal = {Pediatr Diabetes}, volume = {19}, year = {2018}, month = {2018 05}, pages = {388-392}, abstract = {

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.

}, keywords = {Diabetes Mellitus, Diabetes Mellitus, Type 1, Diarrhea, Forkhead Transcription Factors, Genetic Diseases, X-Linked, Humans, Immune System Diseases, Infant, Infant, Newborn, Male, Registries}, issn = {1399-5448}, doi = {10.1111/pedi.12612}, author = {Hwang, Jessica L and Park, Soo-Young and Ye, Honggang and Sanyoura, May and Pastore, Ashley N and Carmody, David and Del Gaudio, Daniela and Wilson, Janna F and Hanis, Craig L and Liu, Xiaoming and Atzmon, Gil and Glaser, Benjamin and Philipson, Louis H and Greeley, Siri Atma W} } @article {543, title = {Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 Feb 01}, pages = {309-320}, abstract = {

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in~vitro, and in~vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.12.015}, author = {Martinelli, Simone and Krumbach, Oliver H F and Pantaleoni, Francesca and Coppola, Simona and Amin, Ehsan and Pannone, Luca and Nouri, Kazem and Farina, Luciapia and Dvorsky, Radovan and Lepri, Francesca and Buchholzer, Marcel and Konopatzki, Raphael and Walsh, Laurence and Payne, Katelyn and Pierpont, Mary Ella and Vergano, Samantha Schrier and Langley, Katherine G and Larsen, Douglas and Farwell, Kelly D and Tang, Sha and Mroske, Cameron and Gallotta, Ivan and Di Schiavi, Elia and Della Monica, Matteo and Lugli, Licia and Rossi, Cesare and Seri, Marco and Cocchi, Guido and Henderson, Lindsay and Baskin, Berivan and Alders, Marielle and Mendoza-Londono, Roberto and Dupuis, Lucie and Nickerson, Deborah A and Chong, Jessica X and Meeks, Naomi and Brown, Kathleen and Causey, Tahnee and Cho, Megan T and Demuth, Stephanie and Digilio, Maria Cristina and Gelb, Bruce D and Bamshad, Michael J and Zenker, Martin and Ahmadian, Mohammad Reza and Hennekam, Raoul C and Tartaglia, Marco and Mirzaa, Ghayda M} } @article {661, title = {FUT2 Variants Confer Susceptibility to Familial Otitis Media.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 11 01}, pages = {679-690}, abstract = {

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2~{\texttimes} 10) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154, and p.Arg202-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.010}, author = {Santos-Cortez, Regie Lyn P and Chiong, Charlotte M and Frank, Daniel N and Ryan, Allen F and Giese, Arnaud P J and Bootpetch Roberts, Tori and Daly, Kathleen A and Steritz, Matthew J and Szeremeta, Wasyl and Pedro, Melquiadesa and Pine, Harold and Yarza, Talitha Karisse L and Scholes, Melissa A and Llanes, Erasmo Gonzalo D V and Yousaf, Saira and Friedman, Norman and Tantoco, Ma Leah C and Wine, Todd M and Labra, Patrick John and Benoit, Jeanne and Ruiz, Amanda G and de la Cruz, Rhodieleen Anne R and Greenlee, Christopher and Yousaf, Ayesha and Cardwell, Jonathan and Nonato, Rachelle Marie A and Ray, Dylan and Ong, Kimberly Mae C and So, Edward and Robertson, Charles E and Dinwiddie, Jordyn and Lagrana-Villagracia, Sheryl Mae and Gubbels, Samuel P and Shaikh, Rehan S and Cass, Stephen P and Einarsdottir, Elisabet and Lee, Nanette R and Schwartz, David A and Gloria-Cruz, Teresa Luisa I and Bamshad, Michael J and Yang, Ivana V and Kere, Juha and Abes, Generoso T and Prager, Jeremy D and Riazuddin, Saima and Chan, Abner L and Yoon, Patricia J and Nickerson, Deborah A and Cutiongco-de la Paz, Eva Maria and Streubel, Sven-Olrik and Reyes-Quintos, Maria Rina T and Jenkins, Herman A and Mattila, Petri and Chan, Kenny H and Mohlke, Karen L and Leal, Suzanne M and Hafr{\'e}n, Lena and Chonmaitree, Tasnee and Sale, Michele M and Ahmed, Zubair M} } @article {619, title = {Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.}, journal = {Blood}, volume = {132}, year = {2018}, month = {2018 Jul 05}, pages = {89-100}, abstract = {

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19\%) and correlated with presentation at younger than 1 year of age ( < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58\%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45\%, and increased mortality correlated with HLH triggered by infection or malignancy ( < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

}, issn = {1528-0020}, doi = {10.1182/blood-2017-11-814244}, author = {Chinn, Ivan K and Eckstein, Olive S and Peckham-Gregory, Erin C and Goldberg, Baruch R and Forbes, Lisa R and Nicholas, Sarah K and Mace, Emily M and Vogel, Tiphanie P and Abhyankar, Harshal A and Diaz, Maria I and Heslop, Helen E and Krance, Robert A and Martinez, Caridad A and Nguyen, Trung C and Bashir, Dalia A and Goldman, Jordana R and Stray-Pedersen, Asbj{\o}rg and Pedroza, Luis A and Poli, M Cecilia and Aldave-Becerra, Juan C and McGhee, Sean A and Al-Herz, Waleed and Chamdin, Aghiad and Coban-Akdemir, Zeynep H and Jhangiani, Shalini N and Muzny, Donna M and Cao, Tram N and Hong, Diana N and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and McClain, Kenneth L and Allen, Carl E} } @article {500, title = {Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {753-768}, abstract = {

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant~located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

}, keywords = {Adolescent, Adult, Carrier Proteins, Channelopathies, Child, Child, Preschool, Developmental Disabilities, Female, Genetic Markers, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Phenotype, Sodium Channels, Young Adult}, issn = {1432-1203}, doi = {10.1007/s00439-018-1929-5}, author = {Bramswig, Nuria C and Bertoli-Avella, Aida M and Albrecht, Beate and Al Aqeel, Aida I and Alhashem, Amal and Al-Sannaa, Nouriya and Bah, Maissa and Br{\"o}hl, Katharina and Depienne, Christel and Dorison, Nathalie and Doummar, Diane and Ehmke, Nadja and Elbendary, Hasnaa M and Gorokhova, Svetlana and H{\'e}ron, Delphine and Horn, Denise and James, Kiely and Keren, Boris and Kuechler, Alma and Ismail, Samira and Issa, Mahmoud Y and Marey, Isabelle and Mayer, Mich{\`e}le and McEvoy-Venneri, Jennifer and Megarbane, Andre and Mignot, Cyril and Mohamed, Sarar and Nava, Caroline and Philip, Nicole and Ravix, Cecile and Rolfs, Arndt and Sadek, Abdelrahim Abdrabou and Segebrecht, Lara and Stanley, Valentina and Trautman, Camille and Valence, Stephanie and Villard, Laurent and Wieland, Thomas and Engels, Hartmut and Strom, Tim M and Zaki, Maha S and Gleeson, Joseph G and L{\"u}decke, Hermann-Josef and Bauer, Peter and Wieczorek, Dagmar} } @article {473, title = {Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1126-1142}, abstract = {

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that~perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in~any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune~phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

}, keywords = {Base Sequence, Cell Line, Endoplasmic Reticulum Stress, Exons, Family, Frameshift Mutation, Genetic Predisposition to Disease, Heterozygote, Humans, Immunologic Deficiency Syndromes, Immunophenotyping, Infant, Newborn, Inflammation, Interferon Type I, Male, Molecular Chaperones, Mutant Proteins, Mutation, Nonsense Mediated mRNA Decay, Phenotype, Proteasome Endopeptidase Complex, RNA, Messenger, Syndrome, Unfolded Protein Response}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.010}, author = {Poli, M Cecilia and Ebstein, Fr{\'e}d{\'e}ric and Nicholas, Sarah K and de Guzman, Marietta M and Forbes, Lisa R and Chinn, Ivan K and Mace, Emily M and Vogel, Tiphanie P and Carisey, Alexandre F and Benavides, Felipe and Coban-Akdemir, Zeynep H and Gibbs, Richard A and Jhangiani, Shalini N and Muzny, Donna M and Carvalho, Claudia M B and Schady, Deborah A and Jain, Mahim and Rosenfeld, Jill A and Emrick, Lisa and Lewis, Richard A and Lee, Brendan and Zieba, Barbara A and K{\"u}ry, S{\'e}bastien and Kr{\"u}ger, Elke and Lupski, James R and Bostwick, Bret L and Orange, Jordan S} } @article {545, title = {A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0191224}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause (40-50\%) of chronic kidney disease (CKD) in children. About 40 monogenic causes of CAKUT have so far been discovered. To date less than 20\% of CAKUT cases can be explained by mutations in these 40 genes. To identify additional monogenic causes of CAKUT, we performed whole exome sequencing (WES) and homozygosity mapping (HM) in a patient with CAKUT from Indian origin and consanguineous descent. We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys) in the gene Von Willebrand factor A domain containing 2 (VWA2). With immunohistochemistry studies on kidneys of newborn (P1) mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1) co-localize in the nephrogenic zone of the renal cortex. We identified a pronounced expression of Vwa2 in the basement membrane of the ureteric bud (UB) and derivatives of the metanephric mesenchyme (MM). By applying in vitro assays, we demonstrate that the Arg446Cys mutation decreases translocation of monomeric VWA2 protein and increases translocation of aggregated VWA2 protein into the extracellular space. This is potentially due to the additional, unpaired cysteine residue in the mutated protein that is used for intermolecular disulfide bond formation. VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC). FC-encoding genes and interacting proteins have previously been implicated in the pathogenesis of syndromic and/or isolated CAKUT phenotypes in humans. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes. Our results from in vitro experiments indicate a dose-dependent neomorphic effect of the Arg446Cys homozygous mutation in VWA2.

}, keywords = {Amino Acid Sequence, Amino Acid Substitution, Animals, Animals, Newborn, Biomarkers, Tumor, Child, Consanguinity, Conserved Sequence, Exons, Extracellular Matrix Proteins, Fraser Syndrome, Gene Expression Regulation, Developmental, Homozygote, Humans, Male, Mice, Models, Animal, Models, Molecular, Mutation, Missense, Pedigree, Sequence Homology, Amino Acid, Urogenital Abnormalities, Urogenital System, Vesico-Ureteral Reflux}, issn = {1932-6203}, doi = {10.1371/journal.pone.0191224}, author = {van der Ven, Amelie T and Kobbe, Birgit and Kohl, Stefan and Shril, Shirlee and Pogoda, Hans-Martin and Imhof, Thomas and Ityel, Hadas and Vivante, Asaf and Chen, Jing and Hwang, Daw-Yang and Connaughton, Dervla M and Mann, Nina and Widmeier, Eugen and Taglienti, Mary and Schmidt, Johanna Magdalena and Nakayama, Makiko and Senguttuvan, Prabha and Kumar, Selvin and Tasic, Velibor and Kehinde, Elijah O and Mane, Shrikant M and Lifton, Richard P and Soliman, Neveen and Lu, Weining and Bauer, Stuart B and Hammerschmidt, Matthias and Wagener, Raimund and Hildebrandt, Friedhelm} } @article {510, title = {Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis.}, journal = {Mol Genet Metab}, volume = {125}, year = {2018}, month = {2018 11}, pages = {302-304}, abstract = {

Charcot-Marie-Tooth (CMT) disease type 1 is an inherited peripheral neuropathy characterized by demyelination and reduced nerve conduction velocities. We present a multi-generational family with peripheral neuropathy in whom clinical CMT panel testing failed to conclude a molecular diagnosis. We found a PMP2 pathogenic variant c.155T > C, p.(Ile52Thr) that segregates with disease suggesting that PMP2 variants should be considered in patients with neuropathy and that it may be prudent to include in clinical CMT gene panels.

}, issn = {1096-7206}, doi = {10.1016/j.ymgme.2018.08.005}, author = {Punetha, Jaya and Mackay-Loder, Loren and Harel, Tamar and Coban-Akdemir, Zeynep and Jhangiani, Shalini N and Gibbs, Richard A and Lee, Ian and Terespolsky, Deborah and Lupski, James R and Posey, Jennifer E} } @article {523, title = {Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {689-703}, abstract = {

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM $\#$150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM $\#$614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM $\#$104530; Epidermolysis bullosa, junctional, MIMs $\#$226700 and $\#$226650), and BCOR (Microphthalmia, syndromic 2, MIM $\#$300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.

}, keywords = {Anodontia, Cell Adhesion Molecules, Child, Child, Preschool, Female, Genetic Markers, Humans, Male, Mutation, Pedigree, Phenotype, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Turkey, Wnt Proteins}, issn = {1432-1203}, doi = {10.1007/s00439-018-1907-y}, author = {Du, Renqian and Dinckan, Nuriye and Song, Xiaofei and Coban-Akdemir, Zeynep and Jhangiani, Shalini N and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Petty, Lauren E and Muzny, Donna M and Below, Jennifer E and Boerwinkle, Eric and Wu, Nan and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Letra, Ariadne and Uyguner, Z Oya} } @article {524, title = {Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 08 02}, pages = {171-187}, abstract = {

Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.06.009}, author = {Coban-Akdemir, Zeynep and White, Janson J and Song, Xiaofei and Jhangiani, Shalini N and Fatih, Jawid M and Gambin, Tomasz and Bayram, Yavuz and Chinn, Ivan K and Karaca, Ender and Punetha, Jaya and Poli, Cecilia and Boerwinkle, Eric and Shaw, Chad A and Orange, Jordan S and Gibbs, Richard A and Lappalainen, Tuuli and Lupski, James R and Carvalho, Claudia M B} } @article {489, title = {Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations.}, journal = {Nature}, volume = {559}, year = {2018}, month = {2018 07}, pages = {350-355}, abstract = {

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50~kb to 249~Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9\%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50\%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.

}, keywords = {Adult, Aged, Alleles, Biological Specimen Banks, Chromosome Aberrations, Chromosome Breakage, Chromosome Fragile Sites, Chromosomes, Human, Pair 10, Clone Cells, Female, Health, Hematologic Neoplasms, Hematopoiesis, Humans, Male, Middle Aged, Mosaicism, Penetrance, United Kingdom}, issn = {1476-4687}, doi = {10.1038/s41586-018-0321-x}, author = {Loh, Po-Ru and Genovese, Giulio and Handsaker, Robert E and Finucane, Hilary K and Reshef, Yakir A and Palamara, Pier Francesco and Birmann, Brenda M and Talkowski, Michael E and Bakhoum, Samuel F and McCarroll, Steven A and Price, Alkes L} } @article {514, title = {Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome.}, journal = {Ann Neurol}, volume = {84}, year = {2018}, month = {2018 Nov}, pages = {638-647}, abstract = {

OBJECTIVE: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome.

METHODS: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression.

RESULTS: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth.

INTERPRETATION: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646-655.

}, issn = {1531-8249}, doi = {10.1002/ana.25327}, author = {Guemez-Gamboa, Alicia and {\c C}a{\u g}layan, Ahmet Okay and Stanley, Valentina and Gregor, Anne and Zaki, Maha S and Saleem, Sahar N and Musaev, Damir and McEvoy-Venneri, Jennifer and Belandres, Denice and Akizu, Naiara and Silhavy, Jennifer L and Schroth, Jana and Rosti, Rasim Ozgur and Copeland, Brett and Lewis, Steven M and Fang, Rebecca and Issa, Mahmoud Y and Per, H{\"u}seyin and G{\"u}m{\"u}{\c s}, Hakan and Bayram, Ayse Kacar and Kumanda{\c s}, Sefer and Akg{\"u}m{\"u}{\c s}, G{\"o}zde Tu{\u g}ce and Erson-Omay, Emine Z and Yasuno, Katsuhito and Bilguvar, Kaya and Heimer, Gali and Pillar, Nir and Shomron, Noam and Weissglas-Volkov, Daphna and Porat, Yuval and Einhorn, Yaron and Gabriel, Stacey and Ben-Zeev, Bruria and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {560, title = {Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.}, journal = {EMBO J}, volume = {37}, year = {2018}, month = {2018 Dec 03}, abstract = {

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the () mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

}, issn = {1460-2075}, doi = {10.15252/embj.2018100540}, author = {Shashi, Vandana and Magiera, Maria M and Klein, Dennis and Zaki, Maha and Schoch, Kelly and Rudnik-Sch{\"o}neborn, Sabine and Norman, Andrew and Lopes Abath Neto, Osorio and Dusl, Marina and Yuan, Xidi and Bartesaghi, Luca and De Marco, Patrizia and Alfares, Ahmed A and Marom, Ronit and Arold, Stefan T and Guzm{\'a}n-Vega, Francisco J and Pena, Loren Dm and Smith, Edward C and Steinlin, Maja and Babiker, Mohamed Oe and Mohassel, Payam and Foley, A Reghan and Donkervoort, Sandra and Kaur, Rupleen and Ghosh, Partha S and Stanley, Valentina and Musaev, Damir and Nava, Caroline and Mignot, Cyril and Keren, Boris and Scala, Marcello and Tassano, Elisa and Picco, Paolo and Doneda, Paola and Fiorillo, Chiara and Issa, Mahmoud Y and Alassiri, Ali and Alahmad, Ahmed and Gerard, Amanda and Liu, Pengfei and Yang, Yaping and Ertl-Wagner, Birgit and Kranz, Peter G and Wentzensen, Ingrid M and Stucka, Rolf and Stong, Nicholas and Allen, Andrew S and Goldstein, David B and Schoser, Benedikt and R{\"o}sler, Kai M and Alfadhel, Majid and Capra, Valeria and Chrast, Roman and Strom, Tim M and Kamsteeg, Erik-Jan and B{\"o}nnemann, Carsten G and Gleeson, Joseph G and Martini, Rudolf and Janke, Carsten and Senderek, Jan} } @article {626, title = {LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 04 05}, pages = {706-712}, abstract = {

The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs25 and p.Glu750) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.

}, keywords = {Adult, Aged, 80 and over, Aneurysm, Dissecting, Animals, Aortic Aneurysm, Thoracic, Blood Pressure, Female, Genetic Predisposition to Disease, Homozygote, Humans, Latent TGF-beta Binding Proteins, Male, Mice, Middle Aged, Mutation, Pedigree}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.002}, author = {Guo, Dong-Chuan and Regalado, Ellen S and Pinard, Amelie and Chen, Jiyuan and Lee, Kwanghyuk and Rigelsky, Christina and Zilberberg, Lior and Hostetler, Ellen M and Aldred, Micheala and Wallace, Stephanie E and Prakash, Siddharth K and Leal, Suzanne M and Bamshad, Michael J and Nickerson, Deborah A and Natowicz, Marvin and Rifkin, Daniel B and Milewicz, Dianna M} } @article {511, title = {matchbox: An open-source tool for patient matching via the Matchmaker Exchange.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 Dec}, pages = {1827-1834}, abstract = {

Rare disease investigators constantly face challenges in identifying additional cases to build evidence for gene-disease causality. The Matchmaker Exchange (MME) addresses this limitation by providing a mechanism for matching patients across genomic centers via a federated network. The MME has revolutionized searching for additional cases by making it possible to query across institutional boundaries, so that what was once a laborious and manual process of contacting researchers is now automated and computable. However, while the MME network is beginning to scale, the growth of additional nodes is limited by the lack of easy-to-use solutions that can be implemented by any rare disease database owner, even one without significant software engineering resources. Here, we describe matchbox, which is an open-source, platform-independent, portable bridge between any given rare disease genomic center and the MME network, which has already led to novel gene discoveries. We also describe how matchbox greatly reduces the barrier to participation by overcoming challenges for new databases to join the MME.

}, issn = {1098-1004}, doi = {10.1002/humu.23655}, author = {Arachchi, Harindra and Wojcik, Monica H and Weisburd, Benjamin and Jacobsen, Julius O B and Valkanas, Elise and Baxter, Samantha and Byrne, Alicia B and O{\textquoteright}Donnell-Luria, Anne H and Haendel, Melissa and Smedley, Damian and MacArthur, Daniel G and Philippakis, Anthony A and Rehm, Heidi L} } @article {383, title = {Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 04}, pages = {411-419}, abstract = {

PurposeOsteogenesis imperfecta (OI) is a heritable skeletal dysplasia. Dominant pathogenic variants in COL1A1 and COL1A2 explain the majority of OI cases. At least 15 additional genes have been identified, but those still do not account for all OI phenotypes that present. We sought the genetic cause of mild and lethal OI phenotypes in an unsolved family.MethodsWe performed exome sequencing on seven members of the family, both affected and unaffected.ResultsWe identified a variant in cyclic AMP responsive element binding protein 3-like 1 (CREB3L1) in a consanguineous family. The variant caused a prenatal/perinatal lethal OI in homozygotes, similar to that seen in OI type II as a result of mutations in type I collagen genes, and a mild phenotype (fractures, blue sclerae) in multiple heterozygous family members. CREB3L1 encodes old astrocyte specifically induced substance (OASIS), an endoplasmic reticulum stress transducer. The variant disrupts a DNA-binding site and prevents OASIS from acting on its transcriptional targets including SEC24D, which encodes a component of the coat protein II complex.ConclusionThis report confirms that CREB3L1 is an OI-related gene and suggests the pathogenic mechanism of CREB3L1-associated OI involves the altered regulation of proteins involved in cellular secretion.

}, keywords = {Alleles, Amino Acid Sequence, Collagen Type I, Cyclic AMP Response Element-Binding Protein, DNA Mutational Analysis, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Mutation, Nerve Tissue Proteins, Osteogenesis Imperfecta, Pedigree, Phenotype, Radiography, Sequence Analysis, DNA, Severity of Illness Index, Ultrasonography, Prenatal}, issn = {1530-0366}, doi = {10.1038/gim.2017.115}, author = {Keller, Rachel B and Tran, Thao T and Pyott, Shawna M and Pepin, Melanie G and Savarirayan, Ravi and McGillivray, George and Nickerson, Deborah A and Bamshad, Michael J and Byers, Peter H} } @article {496, title = {Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {832-844}, abstract = {

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with \~{}7\% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

}, keywords = {Adult, Aged, Aged, 80 and over, Alleles, Amino Acid Sequence, Base Sequence, Epithelial Cells, Family, Female, HSP40 Heat-Shock Proteins, Humans, Loop of Henle, Male, Middle Aged, Mutation, Pedigree, Polycystic Kidney, Autosomal Dominant, TRPP Cation Channels, Uromodulin, Whole Exome Sequencing, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.013}, author = {Cornec-Le Gall, Emilie and Olson, Rory J and Besse, Whitney and Heyer, Christina M and Gainullin, Vladimir G and Smith, Jessica M and Audr{\'e}zet, Marie-Pierre and Hopp, Katharina and Porath, Binu and Shi, Beili and Baheti, Saurabh and Senum, Sarah R and Arroyo, Jennifer and Madsen, Charles D and F{\'e}rec, Claude and Joly, Dominique and Jouret, Fran{\c c}ois and Fikri-Benbrahim, Oussamah and Charasse, Christophe and Coulibaly, Jean-Marie and Yu, Alan S and Khalili, Korosh and Pei, York and Somlo, Stefan and Le Meur, Yannick and Torres, Vicente E and Harris, Peter C} } @article {432, title = {Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive~TNNT3~splice variant.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 03}, pages = {383-388}, abstract = {

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G~>~A, NM_006757.3:c.681+1G~>~A). TNNT3 encodes skeletal troponin-T and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-T protein with secondary loss of troponin-I . We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type-2 fibers and deficiency of troponin-T .

}, keywords = {Arthrogryposis, Genes, Recessive, Humans, Infant, Infant, Newborn, Male, Myopathies, Nemaline, RNA Splice Sites, RNA Splicing, RNA, Messenger, Troponin T}, issn = {1098-1004}, doi = {10.1002/humu.23385}, author = {Sandaradura, Sarah A and Bournazos, Adam and Mallawaarachchi, Amali and Cummings, Beryl B and Waddell, Leigh B and Jones, Kristi J and Troedson, Christopher and Sudarsanam, Annapurna and Nash, Benjamin M and Peters, Gregory B and Algar, Elizabeth M and MacArthur, Daniel G and North, Kathryn N and Brammah, Susan and Charlton, Amanda and Laing, Nigel G and Wilson, Meredith J and Davis, Mark R and Cooper, Sandra T} } @article {613, title = {A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy.}, journal = {Eur J Hum Genet}, volume = {26}, year = {2018}, month = {2018 09}, pages = {1294-1305}, abstract = {

The NAA10-NAA15 complex (NatA) is an N-terminal acetyltransferase that catalyzes N-terminal acetylation of ~40\% of all human proteins. N-terminal acetylation has several different roles in the cell, including altering protein stability and degradation, protein localization and protein-protein interactions. In recent years several X-linked NAA10 variants have been associated with genetic disorders. We have identified a previously undescribed NAA10 c.215T>C p.(Ile72Thr) variant in three boys from two unrelated families with a milder phenotypic spectrum in comparison to most of the previously described patients with NAA10 variants. These boys have development delay, intellectual disability, and cardiac abnormalities as overlapping phenotypes. Functional studies reveal that NAA10 Ile72Thr is destabilized, while binding to NAA15 most likely is intact. Surprisingly, the NatA activity of NAA10 Ile72Thr appears normal while its monomeric activity is decreased. This study further broadens the phenotypic spectrum associated with NAA10 deficiency, and adds to the evidence that genotype-phenotype correlations for NAA10 variants are much more complex than initially anticipated.

}, keywords = {Cardiomyopathy, Hypertrophic, Child, Preschool, Developmental Disabilities, Enzyme Stability, HeLa Cells, Humans, Infant, Intellectual Disability, Male, Mutation, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Phenotype, Protein Binding, Syndrome}, issn = {1476-5438}, doi = {10.1038/s41431-018-0136-0}, author = {St{\o}ve, Svein Isungset and Blenski, Marina and Stray-Pedersen, Asbj{\o}rg and Wierenga, Klaas J and Jhangiani, Shalini N and Akdemir, Zeynep Coban and Crawford, David and McTiernan, Nina and Myklebust, Line M and Purcarin, Gabriela and McNall-Knapp, Rene and Wadley, Alexandrea and Belmont, John W and Kim, Jeffrey J and Lupski, James R and Arnesen, Thomas} } @article {507, title = {Novel STAT1 Gain-of-Function Mutation Presenting as Combined Immunodeficiency.}, journal = {J Clin Immunol}, volume = {38}, year = {2018}, month = {2018 Oct}, pages = {753-756}, abstract = {

}, issn = {1573-2592}, doi = {10.1007/s10875-018-0554-3}, author = {Hartono, Stella P and Vargas-Hernandez, Alexander and Ponsford, Mark J and Chinn, Ivan K and Jolles, Stephen and Wilson, Keith and Forbes, Lisa R} } @article {517, title = {Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM).}, journal = {J Med Genet}, volume = {55}, year = {2018}, month = {2018 Oct}, pages = {675-684}, abstract = {

BACKGROUND: Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10-18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM.

METHODS: We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model.

RESULTS: We identified four pathogenic heterozygous variants in four patients, including one in the established BAVM-related gene, , and three damaging variants in novel candidate genes: , and , which we then functionally validated in zebrafish. In addition, eight likely pathogenic heterozygous variants (, and ) were identified in eight patients, and 16 patients carried one or more variants of uncertain significance. Potential oligogenic inheritance ( with , with and with ) was identified in three patients. Regulation of sma- and mad-related proteins (SMADs) (involved in bone morphogenic protein (BMP)/transforming growth factor beta (TGF-β) signalling) and vascular endothelial growth factor (VEGF)/vascular endotheliual growth factor recepter 2 (VEGFR2) binding and activity (affecting the VEGF signalling pathway) were the most significantly affected biological process involved in the pathogenesis of BAVM.

CONCLUSIONS: Our study highlights the specific role of BMP/TGF-β and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2017-105224}, author = {Wang, Kun and Zhao, Sen and Liu, Bowen and Zhang, Qianqian and Li, Yaqi and Liu, Jiaqi and Shen, Yan and Ding, Xinghuan and Lin, Jiachen and Wu, Yong and Yan, Zihui and Chen, Jia and Li, Xiaoxin and Song, Xiaofei and Niu, Yuchen and Liu, Jian and Chen, Weisheng and Ming, Yue and Du, Renqian and Chen, Cong and Long, Bo and Zhang, Yisen and Tong, Xiangjun and Zhang, Shuyang and Posey, Jennifer E and Zhang, Bo and Wu, Zhihong and Wythe, Joshua D and Liu, Pengfei and Lupski, James R and Yang, Xinjian and Wu, Nan} } @article {612, title = {Phenotypic expansion illuminates multilocus pathogenic variation.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 12}, pages = {1528-1537}, abstract = {

PURPOSE: Multilocus variation-pathogenic variants in two or more disease genes-can potentially explain the underlying genetic basis for apparent phenotypic expansion in cases for which the observed clinical features extend beyond those reported in association with a "known" disease gene.

METHODS: Analyses focused on 106 patients, 19 for whom apparent phenotypic expansion was previously attributed to variation at known disease genes. We performed a retrospective computational reanalysis of whole-exome sequencing data using stringent Variant Call File filtering criteria to determine whether molecular diagnoses involving additional disease loci might explain the observed expanded phenotypes.

RESULTS: Multilocus variation was identified in 31.6\% (6/19) of families with phenotypic expansion and 2.3\% (2/87) without phenotypic expansion. Intrafamilial clinical variability within two families was explained by multilocus variation identified in the more severely affected sibling.

CONCLUSION: Our findings underscore the role of multiple rare variants at different loci in the etiology of genetically and clinically heterogeneous cohorts. Intrafamilial phenotypic and genotypic variability allowed a dissection of genotype-phenotype relationships in two families. Our data emphasize the critical role of the clinician in diagnostic genomic analyses and demonstrate that apparent phenotypic expansion may represent blended phenotypes resulting from pathogenic variation at more than one locus.

}, issn = {1530-0366}, doi = {10.1038/gim.2018.33}, author = {Karaca, Ender and Posey, Jennifer E and Coban Akdemir, Zeynep and Pehlivan, Davut and Harel, Tamar and Jhangiani, Shalini N and Bayram, Yavuz and Song, Xiaofei and Bahrambeigi, Vahid and Yuregir, Ozge Ozalp and Bozdogan, Sevcan and Yesil, G{\"o}zde and Isikay, Sedat and Muzny, Donna and Gibbs, Richard A and Lupski, James R} } @article {506, title = {Phenotypic expansion in - a common cause of intellectual disability in females.}, journal = {Ann Clin Transl Neurol}, volume = {5}, year = {2018}, month = {2018 Oct}, pages = {1277-1285}, abstract = {

De variants in account for 1-3\% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with disorders.

}, issn = {2328-9503}, doi = {10.1002/acn3.622}, author = {Wang, Xia and Posey, Jennifer E and Rosenfeld, Jill A and Bacino, Carlos A and Scaglia, Fernando and Immken, LaDonna and Harris, Jill M and Hickey, Scott E and Mosher, Theresa M and Slavotinek, Anne and Zhang, Jing and Beuten, Joke and Leduc, Magalie S and He, Weimin and Vetrini, Francesco and Walkiewicz, Magdalena A and Bi, Weimin and Xiao, Rui and Liu, Pengfei and Shao, Yunru and Gezdirici, Alper and Gulec, Elif Y and Jiang, Yunyun and Darilek, Sandra A and Hansen, Adam W and Khayat, Michael M and Pehlivan, Davut and Piard, Juliette and Muzny, Donna M and Hanchard, Neil and Belmont, John W and Van Maldergem, Lionel and Gibbs, Richard A and Eldomery, Mohammad K and Akdemir, Zeynep C and Adesina, Adekunle M and Chen, Shan and Lee, Yi-Chien and Lee, Brendan and Lupski, James R and Eng, Christine M and Xia, Fan and Yang, Yaping and Graham, Brett H and Moretti, Paolo} } @article {461, title = {The phenotypic spectrum of Xia-Gibbs syndrome.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 06}, pages = {1315-1326}, abstract = {

Xia-Gibbs syndrome (XGS: OMIM $\#$ 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38699}, author = {Jiang, Yunyun and Wangler, Michael F and McGuire, Amy L and Lupski, James R and Posey, Jennifer E and Khayat, Michael M and Murdock, David R and Sanchez-Pulido, Luis and Ponting, Chris P and Xia, Fan and Hunter, Jill V and Meng, Qingchang and Murugan, Mullai and Gibbs, Richard A} } @article {544, title = {A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in LAMA5.}, journal = {Ann N Y Acad Sci}, volume = {1413}, year = {2018}, month = {2018 02}, pages = {119-125}, abstract = {

We report a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin α5 subunit gene (LAMA5). The variant c.8046C > T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had normal cognitive function, but magnetic resonance brain imaging showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation at 2 Hz showed 50\% decrement of compound muscle action potential amplitudes but 250\% facilitation immediately after exercise, similar to that seen in Lambert-Eaton myasthenic syndrome. Endplate studies demonstrated a profound reduction of the endplate potential quantal content but normal amplitudes of miniature endplate potentials. Electron microscopy showed endplates with increased postsynaptic folding that were denuded or only partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin α5 to SV2A and impaired laminin-521 cell adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding α-laminins.

}, keywords = {Adult, Female, Humans, Lambert-Eaton Myasthenic Syndrome, Laminin, Motor Endplate, Myasthenic Syndromes, Congenital, Synaptic Transmission}, issn = {1749-6632}, doi = {10.1111/nyas.13585}, author = {Maselli, Ricardo A and Arredondo, Juan and V{\'a}zquez, Jessica and Chong, Jessica X and Bamshad, Michael J and Nickerson, Deborah A and Lara, Marian and Ng, Fiona and Lo, Victoria Lee and Pytel, Peter and McDonald, Craig M} } @article {559, title = {Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm.}, journal = {J Pediatr Genet}, volume = {7}, year = {2018}, month = {2018 Dec}, pages = {164-173}, abstract = {

Wolf-Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified , , , , , , , and as genes whose haploinsufficiency may contribute to the development of CDH.

}, issn = {2146-4596}, doi = {10.1055/s-0038-1655755}, author = {Callaway, Danielle A and Campbell, Ian M and Stover, Samantha R and Hernandez-Garcia, Andres and Jhangiani, Shalini N and Punetha, Jaya and Paine, Ingrid S and Posey, Jennifer E and Muzny, Donna and Lally, Kevin P and Lupski, James R and Shaw, Chad A and Fernandes, Caraciolo J and Scott, Daryl A} } @article {463, title = {Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING.}, journal = {Cell Rep}, volume = {23}, year = {2018}, month = {2018 Apr 24}, pages = {1112-1123}, abstract = {

The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial or self-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of autoinflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype. Control of the Unc-51-like autophagy activating kinase 1 (ULK1) pathway, which has previously been shown to influence STING function, was potently able to suppress STING (R284S) activity to alleviate~cytokine production. Our findings add to the growing~list of inflammatory syndromes associated with spontaneous STING signaling and provide a therapeutic strategy for the treatment of STING-induced inflammatory disease.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2018.03.115}, author = {Konno, Hiroyasu and Chinn, Ivan K and Hong, Diana and Orange, Jordan S and Lupski, James R and Mendoza, Alejandra and Pedroza, Luis A and Barber, Glen N} } @article {465, title = {The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 06 15}, pages = {2064-2075}, abstract = {

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8\% of Frem2ne/ne and 1\% of Fras1Q1263*/Q1263* mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

}, keywords = {Animals, Child, Child, Preschool, Epithelium, Extracellular Matrix Proteins, Female, Hernias, Diaphragmatic, Congenital, Humans, Infant, Infant, Newborn, Male, Mice, Mice, Knockout, Mutation, Pregnancy, Receptors, Interleukin}, issn = {1460-2083}, doi = {10.1093/hmg/ddy110}, author = {Jordan, Valerie K and Beck, Tyler F and Hernandez-Garcia, Andres and Kundert, Peter N and Kim, Bum-Jun and Jhangiani, Shalini N and Gambin, Tomasz and Starkovich, Molly and Punetha, Jaya and Paine, Ingrid S and Posey, Jennifer E and Li, Alexander H and Muzny, Donna and Hsu, Chih-Wei and Lashua, Amber J and Sun, Xin and Fernandes, Caraciolo J and Dickinson, Mary E and Lally, Kevin P and Gibbs, Richard A and Boerwinkle, Eric and Lupski, James R and Scott, Daryl A} } @article {618, title = {Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 08}, pages = {1126-1138}, abstract = {

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.

}, issn = {1098-1004}, doi = {10.1002/humu.23557}, author = {Kumar, Raman and Gardner, Alison and Homan, Claire C and Douglas, Evelyn and Mefford, Heather and Wieczorek, Dagmar and L{\"u}decke, Hermann-Josef and Stark, Zornitza and Sadedin, Simon and Nowak, Catherine Bearce and Douglas, Jessica and Parsons, Gretchen and Mark, Paul and Loidi, Lourdes and Herman, Gail E and Mihalic Mosher, Theresa and Gillespie, Meredith K and Brady, Lauren and Tarnopolsky, Mark and Madrigal, Irene and Eiris, Jes{\'u}s and Dom{\`e}nech Salgado, Laura and Rabionet, Raquel and Strom, Tim M and Ishihara, Naoko and Inagaki, Hidehito and Kurahashi, Hiroki and Dudding-Byth, Tracy and Palmer, Elizabeth E and Field, Michael and Gecz, Jozef} } @article {503, title = {Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.}, journal = {Ann Neurol}, volume = {83}, year = {2018}, month = {2018 Jun}, pages = {1133-1146}, abstract = {

OBJECTIVE: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD.

METHODS: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD.

RESULTS: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17\%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14\%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53\%; Evidence for FCD was not observed in either brain tissue specimen.

INTERPRETATION: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

}, issn = {1531-8249}, doi = {10.1002/ana.25243}, author = {Winawer, Melodie R and Griffin, Nicole G and Samanamud, Jorge and Baugh, Evan H and Rathakrishnan, Dinesh and Ramalingam, Senthilmurugan and Zagzag, David and Schevon, Catherine A and Dugan, Patricia and Hegde, Manu and Sheth, Sameer A and McKhann, Guy M and Doyle, Werner K and Grant, Gerald A and Porter, Brenda E and Mikati, Mohamad A and Muh, Carrie R and Malone, Colin D and Bergin, Ann Marie R and Peters, Jurriaan M and McBrian, Danielle K and Pack, Alison M and Akman, Cigdem I and LaCoursiere, Christopher M and Keever, Katherine M and Madsen, Joseph R and Yang, Edward and Lidov, Hart G W and Shain, Catherine and Allen, Andrew S and Canoll, Peter D and Crino, Peter B and Poduri, Annapurna H and Heinzen, Erin L} } @article {501, title = {STRetch: detecting and discovering pathogenic short tandem repeat expansions.}, journal = {Genome Biol}, volume = {19}, year = {2018}, month = {2018 08 21}, pages = {121}, abstract = {

Short tandem repeat (STR) expansions have been identified as the causal DNA mutation in dozens of Mendelian diseases. Most existing tools for detecting STR variation with short reads do so within the read length and so are unable to detect the majority of pathogenic expansions. Here we present STRetch, a new genome-wide method to scan for STR expansions at all loci across the human genome. We demonstrate the use of STRetch for detecting STR expansions using short-read whole-genome sequencing data at known pathogenic loci as well as novel STR loci. STRetch is open source software, available from github.com/Oshlack/STRetch .

}, keywords = {Alleles, Chromosomes, Human, DNA Repeat Expansion, Genetic Loci, Genome, Human, Humans, Microsatellite Repeats, Polymerase Chain Reaction, Software}, issn = {1474-760X}, doi = {10.1186/s13059-018-1505-2}, author = {Dashnow, Harriet and Lek, Monkol and Phipson, Belinda and Halman, Andreas and Sadedin, Simon and Lonsdale, Andrew and Davis, Mark and Lamont, Phillipa and Clayton, Joshua S and Laing, Nigel G and MacArthur, Daniel G and Oshlack, Alicia} } @article {610, title = {SYT1-associated neurodevelopmental disorder: a case series.}, journal = {Brain}, volume = {141}, year = {2018}, month = {2018 Sep 01}, pages = {2576-2591}, abstract = {

Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals{\textquoteright} phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.

}, issn = {1460-2156}, doi = {10.1093/brain/awy209}, author = {Baker, Kate and Gordon, Sarah L and Melland, Holly and Bumbak, Fabian and Scott, Daniel J and Jiang, Tess J and Owen, David and Turner, Bradley J and Boyd, Stewart G and Rossi, Mari and Al-Raqad, Mohammed and Elpeleg, Orly and Peck, Dawn and Mancini, Grazia M S and Wilke, Martina and Zollino, Marcella and Marangi, Giuseppe and Weigand, Heike and Borggraefe, Ingo and Haack, Tobias and Stark, Zornitza and Sadedin, Simon and Tan, Tiong Yang and Jiang, Yunyun and Gibbs, Richard A and Ellingwood, Sara and Amaral, Michelle and Kelley, Whitley and Kurian, Manju A and Cousin, Michael A and Raymond, F Lucy} } @article {464, title = {Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {985-994}, abstract = {

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Autism Spectrum Disorder, Cell Line, Child, Exons, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Humans, Intellectual Disability, Male, Middle Aged, Mutation, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Pedigree, Phenotype, RNA, Messenger, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.004}, author = {Cheng, Hanyin and Dharmadhikari, Avinash V and Varland, Sylvia and Ma, Ning and Domingo, Deepti and Kleyner, Robert and Rope, Alan F and Yoon, Margaret and Stray-Pedersen, Asbj{\o}rg and Posey, Jennifer E and Crews, Sarah R and Eldomery, Mohammad K and Akdemir, Zeynep Coban and Lewis, Andrea M and Sutton, Vernon R and Rosenfeld, Jill A and Conboy, Erin and Agre, Katherine and Xia, Fan and Walkiewicz, Magdalena and Longoni, Mauro and High, Frances A and van Slegtenhorst, Marjon A and Mancini, Grazia M S and Finnila, Candice R and van Haeringen, Arie and den Hollander, Nicolette and Ruivenkamp, Claudia and Naidu, Sakkubai and Mahida, Sonal and Palmer, Elizabeth E and Murray, Lucinda and Lim, Derek and Jayakar, Parul and Parker, Michael J and Giusto, Stefania and Stracuzzi, Emanuela and Romano, Corrado and Beighley, Jennifer S and Bernier, Raphael A and K{\"u}ry, S{\'e}bastien and Nizon, Mathilde and Corbett, Mark A and Shaw, Marie and Gardner, Alison and Barnett, Christopher and Armstrong, Ruth and Kassahn, Karin S and Van Dijck, Anke and Vandeweyer, Geert and Kleefstra, Tjitske and Schieving, Jolanda and Jongmans, Marjolijn J and de Vries, Bert B A and Pfundt, Rolph and Kerr, Bronwyn and Rojas, Samantha K and Boycott, Kym M and Person, Richard and Willaert, Rebecca and Eichler, Evan E and Kooy, R Frank and Yang, Yaping and Wu, Joseph C and Lupski, James R and Arnesen, Thomas and Cooper, Gregory M and Chung, Wendy K and Gecz, Jozef and Stessman, Holly A F and Meng, Linyan and Lyon, Gholson J} } @article {564, title = {Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.}, journal = {Sci Immunol}, volume = {3}, year = {2018}, month = {2018 Dec 21}, abstract = {

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 {\texttimes} 10; odds ratio, 89.31; 95\% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9\% to 4.2\%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.

}, issn = {2470-9468}, doi = {10.1126/sciimmunol.aau8714}, author = {Boisson-Dupuis, St{\'e}phanie and Ramirez-Alejo, Noe and Li, Zhi and Patin, Etienne and Rao, Geetha and Kerner, Gaspard and Lim, Che Kang and Krementsov, Dimitry N and Hernandez, Nicholas and Ma, Cindy S and Zhang, Qian and Markle, Janet and Martinez-Barricarte, Ruben and Payne, Kathryn and Fisch, Robert and Deswarte, Caroline and Halpern, Joshua and Bouaziz, Matthieu and Mulwa, Jeanette and Sivanesan, Durga and Lazarov, Tomi and Naves, Rodrigo and Garcia, Patricia and Itan, Yuval and Boisson, Bertrand and Checchi, Alix and Jabot-Hanin, Fabienne and Cobat, Aurelie and Guennoun, Andrea and Jackson, Carolyn C and Pekcan, Sevgi and Caliskaner, Zafer and Inostroza, Jaime and Costa-Carvalho, Beatriz Tavares and de Albuquerque, Jose Antonio Tavares and Garcia-Ortiz, Humberto and Orozco, Lorena and Ozcelik, Tayfun and Abid, Ahmed and Rhorfi, Ismail Abderahmani and Souhi, Hicham and Amrani, Hicham Naji and Zegmout, Adil and Geissmann, Fr{\'e}d{\'e}ric and Michnick, Stephen W and Muller-Fleckenstein, Ingrid and Fleckenstein, Bernhard and Puel, Anne and Ciancanelli, Michael J and Marr, Nico and Abolhassani, Hassan and Balcells, Mar{\'\i}a Elvira and Condino-Neto, Antonio and Strickler, Alexis and Abarca, Katia and Teuscher, Cory and Ochs, Hans D and Reisli, Ismail and Sayar, Esra H and El-Baghdadi, Jamila and Bustamante, Jacinta and Hammarstr{\"o}m, Lennart and Tangye, Stuart G and Pellegrini, Sandra and Quintana-Murci, Lluis and Abel, Laurent and Casanova, Jean-Laurent} } @article {522, title = {Whole exome sequencing analysis in severe chronic obstructive pulmonary disease.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 11 01}, pages = {3801-3812}, abstract = {

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value~<~2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value~=~0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

}, keywords = {Adolescent, Adult, Aged, Case-Control Studies, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Whole Exome Sequencing, Young Adult}, issn = {1460-2083}, doi = {10.1093/hmg/ddy269}, author = {Qiao, Dandi and Ameli, Asher and Prokopenko, Dmitry and Chen, Han and Kho, Alvin T and Parker, Margaret M and Morrow, Jarrett and Hobbs, Brian D and Liu, Yanhong and Beaty, Terri H and Crapo, James D and Barnes, Kathleen C and Nickerson, Deborah A and Bamshad, Michael and Hersh, Craig P and Lomas, David A and Agusti, Alvar and Make, Barry J and Calverley, Peter M A and Donner, Claudio F and Wouters, Emiel F and Vestbo, J{\o}rgen and Par{\'e}, Peter D and Levy, Robert D and Rennard, Stephen I and Tal-Singer, Ruth and Spitz, Margaret R and Sharma, Amitabh and Ruczinski, Ingo and Lange, Christoph and Silverman, Edwin K and Cho, Michael H} } @article {630, title = {Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.}, journal = {Clin J Am Soc Nephrol}, volume = {13}, year = {2018}, month = {2018 01 06}, pages = {53-62}, abstract = {

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30\% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.

RESULTS: In 74 of 300 families (25\%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7\%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38\% of consanguineous families and in 13\% of nonconsanguineous families, and 48\% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. , , , and were the most common genes in which we detected a mutation. In another 28\% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.

CONCLUSIONS: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

}, issn = {1555-905X}, doi = {10.2215/CJN.04120417}, author = {Warejko, Jillian K and Tan, Weizhen and Daga, Ankana and Schapiro, David and Lawson, Jennifer A and Shril, Shirlee and Lovric, Svjetlana and Ashraf, Shazia and Rao, Jia and Hermle, Tobias and Jobst-Schwan, Tilman and Widmeier, Eugen and Majmundar, Amar J and Schneider, Ronen and Gee, Heon Yung and Schmidt, J Magdalena and Vivante, Asaf and van der Ven, Amelie T and Ityel, Hadas and Chen, Jing and Sadowski, Carolin E and Kohl, Stefan and Pabst, Werner L and Nakayama, Makiko and Somers, Michael J G and Rodig, Nancy M and Daouk, Ghaleb and Baum, Michelle and Stein, Deborah R and Ferguson, Michael A and Traum, Avram Z and Soliman, Neveen A and Kari, Jameela A and El Desoky, Sherif and Fathy, Hanan and Zenker, Martin and Bakkaloglu, Sevcan A and M{\"u}ller, Dominik and Noyan, Aytul and Ozaltin, Fatih and Cadnapaphornchai, Melissa A and Hashmi, Seema and Hopcian, Jeffrey and Kopp, Jeffrey B and Benador, Nadine and Bockenhauer, Detlef and Bogdanovic, Radovan and Staji{\'c}, Natasa and Chernin, Gil and Ettenger, Robert and Fehrenbach, Henry and Kemper, Markus and Munarriz, Reyner Loza and Podracka, Ludmila and B{\"u}scher, Rainer and Serdaroglu, Erkin and Tasic, Velibor and Mane, Shrikant and Lifton, Richard P and Braun, Daniela A and Hildebrandt, Friedhelm} } @article {497, title = {Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43\% of 35 Families With Midaortic Syndrome.}, journal = {Hypertension}, volume = {71}, year = {2018}, month = {2018 04}, pages = {691-699}, abstract = {

Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9\%), we detected likely causal dominant mutations. In 15 of 35 (42.9\%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (, , , , and ). Ten of the 15 mutations have not previously been reported. This is the first report of , , or mutations in individuals with MAS. Mutations were detected in (6/15 families), (4/15 families), (3/15 families), and one family each for and Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS.

}, keywords = {Adolescent, Aorta, Abdominal, Aortic Valve Stenosis, Child, Child, Preschool, Cohort Studies, Female, Genetic Association Studies, Humans, Hypertension, Jagged-1 Protein, Male, Mutation, Neurofibromatoses, Neurofibromin 1, Pedigree, Syndrome, United States, Whole Exome Sequencing}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.10296}, author = {Warejko, Jillian K and Schueler, Markus and Vivante, Asaf and Tan, Weizhen and Daga, Ankana and Lawson, Jennifer A and Braun, Daniela A and Shril, Shirlee and Amann, Kassaundra and Somers, Michael J G and Rodig, Nancy M and Baum, Michelle A and Daouk, Ghaleb and Traum, Avram Z and Kim, Heung Bae and Vakili, Khashayar and Porras, Diego and Lock, James and Rivkin, Michael J and Chaudry, Gulraiz and Smoot, Leslie B and Singh, Michael N and Smith, Edward R and Mane, Shrikant M and Lifton, Richard P and Stein, Deborah R and Ferguson, Michael A and Hildebrandt, Friedhelm} } @article {385, title = {Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.}, journal = {J Dent Res}, volume = {97}, year = {2018}, month = {2018 Jan}, pages = {49-59}, abstract = {

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

}, keywords = {Anodontia, Female, Genetic Linkage, Genetic Variation, Humans, Intercellular Signaling Peptides and Proteins, Laminin, Low Density Lipoprotein Receptor-Related Protein-6, Male, Membrane Proteins, Mutation, Missense, Pedigree, Real-Time Polymerase Chain Reaction, Turkey, Whole Exome Sequencing, Wnt Proteins}, issn = {1544-0591}, doi = {10.1177/0022034517724149}, author = {Dinckan, N and Du, R and Petty, L E and Coban-Akdemir, Z and Jhangiani, S N and Paine, I and Baugh, E H and Erdem, A P and Kayserili, H and Doddapaneni, H and Hu, J and Muzny, D M and Boerwinkle, E and Gibbs, R A and Lupski, J R and Uyguner, Z O and Below, J E and Letra, A} } @article {446, title = {WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 01 04}, pages = {27-43}, abstract = {

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, \~{}70\% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

}, keywords = {Adolescent, Adult, Base Sequence, Child, Child, Preschool, Chromosome Segregation, Craniofacial Abnormalities, Diagnosis, Differential, Dwarfism, Female, Genes, Dominant, Genetic Association Studies, Genetic Heterogeneity, Humans, Limb Deformities, Congenital, Male, Middle Aged, Mutation, Missense, Phenotype, Urogenital Abnormalities, Wnt Signaling Pathway}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.10.002}, author = {White, Janson J and Mazzeu, Juliana F and Coban-Akdemir, Zeynep and Bayram, Yavuz and Bahrambeigi, Vahid and Hoischen, Alexander and van Bon, Bregje W M and Gezdirici, Alper and Gulec, Elif Yilmaz and Ramond, Francis and Touraine, Renaud and Thevenon, Julien and Shinawi, Marwan and Beaver, Erin and Heeley, Jennifer and Hoover-Fong, Julie and Durmaz, Ceren D and Karabulut, Halil Gurhan and Marzioglu-Ozdemir, Ebru and Cayir, Atilla and Duz, Mehmet B and Seven, Mehmet and Price, Susan and Ferreira, Barbara Merfort and Vianna-Morgante, Angela M and Ellard, Sian and Parrish, Andrew and Stals, Karen and Flores-Daboub, Josue and Jhangiani, Shalini N and Gibbs, Richard A and Brunner, Han G and Sutton, V Reid and Lupski, James R and Carvalho, Claudia M B} } @article {367, title = {22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Apr}, pages = {1066-1070}, abstract = {

Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., (2004); AJMGA 127: 149-151], of an individual with 22q duplication and sex-reversal syndrome. The subject{\textquoteright}s phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain of function rather than dominant negative activity underlies PCWH.

}, keywords = {46, XX Testicular Disorders of Sex Development, African Americans, Chromosome Duplication, Chromosomes, Human, Pair 22, Demyelinating Diseases, Hirschsprung Disease, Humans, Kidney Failure, Chronic, Male, Pelizaeus-Merzbacher Disease, SOXE Transcription Factors, Waardenburg Syndrome}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38109}, author = {Falah, Nadia and Posey, Jennifer E and Thorson, Willa and Benke, Paul and Tekin, Mustafa and Tarshish, Brocha and Lupski, James R and Harel, Tamar} } @article {437, title = {Asprosin is a centrally acting orexigenic hormone.}, journal = {Nat Med}, volume = {23}, year = {2017}, month = {2017 Dec}, pages = {1444-1453}, abstract = {

Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.

}, keywords = {Adolescent, Adult, Animals, Appetite Depressants, Appetite Regulation, Female, Humans, Hypothalamus, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Neurons, Peptide Fragments, Peptide Hormones, Rats, Signal Transduction, Young Adult}, issn = {1546-170X}, doi = {10.1038/nm.4432}, author = {Duerrschmid, Clemens and He, Yanlin and Wang, Chunmei and Li, Chia and Bournat, Juan C and Romere, Chase and Saha, Pradip K and Lee, Mark E and Phillips, Kevin J and Jain, Mahim and Jia, Peilin and Zhao, Zhongming and Farias, Monica and Wu, Qi and Milewicz, Dianna M and Sutton, V Reid and Moore, David D and Butte, Nancy F and Krashes, Michael J and Xu, Yong and Chopra, Atul R} } @article {341, title = {Biallelic mutations in IRF8 impair human NK cell maturation and function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 01 03}, pages = {306-320}, abstract = {

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8-/-, but not Irf8+/-, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense.

}, keywords = {Alleles, Animals, CD56 Antigen, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Interferon Regulatory Factors, Killer Cells, Natural, Male, Mice, Mice, Knockout, Mutation, Virus Diseases}, issn = {1558-8238}, doi = {10.1172/JCI86276}, author = {Mace, Emily M and Bigley, Venetia and Gunesch, Justin T and Chinn, Ivan K and Angelo, Laura S and Care, Matthew A and Maisuria, Sheetal and Keller, Michael D and Togi, Sumihito and Watkin, Levi B and LaRosa, David F and Jhangiani, Shalini N and Muzny, Donna M and Stray-Pedersen, Asbj{\o}rg and Coban Akdemir, Zeynep and Smith, Jansen B and Hern{\'a}ndez-Sanabria, Mayra and Le, Duy T and Hogg, Graham D and Cao, Tram N and Freud, Aharon G and Szymanski, Eva P and Savic, Sinisa and Collin, Matthew and Cant, Andrew J and Gibbs, Richard A and Holland, Steven M and Caligiuri, Michael A and Ozato, Keiko and Paust, Silke and Doody, Gina M and Lupski, James R and Orange, Jordan S} } @article {351, title = {Biallelic mutations in the 3{\textquoteright} exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Mar}, pages = {457-464}, abstract = {

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg-dependent 3{\textquoteright}-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3{\textquoteright} genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3{\textquoteright}-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3{\textquoteright}-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3{\textquoteright} ends.

}, keywords = {Alleles, Animals, Cerebellar Diseases, Exonucleases, Female, Humans, Male, Mice, Mutation, Neurodegenerative Diseases, Nuclear Proteins, RNA, Messenger, RNA, Small Nuclear, Spliceosomes, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3762}, author = {Lardelli, Rea M and Schaffer, Ashleigh E and Eggens, Veerle R C and Zaki, Maha S and Grainger, Stephanie and Sathe, Shashank and Van Nostrand, Eric L and Schlachetzki, Zinayida and Rosti, Basak and Akizu, Naiara and Scott, Eric and Silhavy, Jennifer L and Heckman, Laura Dean and Rosti, Rasim Ozgur and Dikoglu, Esra and Gregor, Anne and Guemez-Gamboa, Alicia and Musaev, Damir and Mande, Rohit and Widjaja, Ari and Shaw, Tim L and Markmiller, Sebastian and Marin-Valencia, Isaac and Davies, Justin H and de Meirleir, Linda and Kayserili, H{\"u}lya and Altunoglu, Umut and Freckmann, Mary Louise and Warwick, Linda and Chitayat, David and Blaser, Susan and {\c C}a{\u g}layan, Ahmet Okay and Bilguvar, Kaya and Per, H{\"u}seyin and Fagerberg, Christina and Christesen, Henrik T and Kibaek, Maria and Aldinger, Kimberly A and Manchester, David and Matsumoto, Naomichi and Muramatsu, Kazuhiro and Saitsu, Hirotomo and Shiina, Masaaki and Ogata, Kazuhiro and Foulds, Nicola and Dobyns, William B and Chi, Neil C and Traver, David and Spaccini, Luigina and Bova, Stefania Maria and Gabriel, Stacey B and G{\"u}nel, Murat and Valente, Enza Maria and Nassogne, Marie-Cecile and Bennett, Eric J and Yeo, Gene W and Baas, Frank and Lykke-Andersen, Jens and Gleeson, Joseph G} } @article {637, title = {Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Jul}, pages = {e1006905}, abstract = {

Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.

}, keywords = {Alleles, Animals, Animals, Genetically Modified, Calcium Channels, Cerebellar Ataxia, Child, Child, Preschool, Drosophila melanogaster, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Microscopy, Electron, Transmission, Mutation, Missense, Neurodegenerative Diseases, Neuroimaging, Phenotype, Point Mutation}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006905}, author = {Luo, Xi and Rosenfeld, Jill A and Yamamoto, Shinya and Harel, Tamar and Zuo, Zhongyuan and Hall, Melissa and Wierenga, Klaas J and Pastore, Matthew T and Bartholomew, Dennis and Delgado, Mauricio R and Rotenberg, Joshua and Lewis, Richard Alan and Emrick, Lisa and Bacino, Carlos A and Eldomery, Mohammad K and Coban Akdemir, Zeynep and Xia, Fan and Yang, Yaping and Lalani, Seema R and Lotze, Timothy and Lupski, James R and Lee, Brendan and Bellen, Hugo J and Wangler, Michael F} } @article {443, title = {Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains.}, journal = {Neuromuscul Disord}, volume = {27}, year = {2017}, month = {2017 Sep}, pages = {861-872}, abstract = {

Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype-phenotype correlation with mutations in the N-terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIM1 variants were identified by exome sequencing or STIM1 direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIM1. STIM1 mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra-neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIM1 disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra-neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain.

}, keywords = {Adult, Blood Platelet Disorders, Calcium, Cell Culture Techniques, DNA Mutational Analysis, Dyslexia, Erythrocytes, Abnormal, Family Health, Female, Fibroblasts, Genetic Association Studies, Humans, Ichthyosis, Magnetic Resonance Imaging, Male, Microscopy, Electron, Middle Aged, Migraine Disorders, Miosis, Models, Molecular, Muscle Fatigue, Muscle, Skeletal, Mutation, Myopathies, Structural, Congenital, NAD, Neoplasm Proteins, Spleen, Stromal Interaction Molecule 1}, issn = {1873-2364}, doi = {10.1016/j.nmd.2017.05.002}, author = {Harris, Elizabeth and Burki, Umar and Marini-Bettolo, Chiara and Neri, Marcella and Scotton, Chiara and Hudson, Judith and Bertoli, Marta and Evangelista, Teresinha and Vroling, Bas and Polvikoski, Tuomo and Roberts, Mark and Topf, Ana and Bushby, Kate and McArthur, Daniel and Lochm{\"u}ller, Hanns and Ferlini, Alessandra and Straub, Volker and Barresi, Rita} } @article {426, title = {Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Nov}, pages = {1593-1601}, abstract = {

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8\%, including a recessive founder mutation in GDF1 accounting for \~{}5\% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for \~{}11\% of Shone complex, and dominant FLT4 mutations accounting for 2.3\% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8\% of cases, including \~{}3\% of isolated CHD patients and \~{}28\% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70\% probability of being disease related. DNMs in \~{}440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

}, keywords = {Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3}, issn = {1546-1718}, doi = {10.1038/ng.3970}, author = {Jin, Sheng Chih and Homsy, Jason and Zaidi, Samir and Lu, Qiongshi and Morton, Sarah and DePalma, Steven R and Zeng, Xue and Qi, Hongjian and Chang, Weni and Sierant, Michael C and Hung, Wei-Chien and Haider, Shozeb and Zhang, Junhui and Knight, James and Bjornson, Robert D and Castaldi, Christopher and Tikhonoa, Irina R and Bilguvar, Kaya and Mane, Shrikant M and Sanders, Stephan J and Mital, Seema and Russell, Mark W and Gaynor, J William and Deanfield, John and Giardini, Alessandro and Porter, George A and Srivastava, Deepak and Lo, Cecelia W and Shen, Yufeng and Watkins, W Scott and Yandell, Mark and Yost, H Joseph and Tristani-Firouzi, Martin and Newburger, Jane W and Roberts, Amy E and Kim, Richard and Zhao, Hongyu and Kaltman, Jonathan R and Goldmuntz, Elizabeth and Chung, Wendy K and Seidman, Jonathan G and Gelb, Bruce D and Seidman, Christine E and Lifton, Richard P and Brueckner, Martina} } @article {636, title = {Copy Number Changes Identified Using Whole Exome Sequencing in Nonsyndromic Cleft Lip and Palate in a Honduran Population.}, journal = {Birth Defects Res}, volume = {109}, year = {2017}, month = {2017 Oct 02}, pages = {1257-1267}, abstract = {

BACKGROUND: The majority of cleft lip with or without cleft palate cases appear as an isolated, nonsyndromic entity (NSCLP). With the advent of next generation sequencing, whole exome sequencing (WES) has been used to identify single nucleotide variants and insertion/deletions which cause or increase the risk of NSCLP. However, to our knowledge, there are no published studies using WES in NSCLP to investigate copy number changes (CNCs), which are a major component of human genetic variation. Our study aimed to identify CNCs associated with NSCLP in a Honduran population using WES.

METHODS: WES was performed on two to four members of 27 multiplex Honduran families. CNCs were identified using two algorithms, CoNIFER and XHMM. Priority was given to CNCs that were identified in more than one patient and had variant frequencies of less than 5\% in reference data sets.

RESULTS: WES completion was defined as >90\% of the WES target at >8 {\texttimes} coverage and >80\% of the WES target at >20 {\texttimes} coverage. Twenty-four CNCs that met our inclusion criteria were identified by both CoNIFER and XHMM. These CNCs were confirmed using quantitative PCR. Pedigree analysis produced three CNCs corresponding to ADH7, AHR, and CRYZ segregating with NSCLP. Two of the three CNCs implicate genes, AHR and ADH7, whose known biological functions could plausibly play a role in NSCLP.

CONCLUSION: WES can be used to detect candidate CNCs that may be involved in the pathophysiology of NSCLP. Birth Defects Research 109:1257-1267, 2017. {\textcopyright} 2017 Wiley Periodicals, Inc.

}, keywords = {Adolescent, Adult, Alcohol Dehydrogenase, Alleles, Basic Helix-Loop-Helix Transcription Factors, Child, Child, Preschool, Cleft Lip, Cleft Palate, DNA Copy Number Variations, Family, Female, Gene Frequency, Genetic Variation, High-Throughput Nucleotide Sequencing, Honduras, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Receptors, Aryl Hydrocarbon, Whole Exome Sequencing}, issn = {2472-1727}, doi = {10.1002/bdr2.1063}, author = {Cai, Yi and Patterson, Karynne E and Reinier, Frederic and Keesecker, Sarah E and Blue, Elizabeth and Bamshad, Michael and Haddad, Joseph} } @article {335, title = {De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {352-363}, abstract = {

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

}, keywords = {Adolescent, Animals, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Down-Regulation, Female, Gene Deletion, Humans, Infant, Intellectual Disability, Male, Microcephaly, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.01.003}, author = {K{\"u}ry, S{\'e}bastien and Besnard, Thomas and Ebstein, Fr{\'e}d{\'e}ric and Khan, Tahir N and Gambin, Tomasz and Douglas, Jessica and Bacino, Carlos A and Craigen, William J and Sanders, Stephan J and Lehmann, Andrea and Latypova, X{\'e}nia and Khan, Kamal and Pacault, Mathilde and Sacharow, Stephanie and Glaser, Kimberly and Bieth, Eric and Perrin-Sabourin, Laurence and Jacquemont, Marie-Line and Cho, Megan T and Roeder, Elizabeth and Denomm{\'e}-Pichon, Anne-Sophie and Monaghan, Kristin G and Yuan, Bo and Xia, Fan and Simon, Sylvain and Bonneau, Dominique and Parent, Philippe and Gilbert-Dussardier, Brigitte and Odent, Sylvie and Toutain, Annick and Pasquier, Laurent and Barbouth, Deborah and Shaw, Chad A and Patel, Ankita and Smith, Janice L and Bi, Weimin and Schmitt, S{\'e}bastien and Deb, Wallid and Nizon, Mathilde and Mercier, Sandra and Vincent, Marie and Rooryck, Caroline and Malan, Val{\'e}rie and Brice{\~n}o, Ignacio and G{\'o}mez, Alberto and Nugent, Kimberly M and Gibson, James B and Cogn{\'e}, Benjamin and Lupski, James R and Stessman, Holly A F and Eichler, Evan E and Retterer, Kyle and Yang, Yaping and Redon, Richard and Katsanis, Nicholas and Rosenfeld, Jill A and Kloetzel, Peter-Michael and Golzio, Christelle and B{\'e}zieau, St{\'e}phane and Stankiewicz, Pawe{\l} and Isidor, Bertrand} } @article {424, title = {De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {716-724}, abstract = {

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in~vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

}, keywords = {Adenosine Triphosphatases, Adolescent, Amino Acids, Cell Line, Cell Line, Tumor, Central Nervous System, Child, Child, Preschool, Developmental Disabilities, Female, HEK293 Cells, Humans, Intellectual Disability, Male, Mutation, Missense, RNA, RNA Helicases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.014}, author = {Lessel, Davor and Schob, Claudia and K{\"u}ry, S{\'e}bastien and Reijnders, Margot R F and Harel, Tamar and Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Denecke, Jonas and Edvardson, Shimon and Colin, Estelle and Stegmann, Alexander P A and Gerkes, Erica H and Tessarech, Marine and Bonneau, Dominique and Barth, Magalie and Besnard, Thomas and Cogn{\'e}, Benjamin and Revah-Politi, Anya and Strom, Tim M and Rosenfeld, Jill A and Yang, Yaping and Posey, Jennifer E and Immken, LaDonna and Oundjian, Nelly and Helbig, Katherine L and Meeks, Naomi and Zegar, Kelsey and Morton, Jenny and Schieving, Jolanda H and Claasen, Ana and Huentelman, Matthew and Narayanan, Vinodh and Ramsey, Keri and Brunner, Han G and Elpeleg, Orly and Mercier, Sandra and B{\'e}zieau, St{\'e}phane and Kubisch, Christian and Kleefstra, Tjitske and Kindler, Stefan and Lupski, James R and Kreienkamp, Hans-J{\"u}rgen} } @article {386, title = {De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 08 29}, pages = {E7341-E7347}, abstract = {

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95\% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, = 2.4 {\texttimes} 10). had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10\% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near increased the penetrance of mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

}, keywords = {Adult, Animals, Bone Morphogenetic Proteins, Child, Child, Preschool, Cranial Sutures, Craniosynostoses, Exome, Female, Humans, Male, MAP Kinase Signaling System, Mutation, Osteogenesis, Penetrance, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction, Smad6 Protein, Whole Exome Sequencing}, issn = {1091-6490}, doi = {10.1073/pnas.1709255114}, author = {Timberlake, Andrew T and Furey, Charuta G and Choi, Jungmin and Nelson-Williams, Carol and Loring, Erin and Galm, Amy and Kahle, Kristopher T and Steinbacher, Derek M and Larysz, Dawid and Persing, John A and Lifton, Richard P} } @article {365, title = {Diagnosis of Chronic Intestinal Pseudo-obstruction and Megacystis by Sequencing the ACTG2 Gene.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {65}, year = {2017}, month = {2017 10}, pages = {384-387}, abstract = {

OBJECTIVES: The diagnosis of chronic intestinal pseudo-obstruction has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the actin γ-2 (ACTG2) gene for diagnosis. In addition, the goal was to determine how often a mutation would be found in our randomly collected cohort of probands and those probands published previously.

METHODS: Whole exome sequencing was performed in 4 probands with chronic intestinal pseudo-obstruction. Subsequently, only the ACTG2 gene was sequenced in another 24 probands (total 28). We analyzed published data of 83 probands and our 28 (total 111) and determined how many had pathogenic variants and the precise genotype.

RESULTS: Whole exome and Sanger sequencing revealed a pathogenic variant in the ACTG2 gene in 4 out of 28 of our probands and in 45 out of 83 published probands (49/111 [44.1\%]). Moreover, a mutational hotspot in the ACTG2 gene was recognized. Genetic heterogeneity is evident.

CONCLUSIONS: Pooled gene sequencing results from 1 individual in each of 111 families enabled a precise diagnosis of an ACTG2 mutation in 49 (44\%). The benefit to patients and families of early confirmation of a motility disorder not only helps avoid unnecessary intervention, but also enables institution of appropriate treatments and avoidance of secondary disorders such as malnutrition and poor growth. Knowledge of a pathogenic variant in a parent, with a 50\% risk of recurrence, provides an opportunity for genetic counseling.

}, keywords = {Actins, Adult, Child, Child, Preschool, Chronic Disease, Duodenum, Female, Fetal Diseases, Genetic Markers, Genetic Testing, Humans, Infant, Infant, Newborn, Intestinal Pseudo-Obstruction, Male, Mutation, Sequence Analysis, DNA, Urinary Bladder, Whole Exome Sequencing}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000001608}, author = {Milunsky, Aubrey and Baldwin, Clinton and Zhang, Xiaoying and Primack, Daniel and Curnow, Adrian and Milunsky, Jeff} } @article {15, title = {Dominant Transmission Observed in Adolescents and Families With Orthostatic Intolerance.}, journal = {Pediatr Neurol}, volume = {66}, year = {2017}, month = {2017 Jan}, pages = {53-58.e5}, abstract = {

BACKGROUND: Orthostatic intolerance is typically thought to be sporadic and attributed to cerebral autonomic dysfunction. We sought to identify families with inherited autonomic dysfunction manifest as symptomatic orthostatic intolerance to characterize mode of inheritance and clinical features.

METHODS: Sixteen families with two or more first- or second-degree relatives with autonomic dysfunction and orthostatic intolerance were enrolled. A clinical diagnosis of autonomic dysfunction defined by symptomatic orthostatic intolerance diagnosed by head-up tilt table testing was confirmed for each proband. Clinical features and evaluation were obtained from each proband using a standardized intake questionnaire, and family history information was obtained from probands and available relatives.

RESULTS: Comprehensive pedigree analysis of 16 families (39 individuals with orthostatic intolerance~and 40 individuals suspected of having orthostatic intolerance)~demonstrated dominant transmission of autonomic dysfunction with incomplete penetrance. Affected individuals were predominantly female (71.8\%, 28/39; F:M, 2.5:1). Male-to-male transmission, although less common, was observed and demonstrated to transmit through unaffected males with an affected parent. Similar to sporadic orthostatic intolerance, probands report a range of symptoms across multiple organ systems, with headaches and neuromuscular features being most common.

CONCLUSIONS: Familial occurrence and vertical transmission of autonomic dysfunction in 16 families suggest~a novel genetic syndrome with dominant transmission, incomplete penetrance, and skewing of the sex ratio. Elucidation of potential genetic contributions to orthostatic intolerance may inform therapeutic management and identification of individuals at risk. Adolescent evaluation should include identification and treatment of potential at-risk relatives.

}, keywords = {Adolescent, Cohort Studies, Family, Female, Genetic Testing, Humans, Male, Orthostatic Intolerance, Pedigree, Posture, Surveys and Questionnaires, Tilt-Table Test}, issn = {1873-5150}, doi = {10.1016/j.pediatrneurol.2016.09.013}, author = {Posey, Jennifer E and Martinez, Rebecca and Lankford, Jeremy E and Lupski, James R and Numan, Mohammed T and Butler, Ian J} } @article {361, title = {Dual molecular diagnosis contributes to atypical Prader-Willi phenotype in monozygotic twins.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Sep}, pages = {2451-2455}, abstract = {

We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.

}, keywords = {Adolescent, Base Sequence, Child, Chromosome Deletion, Chromosomes, Human, Pair 15, Comparative Genomic Hybridization, Exome, Facies, Female, Humans, Hyperventilation, Intellectual Disability, Obesity, Pathology, Molecular, Phenotype, Prader-Willi Syndrome, Transcription Factor 4, Twins, Monozygotic}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38315}, author = {Jehee, Fernanda S and de Oliveira, Valdirene T and Gurgel-Giannetti, Juliana and Pietra, Rafaella X and Rubatino, Fernando V M and Carobin, Nat{\'a}lia V and Vianna, Gabrielle S and de Freitas, Mariana L and Fernandes, Karla S and Ribeiro, Beatriz S V and Br{\"u}ggenwirth, Hennie T and Ali-Amin, Roza and White, Janson J and Akdemir, Zeynep C and Jhangiani, Shalini N and Gibbs, Richard A and Lupski, James R and Varela, Monica C and Koiffmann, C{\'e}lia and Rosenberg, Carla and Carvalho, Claudia M B} } @article {57, title = {Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2.}, journal = {Genet Med}, volume = {19}, year = {2017}, month = {2017 01}, pages = {13-19}, abstract = {

PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.

METHODS: Twenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.

RESULTS: Three patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5\%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4\%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.

CONCLUSION: The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromatin, DNA Copy Number Variations, Female, Forkhead Transcription Factors, Humans, Infant, Male, Methyl-CpG-Binding Protein 2, Mutation, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases, Rett Syndrome, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/gim.2016.42}, author = {Sajan, Samin A and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and Glaze, Daniel G and Kaufmann, Walter E and Skinner, Steven A and Annese, Fran and Friez, Michael J and Lane, Jane and Percy, Alan K and Neul, Jeffrey L} } @article {635, title = {Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43\% of cases.}, journal = {Pediatr Nephrol}, volume = {32}, year = {2017}, month = {2017 Dec}, pages = {2273-2282}, abstract = {

BACKGROUND: Rhabdomyolysis is a clinical emergency that may cause acute kidney injury (AKI). It can be acquired or due to monogenic mutations. Around 60 different rare monogenic forms of rhabdomyolysis have been reported to date. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to nonspecific presentation, the high number of causative genes, and current lack of data on the prevalence of monogenic forms.

METHODS: We employed whole exome sequencing (WES) to reveal the percentage of rhabdomyolysis cases explained by single-gene (monogenic) mutations in one of 58 candidate genes. We investigated a cohort of 21 unrelated families with rhabdomyolysis, in whom no underlying etiology had been previously established.

RESULTS: Using WES, we identified causative mutations in candidate genes in nine of the 21 families (43\%). We detected disease-causing mutations in eight of 58 candidate genes, grouped into the following categories: (1) disorders of fatty acid metabolism (CPT2), (2) disorders of glycogen metabolism (PFKM and PGAM2), (3) disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A), and (4) disorders of purine metabolism (AHCY).

CONCLUSIONS: Our findings demonstrate a very high detection rate for monogenic etiologies using WES and reveal broad genetic heterogeneity for rhabdomyolysis. These results highlight the importance of molecular genetic diagnostics for establishing an etiologic diagnosis. Because these patients are at risk for recurrent episodes of rhabdomyolysis and subsequent risk for AKI, WES allows adequate prophylaxis and treatment for these patients and their family members and enables a personalized medicine approach.

}, keywords = {Adolescent, Adult, Arabs, Child, Exome, Genetic Predisposition to Disease, Humans, Jews, Mutation, Rhabdomyolysis, Whole Exome Sequencing}, issn = {1432-198X}, doi = {10.1007/s00467-017-3755-8}, author = {Vivante, Asaf and Ityel, Hadas and Pode-Shakked, Ben and Chen, Jing and Shril, Shirlee and van der Ven, Amelie T and Mann, Nina and Schmidt, Johanna Magdalena and Segel, Reeval and Aran, Adi and Zeharia, Avraham and Staretz-Chacham, Orna and Bar-Yosef, Omer and Raas-Rothschild, Annick and Landau, Yuval E and Lifton, Richard P and Anikster, Yair and Hildebrandt, Friedhelm} } @article {368, title = {An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a mutation.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {3}, year = {2017}, month = {2017 03}, pages = {a000984}, abstract = {

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in and , we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.

}, keywords = {Child, Child, Preschool, Cohort Studies, Exome, Eye Diseases, Hereditary, Facial Paralysis, Female, Humans, Infant, Male, Malformations of Cortical Development, Mobius Syndrome, Muscular Diseases, Mutation, Ocular Motility Disorders, Ophthalmoplegia, Orbital Diseases, Pedigree, Tubulin, Whole Exome Sequencing}, issn = {2373-2873}, doi = {10.1101/mcs.a000984}, author = {Patel, Ronak M and Liu, David and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Lu, James T and Sutton, V Reid and Fernbach, Susan D and Azamian, Mahshid and White, Lisa and Edmond, Jane C and Paysse, Evelyn A and Belmont, John W and Muzny, Donna and Lupski, James R and Gibbs, Richard A and Lewis, Richard Alan and Lee, Brendan H and Lalani, Seema R and Campeau, Philippe M} } @article {423, title = {Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {789-802}, abstract = {

Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0~{\texttimes} 10 for novel LOF, increased to p = 4.1~{\texttimes} 10 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3~{\texttimes} 10). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.

}, keywords = {Alleles, Animals, Case-Control Studies, Clustered Regularly Interspaced Short Palindromic Repeats, Congenital Abnormalities, Exome, Female, Genetic Heterogeneity, Genome-Wide Association Study, Genotype, Heredity, Homozygote, Humans, Kidney, Kidney Diseases, Male, Membrane Proteins, Mice, Mutation, Neoplasm Proteins, Phenotype, RNA, Long Noncoding, Urinary Tract, Urogenital Abnormalities, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.018}, author = {Sanna-Cherchi, Simone and Khan, Kamal and Westland, Rik and Krithivasan, Priya and Fievet, Lorraine and Rasouly, Hila Milo and Ionita-Laza, Iuliana and Capone, Valentina P and Fasel, David A and Kiryluk, Krzysztof and Kamalakaran, Sitharthan and Bodria, Monica and Otto, Edgar A and Sampson, Matthew G and Gillies, Christopher E and Vega-Warner, Virginia and Vukojevic, Katarina and Pediaditakis, Igor and Makar, Gabriel S and Mitrotti, Adele and Verbitsky, Miguel and Martino, Jeremiah and Liu, Qingxue and Na, Young-Ji and Goj, Vinicio and Ardissino, Gianluigi and Gigante, Maddalena and Gesualdo, Loreto and Janezcko, Magdalena and Zaniew, Marcin and Mendelsohn, Cathy Lee and Shril, Shirlee and Hildebrandt, Friedhelm and van Wijk, Joanna A E and Arapovic, Adela and Saraga, Marijan and Allegri, Landino and Izzi, Claudia and Scolari, Francesco and Tasic, Velibor and Ghiggeri, Gian Marco and Latos-Bielenska, Anna and Materna-Kiryluk, Anna and Mane, Shrikant and Goldstein, David B and Lifton, Richard P and Katsanis, Nicholas and Davis, Erica E and Gharavi, Ali G} } @article {370, title = {First Case of Deficiency in Ecuador, Diagnosed after Whole Exome Sequencing in a Patient with Severe Cutaneous Histoplasmosis.}, journal = {Front Pediatr}, volume = {5}, year = {2017}, month = {2017}, pages = {17}, abstract = {

Severe infections with are commonly observed in patient with secondary immunodeficiency disorders. We report a two and a half years old boy previously healthy with disseminated cutaneous histoplasmosis. Using whole exome sequencing, we found an mutation at the gene, suggesting a diagnosis of hyper-IgM (HIGM) syndrome, even in the absence of the usual features for the disease. Interestingly, the patient lives in a region endemic for histoplasmosis. The unusual infections in our case suggest that in children with severe histoplasmosis and resident in endemic areas, HIGM syndrome should be considered as a diagnosis.

}, issn = {2296-2360}, doi = {10.3389/fped.2017.00017}, author = {Pedroza, Luis Alberto and Guerrero, Nina and Stray-Pedersen, Asbj{\o}rg and Tafur, Cristina and Macias, Roque and Mu{\~n}oz, Greta and Akdemir, Zeynep Coban and Jhangiani, Shalini N and Watkin, Levi B and Chinn, Ivan K and Lupski, James R and Orange, Jordan S} } @article {350, title = {Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 02 23}, pages = {742-754}, abstract = {

BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.

RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1\% of the patients with congenital kidney anomalies and in 0.01\% of population controls (odds ratio, 81.5; P=4.5{\texttimes}10). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.

CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Animals, Child, Chromosome Deletion, Chromosomes, Human, Pair 22, DiGeorge Syndrome, Exome, Female, Haploinsufficiency, Heterozygote, Humans, Infant, Infant, Newborn, Kidney, Male, Mice, Models, Animal, Nuclear Proteins, Sequence Analysis, DNA, Urinary Tract, Young Adult, Zebrafish}, issn = {1533-4406}, doi = {10.1056/NEJMoa1609009}, author = {Lopez-Rivera, Esther and Liu, Yangfan P and Verbitsky, Miguel and Anderson, Blair R and Capone, Valentina P and Otto, Edgar A and Yan, Zhonghai and Mitrotti, Adele and Martino, Jeremiah and Steers, Nicholas J and Fasel, David A and Vukojevic, Katarina and Deng, Rong and Racedo, Silvia E and Liu, Qingxue and Werth, Max and Westland, Rik and Vivante, Asaf and Makar, Gabriel S and Bodria, Monica and Sampson, Matthew G and Gillies, Christopher E and Vega-Warner, Virginia and Maiorana, Mariarosa and Petrey, Donald S and Honig, Barry and Lozanovski, Vladimir J and Salomon, R{\'e}mi and Heidet, Laurence and Carpentier, Wassila and Gaillard, Dominique and Carrea, Alba and Gesualdo, Loreto and Cusi, Daniele and Izzi, Claudia and Scolari, Francesco and van Wijk, Joanna A E and Arapovic, Adela and Saraga-Babic, Mirna and Saraga, Marijan and Kunac, Nenad and Samii, Ali and McDonald-McGinn, Donna M and Crowley, Terrence B and Zackai, Elaine H and Drozdz, Dorota and Miklaszewska, Monika and Tkaczyk, Marcin and Sikora, Przemyslaw and Szczepanska, Maria and Mizerska-Wasiak, Malgorzata and Krzemien, Grazyna and Szmigielska, Agnieszka and Zaniew, Marcin and Darlow, John M and Puri, Prem and Barton, David and Casolari, Emilio and Furth, Susan L and Warady, Bradley A and Gucev, Zoran and Hakonarson, Hakon and Flogelova, Hana and Tasic, Velibor and Latos-Bielenska, Anna and Materna-Kiryluk, Anna and Allegri, Landino and Wong, Craig S and Drummond, Iain A and D{\textquoteright}Agati, Vivette and Imamoto, Akira and Barasch, Jonathan M and Hildebrandt, Friedhelm and Kiryluk, Krzysztof and Lifton, Richard P and Morrow, Bernice E and Jeanpierre, Cecile and Papaioannou, Virginia E and Ghiggeri, Gian Marco and Gharavi, Ali G and Katsanis, Nicholas and Sanna-Cherchi, Simone} } @article {398, title = {Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Jun}, pages = {e001449}, abstract = {

BACKGROUND: Maternal and inherited (ie, case) genetic factors likely contribute to the pathogenesis of congenital heart defects, but it is unclear whether individual common variants confer a large risk.

METHODS AND RESULTS: To evaluate the relationship between individual common maternal/inherited genotypes and risk for heart defects, we conducted genome-wide association studies in 5 cohorts. Three cohorts were recruited at the Children{\textquoteright}s Hospital of Philadelphia: 670 conotruncal heart defect (CTD) case-parent trios, 317 left ventricular obstructive tract defect (LVOTD) case-parent trios, and 406 CTD cases (n=406) and 2976 pediatric controls. Two cohorts were recruited through the Pediatric Cardiac Genomics Consortium: 355 CTD trios and 192 LVOTD trios. We also conducted meta-analyses using the genome-wide association study results from the CTD cohorts, the LVOTD cohorts, and from the combined CTD and LVOTD cohorts. In the individual genome-wide association studies, several genome-wide significant associations (<=5{\texttimes}10) were observed. In our meta-analyses, 1 genome-wide significant association was detected: the case genotype for rs72820264, an intragenetic single-nucleotide polymorphism associated with LVOTDs (=2.1{\texttimes}10).

CONCLUSIONS: We identified 1 novel candidate region associated with LVOTDs and report on several additional regions with suggestive evidence for association with CTD and LVOTD. These studies were constrained by the relatively small samples sizes and thus have limited power to detect small to moderate associations. Approaches that minimize the multiple testing burden (eg, gene or pathway based) may, therefore, be required to uncover common variants contributing to the risk of these relatively rare conditions.

}, keywords = {Cohort Studies, Databases, Factual, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Heart Defects, Congenital, Humans, Introns, Male, Membrane Proteins, Polymorphism, Single Nucleotide}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001449}, author = {Agopian, A J and Goldmuntz, Elizabeth and Hakonarson, Hakon and Sewda, Anshuman and Taylor, Deanne and Mitchell, Laura E} } @article {358, title = {Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Apr}, pages = {613-617}, abstract = {

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

}, keywords = {Abnormalities, Multiple, Animals, Bone Diseases, Developmental, Cell Line, Chromosome Disorders, Craniofacial Abnormalities, Feeding and Eating Disorders, Female, Fusion Proteins, bcr-abl, Germ-Line Mutation, Heart Defects, Congenital, HEK293 Cells, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Limb Deformities, Congenital, Male, Mice, Mice, Knockout, Philadelphia Chromosome, Phosphorylation, Signal Transduction}, issn = {1546-1718}, doi = {10.1038/ng.3815}, author = {Wang, Xia and Charng, Wu-Lin and Chen, Chun-An and Rosenfeld, Jill A and Al Shamsi, Aisha and Al-Gazali, Lihadh and McGuire, Marianne and Mew, Nicholas Ah and Arnold, Georgianne L and Qu, Chunjing and Ding, Yan and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Plon, Sharon E and Lupski, James R and Schaaf, Christian P and Yang, Yaping} } @article {369, title = {Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.}, journal = {Hum Genet}, volume = {136}, year = {2017}, month = {2017 04}, pages = {377-386}, abstract = {

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.

}, keywords = {Adolescent, Autism Spectrum Disorder, Carrier Proteins, Child, Child, Preschool, Cohort Studies, DNA Copy Number Variations, Facies, Female, Haploinsufficiency, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Ubiquitin-Protein Ligases}, issn = {1432-1203}, doi = {10.1007/s00439-017-1763-1}, author = {Zhang, Jing and Gambin, Tomasz and Yuan, Bo and Szafranski, Przemyslaw and Rosenfeld, Jill A and Balwi, Mohammed Al and Alswaid, Abdulrahman and Al-Gazali, Lihadh and Shamsi, Aisha M Al and Komara, Makanko and Ali, Bassam R and Roeder, Elizabeth and McAuley, Laura and Roy, Daniel S and Manchester, David K and Magoulas, Pilar and King, Lauren E and Hannig, Vickie and Bonneau, Dominique and Denomm{\'e}-Pichon, Anne-Sophie and Charif, Majida and Besnard, Thomas and B{\'e}zieau, St{\'e}phane and Cogn{\'e}, Benjamin and Andrieux, Joris and Zhu, Wenmiao and He, Weimin and Vetrini, Francesco and Ward, Patricia A and Cheung, Sau Wai and Bi, Weimin and Eng, Christine M and Lupski, James R and Yang, Yaping and Patel, Ankita and Lalani, Seema R and Xia, Fan and Stankiewicz, Pawe{\l}} } @article {388, title = {Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Aug 03}, pages = {267-273}, abstract = {

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in~all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5{\textquoteright}- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

}, keywords = {Adolescent, Adult, Atrophy, Brain, Brain Diseases, Cell Nucleolus, Child, Chromatin, DNA-Binding Proteins, Female, Humans, Male, Neurodegenerative Diseases, Pol1 Transcription Initiation Complex Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Ribosomal, 18S, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.07.002}, author = {Edvardson, Simon and Nicolae, Claudia M and Agrawal, Pankaj B and Mignot, Cyril and Payne, Katelyn and Prasad, Asuri Narayan and Prasad, Chitra and Sadler, Laurie and Nava, Caroline and Mullen, Thomas E and Begtrup, Amber and Baskin, Berivan and Powis, Z{\"o}e and Shaag, Avraham and Keren, Boris and Moldovan, George-Lucian and Elpeleg, Orly} } @article {453, title = {High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {664-685}, abstract = {

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32\%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

}, keywords = {Brain Diseases, Child, Child, Preschool, Epilepsy, Female, Genome, Human, Genome-Wide Association Study, Humans, Intellectual Disability, Male, Mutation, Recurrence, Seizures}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.008}, author = {Hamdan, Fadi F and Myers, Candace T and Cossette, Patrick and Lemay, Philippe and Spiegelman, Dan and Laporte, Alexandre Dionne and Nassif, Christina and Diallo, Ousmane and Monlong, Jean and Cadieux-Dion, Maxime and Dobrzeniecka, Sylvia and Meloche, Caroline and Retterer, Kyle and Cho, Megan T and Rosenfeld, Jill A and Bi, Weimin and Massicotte, Christine and Miguet, Marguerite and Brunga, Ledia and Regan, Brigid M and Mo, Kelly and Tam, Cory and Schneider, Amy and Hollingsworth, Georgie and FitzPatrick, David R and Donaldson, Alan and Canham, Natalie and Blair, Edward and Kerr, Bronwyn and Fry, Andrew E and Thomas, Rhys H and Shelagh, Joss and Hurst, Jane A and Brittain, Helen and Blyth, Moira and Lebel, Robert Roger and Gerkes, Erica H and Davis-Keppen, Laura and Stein, Quinn and Chung, Wendy K and Dorison, Sara J and Benke, Paul J and Fassi, Emily and Corsten-Janssen, Nicole and Kamsteeg, Erik-Jan and Mau-Them, Frederic T and Bruel, Ange-Line and Verloes, Alain and {\~O}unap, Katrin and Wojcik, Monica H and Albert, Dara V F and Venkateswaran, Sunita and Ware, Tyson and Jones, Dean and Liu, Yu-Chi and Mohammad, Shekeeb S and Bizargity, Peyman and Bacino, Carlos A and Leuzzi, Vincenzo and Martinelli, Simone and Dallapiccola, Bruno and Tartaglia, Marco and Blumkin, Lubov and Wierenga, Klaas J and Purcarin, Gabriela and O{\textquoteright}Byrne, James J and Stockler, Sylvia and Lehman, Anna and Keren, Boris and Nougues, Marie-Christine and Mignot, Cyril and Auvin, St{\'e}phane and Nava, Caroline and Hiatt, Susan M and Bebin, Martina and Shao, Yunru and Scaglia, Fernando and Lalani, Seema R and Frye, Richard E and Jarjour, Imad T and Jacques, St{\'e}phanie and Boucher, Renee-Myriam and Riou, Emilie and Srour, Myriam and Carmant, Lionel and Lortie, Anne and Major, Philippe and Diadori, Paola and Dubeau, Fran{\c c}ois and D{\textquoteright}Anjou, Guy and Bourque, Guillaume and Berkovic, Samuel F and Sadleir, Lynette G and Campeau, Philippe M and Kibar, Zoha and Lafreni{\`e}re, Ronald G and Girard, Simon L and Mercimek-Mahmutoglu, Saadet and Boelman, Cyrus and Rouleau, Guy A and Scheffer, Ingrid E and Mefford, Heather C and Andrade, Danielle M and Rossignol, Elsa and Minassian, Berge A and Michaud, Jacques L} } @article {421, title = {Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness.}, journal = {Orphanet J Rare Dis}, volume = {12}, year = {2017}, month = {2017 11 17}, pages = {173}, abstract = {

BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250~ng DNA was completed using an Illumina exome capture and a 38~Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants.

RESULTS: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13~T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease.

CONCLUSIONS: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, alpha-Glucosidases, Child, Child, Preschool, Cohort Studies, Female, Genetic Variation, Glycogen Storage Disease Type II, Humans, Male, Middle Aged, Muscle Weakness, Muscular Dystrophies, Limb-Girdle, Whole Exome Sequencing, Young Adult}, issn = {1750-1172}, doi = {10.1186/s13023-017-0722-1}, author = {Johnson, Katherine and Topf, Ana and Bertoli, Marta and Phillips, Lauren and Claeys, Kristl G and Stojanovic, Vidosava Rakocevic and Peri{\'c}, Stojan and Hahn, Andreas and Maddison, Paul and Akay, Ela and Bastian, Alexandra E and {\L}usakowska, Anna and Kostera-Pruszczyk, Anna and Lek, Monkol and Xu, Liwen and MacArthur, Daniel G and Straub, Volker} } @article {376, title = {Identification of novel candidate disease genes from de novo exonic copy number variants.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 09 21}, pages = {83}, abstract = {

BACKGROUND: Exon-targeted microarrays can detect small (<1000~bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.

METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.

RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11\%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224~bp to 1.6~Mb in size) were compared to those in individuals with larger-sized deletions (up to 5~Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.

CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

}, keywords = {Cohort Studies, DNA Copy Number Variations, Exons, Genetic Diseases, Inborn, Genome, Human, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Neurodevelopmental Disorders, Protein-Serine-Threonine Kinases, Retrospective Studies, Transcription Factors, Whole Genome Sequencing}, issn = {1756-994X}, doi = {10.1186/s13073-017-0472-7}, author = {Gambin, Tomasz and Yuan, Bo and Bi, Weimin and Liu, Pengfei and Rosenfeld, Jill A and Coban-Akdemir, Zeynep and Pursley, Amber N and Nagamani, Sandesh C S and Marom, Ronit and Golla, Sailaja and Dengle, Lauren and Petrie, Heather G and Matalon, Reuben and Emrick, Lisa and Proud, Monica B and Treadwell-Deering, Diane and Chao, Hsiao-Tuan and Koillinen, Hannele and Brown, Chester and Urraca, Nora and Mostafavi, Roya and Bernes, Saunder and Roeder, Elizabeth R and Nugent, Kimberly M and Bader, Patricia I and Bellus, Gary and Cummings, Michael and Northrup, Hope and Ashfaq, Myla and Westman, Rachel and Wildin, Robert and Beck, Anita E and Immken, LaDonna and Elton, Lindsay and Varghese, Shaun and Buchanan, Edward and Faivre, Laurence and Lefebvre, Mathilde and Schaaf, Christian P and Walkiewicz, Magdalena and Yang, Yaping and Kang, Sung-Hae L and Lalani, Seema R and Bacino, Carlos A and Beaudet, Arthur L and Breman, Amy M and Smith, Janice L and Cheung, Sau Wai and Lupski, James R and Patel, Ankita and Shaw, Chad A and Stankiewicz, Pawe{\l}} } @article {363, title = {International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 May 04}, pages = {695-705}, abstract = {

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50\%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

}, keywords = {Databases, Factual, Exome, Genome, Human, Humans, International Cooperation, Rare Diseases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.04.003}, author = {Boycott, Kym M and Rath, Ana and Chong, Jessica X and Hartley, Taila and Alkuraya, Fowzan S and Baynam, Gareth and Brookes, Anthony J and Brudno, Michael and Carracedo, Angel and den Dunnen, Johan T and Dyke, Stephanie O M and Estivill, Xavier and Goldblatt, Jack and Gonthier, Catherine and Groft, Stephen C and Gut, Ivo and Hamosh, Ada and Hieter, Philip and H{\"o}hn, Sophie and Hurles, Matthew E and Kaufmann, Petra and Knoppers, Bartha M and Krischer, Jeffrey P and Macek, Milan and Matthijs, Gert and Olry, Annie and Parker, Samantha and Paschall, Justin and Philippakis, Anthony A and Rehm, Heidi L and Robinson, Peter N and Sham, Pak-Chung and Stefanov, Rumen and Taruscio, Domenica and Unni, Divya and Vanstone, Megan R and Zhang, Feng and Brunner, Han and Bamshad, Michael J and Lochm{\"u}ller, Hanns} } @article {402, title = {Isolated polycystic liver disease genes define effectors of polycystin-1 function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 May 01}, pages = {1772-1785}, abstract = {

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40\% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.

}, keywords = {Adult, Animals, Cell Line, Transformed, Cysts, Endoplasmic Reticulum, Female, Genome-Wide Association Study, Glucosidases, Glucosyltransferases, Heterozygote, Humans, Intracellular Signaling Peptides and Proteins, Liver Diseases, Male, Membrane Proteins, Mice, Mutation, SEC Translocation Channels, TRPP Cation Channels}, issn = {1558-8238}, doi = {10.1172/JCI90129}, author = {Besse, Whitney and Dong, Ke and Choi, Jungmin and Punia, Sohan and Fedeles, Sorin V and Choi, Murim and Gallagher, Anna-Rachel and Huang, Emily B and Gulati, Ashima and Knight, James and Mane, Shrikant and Tahvanainen, Esa and Tahvanainen, Pia and Sanna-Cherchi, Simone and Lifton, Richard P and Watnick, Terry and Pei, York P and Torres, Vicente E and Somlo, Stefan} } @article {357, title = {Lessons learned from additional research analyses of unsolved clinical exome cases.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 03 21}, pages = {26}, abstract = {

BACKGROUND: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.

METHODS: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.

RESULTS: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36\% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51\% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6\%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6\%), 1/1 multiplex family involving three affected siblings, and 3/4 (75\%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).

CONCLUSION: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

}, keywords = {Adenosine Triphosphatases, ATPases Associated with Diverse Cellular Activities, Computational Biology, DNA Copy Number Variations, DNA-Binding Proteins, Exome, Female, Genetic Diseases, Inborn, Genomics, GTP-Binding Protein beta Subunits, Humans, Male, Membrane Proteins, Metalloendopeptidases, Mitochondrial Proteins, Pilot Projects, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Transcription Factors}, issn = {1756-994X}, doi = {10.1186/s13073-017-0412-6}, author = {Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Harel, Tamar and Rosenfeld, Jill A and Gambin, Tomasz and Stray-Pedersen, Asbj{\o}rg and K{\"u}ry, S{\'e}bastien and Mercier, Sandra and Lessel, Davor and Denecke, Jonas and Wiszniewski, Wojciech and Penney, Samantha and Liu, Pengfei and Bi, Weimin and Lalani, Seema R and Schaaf, Christian P and Wangler, Michael F and Bacino, Carlos A and Lewis, Richard Alan and Potocki, Lorraine and Graham, Brett H and Belmont, John W and Scaglia, Fernando and Orange, Jordan S and Jhangiani, Shalini N and Chiang, Theodore and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Xia, Fan and Beaudet, Arthur L and Boerwinkle, Eric and Eng, Christine M and Plon, Sharon E and Sutton, V Reid and Gibbs, Richard A and Posey, Jennifer E and Yang, Yaping and Lupski, James R} } @article {337, title = {Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.}, journal = {Neuron}, volume = {93}, year = {2017}, month = {2017 Jan 04}, pages = {115-131}, abstract = {

We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here~we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in~the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH,~which in turn leads to mTORC1 activation and a subsequent reduction in autophagy. Inhibition of mTOR activity by rapamycin or partially restoring autophagy delays neurodegeneration in dNrd1 mutant flies. In summary, this study reveals a novel role for NRD1 as a mitochondrial co-chaperone for OGDH and provides a mechanistic link between mitochondrial metabolic dysfunction, mTORC1 signaling, and impaired autophagy in neurodegeneration.

}, keywords = {Animals, Autophagy, Drosophila, Drosophila melanogaster, Drosophila Proteins, Ketoglutarate Dehydrogenase Complex, Ketoglutaric Acids, Lysine, Mechanistic Target of Rapamycin Complex 1, Metalloendopeptidases, Mitochondria, Molecular Chaperones, Multiprotein Complexes, Neurodegenerative Diseases, TOR Serine-Threonine Kinases}, issn = {1097-4199}, doi = {10.1016/j.neuron.2016.11.038}, author = {Yoon, Wan Hee and Sandoval, Hector and Nagarkar-Jaiswal, Sonal and Jaiswal, Manish and Yamamoto, Shinya and Haelterman, Nele A and Putluri, Nagireddy and Putluri, Vasanta and Sreekumar, Arun and Tos, Tulay and Aksoy, Ayse and Donti, Taraka and Graham, Brett H and Ohno, Mikiko and Nishi, Eiichiro and Hunter, Jill and Muzny, Donna M and Carmichael, Jason and Shen, Joseph and Arboleda, Valerie A and Nelson, Stanley F and Wangler, Michael F and Karaca, Ender and Lupski, James R and Bellen, Hugo J} } @article {340, title = {Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {21-30}, abstract = {

Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

}, keywords = {Adolescent, Adult, Bone and Bones, Brachydactyly, Cell Cycle Checkpoints, Exome, Female, Fibromuscular Dysplasia, Genes, Recessive, Heterozygote, Homozygote, Humans, Learning Disorders, Male, Middle Aged, Muscle, Smooth, Vascular, Mutation, Nuclear Proteins, Pedigree, Syndactyly, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.008}, author = {Guo, Dong-Chuan and Duan, Xue-Yan and Regalado, Ellen S and Mellor-Crummey, Lauren and Kwartler, Callie S and Kim, Dong and Lieberman, Kenneth and de Vries, Bert B A and Pfundt, Rolph and Schinzel, Albert and Kotzot, Dieter and Shen, Xuetong and Yang, Min-Lee and Bamshad, Michael J and Nickerson, Deborah A and Gornik, Heather L and Ganesh, Santhi K and Braverman, Alan C and Grange, Dorothy K and Milewicz, Dianna M} } @article {428, title = {"Matching" consent to purpose: The example of the Matchmaker Exchange.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 10}, pages = {1281-1285}, abstract = {

The Matchmaker Exchange (MME) connects rare disease clinicians and researchers to facilitate the sharing of data from undiagnosed patients for the purpose of novel gene discovery. Such sharing raises the odds that two or more similar patients with candidate genes in common may be found, thereby allowing their condition to be more readily studied and understood. Consent considerations for data sharing in MME included both the ethical and legal differences between clinical and research settings and the level of privacy risk involved in sharing varying amounts of rare disease patient data to enable patient matches. In this commentary, we discuss these consent considerations and the resulting MME Consent Policy as they may be relevant to other international data sharing initiatives.

}, keywords = {Databases, Genetic, Genetic Association Studies, Genetic Diseases, Inborn, Genomics, Humans, Information Dissemination, Patient Selection, Physicians, Rare Diseases, Research Personnel, Translational Medical Research}, issn = {1098-1004}, doi = {10.1002/humu.23278}, author = {Dyke, Stephanie O M and Knoppers, Bartha M and Hamosh, Ada and Firth, Helen V and Hurles, Matthew and Brudno, Michael and Boycott, Kym M and Philippakis, Anthony A and Rehm, Heidi L} } @article {392, title = {Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Jul 06}, pages = {23-36}, abstract = {

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1\% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

}, keywords = {Abnormalities, Multiple, Animals, Armadillo Domain Proteins, Basal Bodies, Base Sequence, Brain, Cerebellum, Cilia, Ciliopathies, Diagnostic Imaging, Exome, Eye Abnormalities, Genetic Predisposition to Disease, Humans, Kidney Diseases, Cystic, Mutation, Phenotype, Retina, Sequence Analysis, DNA, Up-Regulation, Zebrafish, Zebrafish Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.05.010}, author = {Van De Weghe, Julie C and Rusterholz, Tamara D S and Latour, Brooke and Grout, Megan E and Aldinger, Kimberly A and Shaheen, Ranad and Dempsey, Jennifer C and Maddirevula, Sateesh and Cheng, Yong-Han H and Phelps, Ian G and Gesemann, Matthias and Goel, Himanshu and Birk, Ohad S and Alanzi, Talal and Rawashdeh, Rifaat and Khan, Arif O and Bamshad, Michael J and Nickerson, Deborah A and Neuhauss, Stephan C F and Dobyns, William B and Alkuraya, Fowzan S and Roepman, Ronald and Bachmann-Gagescu, Ruxandra and Doherty, Dan} } @article {338, title = {Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {117-127}, abstract = {

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in~situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in \~{}0.1\% of individuals with unexplained neurodevelopmental disorders.

}, keywords = {Adolescent, Adult, Amino Acid Substitution, Ataxia, Child, Child, Preschool, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, Developmental Disabilities, Exome, Face, Female, Gene Expression Regulation, Genes, Reporter, HEK293 Cells, Humans, Intellectual Disability, Language Development Disorders, Male, Models, Molecular, Mosaicism, Mutation, Neurodevelopmental Disorders, Protein Transport, Syndrome, Transcription Factors, Transcription, Genetic}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.012}, author = {Harms, Frederike Leonie and Girisha, Katta M and Hardigan, Andrew A and Kort{\"u}m, Fanny and Shukla, Anju and Alawi, Malik and Dalal, Ashwin and Brady, Lauren and Tarnopolsky, Mark and Bird, Lynne M and Ceulemans, Sophia and Bebin, Martina and Bowling, Kevin M and Hiatt, Susan M and Lose, Edward J and Primiano, Michelle and Chung, Wendy K and Juusola, Jane and Akdemir, Zeynep C and Bainbridge, Matthew and Charng, Wu-Lin and Drummond-Borg, Margaret and Eldomery, Mohammad K and El-Hattab, Ayman W and Saleh, Mohammed A M and B{\'e}zieau, St{\'e}phane and Cogn{\'e}, Benjamin and Isidor, Bertrand and K{\"u}ry, S{\'e}bastien and Lupski, James R and Myers, Richard M and Cooper, Gregory M and Kutsche, Kerstin} } @article {422, title = {Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {815-823}, abstract = {

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo~FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70~kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.

}, keywords = {Adolescent, Adult, Bone and Bones, Bone Diseases, Developmental, Cartilage, Child, Child, Preschool, Exome, Female, Fibronectins, Fractures, Bone, Humans, Male, Mutation, Osteochondrodysplasias, Phenotype, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.019}, author = {Lee, Chae Syng and Fu, He and Baratang, Nissan and Rousseau, Justine and Kumra, Heena and Sutton, V Reid and Niceta, Marcello and Ciolfi, Andrea and Yamamoto, Guilherme and Bertola, D{\'e}bora and Marcelis, Carlo L and Lugtenberg, Dorien and Bartuli, Andrea and Kim, Choel and Hoover-Fong, Julie and Sobreira, Nara and Pauli, Richard and Bacino, Carlos and Krakow, Deborah and Parboosingh, Jillian and Yap, Patrick and Kariminejad, Ariana and McDonald, Marie T and Aracena, Mariana I and Lausch, Ekkehart and Unger, Sheila and Superti-Furga, Andrea and Lu, James T and Cohn, Dan H and Tartaglia, Marco and Lee, Brendan H and Reinhardt, Dieter P and Campeau, Philippe M} } @article {493, title = {Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {856-865}, abstract = {

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs102] and c.920delG [p.Gly307Alafs11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

}, keywords = {Acyltransferases, Adolescent, Adult, Alleles, Atrophy, Bone Diseases, Metabolic, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Epilepsy, Exome, Female, Fibroblasts, Glycosylphosphatidylinositols, Humans, Male, Membrane Glycoproteins, Muscle Hypotonia, Mutation, Pedigree, RNA, Messenger, Seizures}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.020}, author = {Nguyen, Thi Tuyet Mai and Murakami, Yoshiko and Sheridan, Eamonn and Ehresmann, Sophie and Rousseau, Justine and St-Denis, Anik and Chai, Guoliang and Ajeawung, Norbert F and Fairbrother, Laura and Reimschisel, Tyler and Bateman, Alexandra and Berry-Kravis, Elizabeth and Xia, Fan and Tardif, Jessica and Parry, David A and Logan, Clare V and Diggle, Christine and Bennett, Christopher P and Hattingh, Louise and Rosenfeld, Jill A and Perry, Michael Scott and Parker, Michael J and Le Deist, Fran{\c c}oise and Zaki, Maha S and Ignatius, Erika and Isohanni, Pirjo and L{\"o}nnqvist, Tuula and Carroll, Christopher J and Johnson, Colin A and Gleeson, Joseph G and Kinoshita, Taroh and Campeau, Philippe M} } @article {395, title = {Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jun 01}, pages = {978-984}, abstract = {

The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

}, keywords = {Alcohol Oxidoreductases, Ceramides, Genes, Recessive, Genetic Complementation Test, Genetic Predisposition to Disease, Heterozygote, Humans, Intermediate Filament Proteins, Keratosis, Mutation, Polymorphism, Single Nucleotide, RNA Splicing, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.05.003}, author = {Boyden, Lynn M and Vincent, Nicholas G and Zhou, Jing and Hu, Ronghua and Craiglow, Brittany G and Bayliss, Susan J and Rosman, Ilana S and Lucky, Anne W and Diaz, Luis A and Goldsmith, Lowell A and Paller, Amy S and Lifton, Richard P and Baserga, Susan J and Choate, Keith A} } @article {634, title = {Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Oct}, pages = {1529-1538}, abstract = {

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

}, keywords = {Animals, Apoptosis, Carrier Proteins, Cell Movement, CRISPR-Cas Systems, Cytoskeleton, DNA Repair, Endoplasmic Reticulum Stress, Gene Knockout Techniques, Hernia, Hiatal, Humans, Intracellular Signaling Peptides and Proteins, Metalloendopeptidases, Mice, Microcephaly, Models, Molecular, Multiprotein Complexes, Mutation, Nephrosis, Nephrotic Syndrome, Podocytes, Protein Conformation, Protein-Serine-Threonine Kinases, RNA Processing, Post-Transcriptional, RNA, Transfer, Telomere Homeostasis, Zebrafish, Zebrafish Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3933}, author = {Braun, Daniela A and Rao, Jia and Mollet, Geraldine and Schapiro, David and Daugeron, Marie-Claire and Tan, Weizhen and Gribouval, Olivier and Boyer, Olivia and Revy, Patrick and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Lawson, Jennifer A and Schanze, Denny and Ashraf, Shazia and Ullmann, Jeremy F P and Hoogstraten, Charlotte A and Boddaert, Nathalie and Collinet, Bruno and Martin, Ga{\"e}lle and Liger, Dominique and Lovric, Svjetlana and Furlano, Monica and Guerrera, I Chiara and Sanchez-Ferras, Oraly and Hu, Jennifer F and Boschat, Anne-Claire and Sanquer, Sylvia and Menten, Bj{\"o}rn and Vergult, Sarah and De Rocker, Nina and Airik, Merlin and Hermle, Tobias and Shril, Shirlee and Widmeier, Eugen and Gee, Heon Yung and Choi, Won-Il and Sadowski, Carolin E and Pabst, Werner L and Warejko, Jillian K and Daga, Ankana and Basta, Tamara and Matejas, Verena and Scharmann, Karin and Kienast, Sandra D and Behnam, Babak and Beeson, Brendan and Begtrup, Amber and Bruce, Malcolm and Ch{\textquoteright}ng, Gaik-Siew and Lin, Shuan-Pei and Chang, Jui-Hsing and Chen, Chao-Huei and Cho, Megan T and Gaffney, Patrick M and Gipson, Patrick E and Hsu, Chyong-Hsin and Kari, Jameela A and Ke, Yu-Yuan and Kiraly-Borri, Cathy and Lai, Wai-Ming and Lemyre, Emmanuelle and Littlejohn, Rebecca Okashah and Masri, Amira and Moghtaderi, Mastaneh and Nakamura, Kazuyuki and Ozaltin, Fatih and Praet, Marleen and Prasad, Chitra and Prytula, Agnieszka and Roeder, Elizabeth R and Rump, Patrick and Schnur, Rhonda E and Shiihara, Takashi and Sinha, Manish D and Soliman, Neveen A and Soulami, Kenza and Sweetser, David A and Tsai, Wen-Hui and Tsai, Jeng-Daw and Topaloglu, Rezan and Vester, Udo and Viskochil, David H and Vatanavicharn, Nithiwat and Waxler, Jessica L and Wierenga, Klaas J and Wolf, Matthias T F and Wong, Sik-Nin and Leidel, Sebastian A and Truglio, Gessica and Dedon, Peter C and Poduri, Annapurna and Mane, Shrikant and Lifton, Richard P and Bouchard, Maxime and Kannu, Peter and Chitayat, David and Magen, Daniella and Callewaert, Bert and van Tilbeurgh, Herman and Zenker, Martin and Antignac, Corinne and Hildebrandt, Friedhelm} } @article {405, title = {Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 Mar 01}, pages = {912-928}, abstract = {

Steroid-resistant nephrotic syndrome (SRNS) causes 15\% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30\% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

}, keywords = {Aldehyde-Lyases, Animals, Cell Line, Cell Movement, Drosophila melanogaster, Drosophila Proteins, Female, Humans, Ichthyosis, Lamellar, Male, Mesangial Cells, Mice, Mice, Knockout, Mutation, Nephrotic Syndrome, Protein Transport, Rats}, issn = {1558-8238}, doi = {10.1172/JCI89626}, author = {Lovric, Svjetlana and Goncalves, Sara and Gee, Heon Yung and Oskouian, Babak and Srinivas, Honnappa and Choi, Won-Il and Shril, Shirlee and Ashraf, Shazia and Tan, Weizhen and Rao, Jia and Airik, Merlin and Schapiro, David and Braun, Daniela A and Sadowski, Carolin E and Widmeier, Eugen and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Girik, Vladimir and Capitani, Guido and Suh, Jung H and Lachauss{\'e}e, No{\"e}lle and Arrondel, Christelle and Patat, Julie and Gribouval, Olivier and Furlano, Monica and Boyer, Olivia and Schmitt, Alain and Vuiblet, Vincent and Hashmi, Seema and Wilcken, Rainer and Bernier, Francois P and Innes, A Micheil and Parboosingh, Jillian S and Lamont, Ryan E and Midgley, Julian P and Wright, Nicola and Majewski, Jacek and Zenker, Martin and Schaefer, Franz and Kuss, Navina and Greil, Johann and Giese, Thomas and Schwarz, Klaus and Catheline, Vilain and Schanze, Denny and Franke, Ingolf and Sznajer, Yves and Truant, Anne S and Adams, Brigitte and D{\'e}sir, Julie and Biemann, Ronald and Pei, York and Ars, Elisabet and Lloberas, Nuria and Madrid, Alvaro and Dharnidharka, Vikas R and Connolly, Anne M and Willing, Marcia C and Cooper, Megan A and Lifton, Richard P and Simons, Matias and Riezman, Howard and Antignac, Corinne and Saba, Julie D and Hildebrandt, Friedhelm} } @article {384, title = {Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Oct}, pages = {2789-2794}, abstract = {

Nemaline myopathy is a rare inherited disorder characterized by weakness, hypotonia, and depressed deep tendon reflexes. It is clinically and genetically heterogeneous, with the most severe phenotype presenting as perinatal akinesia, severe muscle weakness, feeding difficulties and respiratory failure, leading to early mortality. Pathogenic variants in 12 genes, encoding components of the sarcomere or factors related to myogenesis, have been reported in patients affected with the disorder. Here, we describe an early, lethal presentation of decreased fetal movements, hypotonia, muscle weakness, and neonatal respiratory failure requiring ventilator support in three siblings from a consanguineous family. All exhibited perinatal fractures, and thus, a skeletal dysplasia was considered as possibly contributing to the phenotype. However, whole exome sequencing revealed a homozygous, loss-of-function pathogenic variant in LMOD3, which has recently been associated with nemaline myopathy and, in a subset of patients, perinatal fractures. This case demonstrates the importance of considering congenital neuromuscular disorders in the differential diagnosis of perinatal fractures.

}, keywords = {Female, Fractures, Bone, Homozygote, Humans, Infant, Newborn, Male, Muscle Proteins, Mutation, Myopathies, Structural, Congenital, Pedigree}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38383}, author = {Abbott, Megan and Jain, Mahim and Pferdehirt, Rachel and Chen, Yuqing and Tran, Alyssa and Duz, Mehmet B and Seven, Mehmet and Gibbs, Richard A and Muzny, Donna and Lee, Brendan and Marom, Ronit and Burrage, Lindsay C} } @article {348, title = {An Organismal CNV Mutator Phenotype Restricted to Early Human Development.}, journal = {Cell}, volume = {168}, year = {2017}, month = {2017 02 23}, pages = {830-842.e7}, abstract = {

De novo copy number variants (dnCNVs) arising at~multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We~propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.

}, keywords = {Chromosome Aberrations, Chromosome Breakpoints, Chromosome Duplication, DNA Copy Number Variations, DNA Replication, Embryonic Development, Female, Gametogenesis, Genetic Diseases, Inborn, Genomic Instability, Humans, Male, Mutation}, issn = {1097-4172}, doi = {10.1016/j.cell.2017.01.037}, author = {Liu, Pengfei and Yuan, Bo and Carvalho, Claudia M B and Wuster, Arthur and Walter, Klaudia and Zhang, Ling and Gambin, Tomasz and Chong, Zechen and Campbell, Ian M and Coban Akdemir, Zeynep and Gelowani, Violet and Writzl, Karin and Bacino, Carlos A and Lindsay, Sarah J and Withers, Marjorie and Gonzaga-Jauregui, Claudia and Wiszniewska, Joanna and Scull, Jennifer and Stankiewicz, Pawe{\l} and Jhangiani, Shalini N and Muzny, Donna M and Zhang, Feng and Chen, Ken and Gibbs, Richard A and Rautenstrauss, Bernd and Cheung, Sau Wai and Smith, Janice and Breman, Amy and Shaw, Chad A and Patel, Ankita and Hurles, Matthew E and Lupski, James R} } @article {433, title = {Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 12}, pages = {1335-1344}, abstract = {

Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.

}, keywords = {Abnormalities, Multiple, Case-Control Studies, Child, DNA Methylation, Face, Female, Hematologic Diseases, Histone-Lysine N-Methyltransferase, Humans, Loss of Function Mutation, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Vestibular Diseases}, issn = {1476-5438}, doi = {10.1038/s41431-017-0023-0}, author = {Sobreira, Nara and Brucato, Martha and Zhang, Li and Ladd-Acosta, Christine and Ongaco, Chrissie and Romm, Jane and Doheny, Kimberly F and Mingroni-Netto, Regina C and Bertola, D{\'e}bora and Kim, Chong A and Perez, Ana Ba and Melaragno, Maria I and Valle, David and Meloni, Vera A and Bjornsson, Hans T} } @article {442, title = {Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 08 14}, pages = {73}, abstract = {

BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.

METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.

RESULTS: We demonstrate greater than expected phenotypic heterogeneity, including 33\% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.

CONCLUSIONS: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

}, keywords = {Adolescent, Adult, CDC2 Protein Kinase, Child, Child, Preschool, Face, Female, Heart Defects, Congenital, Humans, Infant, Intellectual Disability, Male, Mutation, Phenotype, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-017-0463-8}, author = {Bostwick, Bret L and McLean, Scott and Posey, Jennifer E and Streff, Haley E and Gripp, Karen W and Blesson, Alyssa and Powell-Hamilton, Nina and Tusi, Jessica and Stevenson, David A and Farrelly, Ellyn and Hudgins, Louanne and Yang, Yaping and Xia, Fan and Wang, Xia and Liu, Pengfei and Walkiewicz, Magdalena and McGuire, Marianne and Grange, Dorothy K and Andrews, Marisa V and Hummel, Marybeth and Madan-Khetarpal, Suneeta and Infante, Elena and Coban-Akdemir, Zeynep and Miszalski-Jamka, Karol and Jefferies, John L and Rosenfeld, Jill A and Emrick, Lisa and Nugent, Kimberly M and Lupski, James R and Belmont, John W and Lee, Brendan and Lalani, Seema R} } @article {399, title = {Phenotypic spectrum of autosomal recessive congenital ichthyosis due to PNPLA1 mutation.}, journal = {Br J Dermatol}, volume = {177}, year = {2017}, month = {2017 07}, pages = {319-322}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Heterozygote, Homozygote, Humans, Ichthyosis, Infant, Lipase, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Young Adult}, issn = {1365-2133}, doi = {10.1111/bjd.15570}, author = {Boyden, L M and Craiglow, B G and Hu, R H and Zhou, J and Browning, J and Eichenfield, L and Lim, Y L and Luu, M and Randolph, L M and Ginarte, M and Fachal, L and Rodriguez-Pazos, L and Vega, A and Kramer, D and Yosipovitch, G and Vahidnezhad, H and Youssefian, L and Uitto, J and Lifton, R P and Paller, A S and Milstone, L M and Choate, K A} } @article {362, title = {Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Aug}, pages = {2240-2245}, abstract = {

Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene (LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50\% decrement of compound muscle action potential amplitudes and 250\% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins.

}, keywords = {Adult, Face, Female, Homozygote, Humans, Laminin, Myasthenic Syndromes, Congenital, Myopia, Neuromuscular Junction Diseases, Tics, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38291}, author = {Maselli, Ricardo A and Arredondo, Juan and V{\'a}zquez, Jessica and Chong, Jessica X and Bamshad, Michael J and Nickerson, Deborah A and Lara, Marian and Ng, Fiona and Lo, Victoria L and Pytel, Peter and McDonald, Craig M} } @article {27, title = {Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.}, journal = {J Allergy Clin Immunol}, volume = {139}, year = {2017}, month = {2017 Jan}, pages = {232-245}, abstract = {

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.

OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.

METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.

RESULTS: A likely molecular diagnosis was achieved in 110 (40\%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30~Kb that would not have been detected with conventional diagnostic CNV arrays.

CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

}, keywords = {Adolescent, Adult, Aged, Child, Child, Preschool, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Infant, Male, Middle Aged, Young Adult}, issn = {1097-6825}, doi = {10.1016/j.jaci.2016.05.042}, author = {Stray-Pedersen, Asbj{\o}rg and Sorte, Hanne S{\o}rmo and Samarakoon, Pubudu and Gambin, Tomasz and Chinn, Ivan K and Coban Akdemir, Zeynep H and Erichsen, Hans Christian and Forbes, Lisa R and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Muzny, Donna M and R{\o}dningen, Olaug Kristin and Sheng, Ying and Nicholas, Sarah K and Noroski, Lenora M and Seeborg, Filiz O and Davis, Carla M and Canter, Debra L and Mace, Emily M and Vece, Timothy J and Allen, Carl E and Abhyankar, Harshal A and Boone, Philip M and Beck, Christine R and Wiszniewski, Wojciech and Fevang, B{\o}rre and Aukrust, P{\r a}l and Tj{\o}nnfjord, Geir E and Gedde-Dahl, Tobias and Hjorth-Hansen, Henrik and Dybedal, Ingunn and Nord{\o}y, Ingvild and J{\o}rgensen, Silje F and Abrahamsen, Tore G and {\O}verland, Torstein and Bechensteen, Anne Grete and Skogen, Vegard and Osnes, Liv T N and Kulseth, Mari Ann and Prescott, Trine E and Rustad, Cecilie F and Heimdal, Ketil R and Belmont, John W and Rider, Nicholas L and Chinen, Javier and Cao, Tram N and Smith, Eric A and Caldirola, Maria Soledad and Bezrodnik, Liliana and Lugo Reyes, Saul Oswaldo and Espinosa Rosales, Francisco J and Guerrero-Cursaru, Nina Denisse and Pedroza, Luis Alberto and Poli, Cecilia M and Franco, Jose L and Trujillo Vargas, Claudia M and Aldave Becerra, Juan Carlos and Wright, Nicola and Issekutz, Thomas B and Issekutz, Andrew C and Abbott, Jordan and Caldwell, Jason W and Bayer, Diana K and Chan, Alice Y and Aiuti, Alessandro and Cancrini, Caterina and Holmberg, Eva and West, Christina and Burstedt, Magnus and Karaca, Ender and Yesil, G{\"o}zde and Artac, Hasibe and Bayram, Yavuz and Atik, Mehmed Musa and Eldomery, Mohammad K and Ehlayel, Mohammad S and Jolles, Stephen and Flat{\o}, Berit and Bertuch, Alison A and Hanson, I Celine and Zhang, Victor W and Wong, Lee-Jun and Hu, Jianhong and Walkiewicz, Magdalena and Yang, Yaping and Eng, Christine M and Boerwinkle, Eric and Gibbs, Richard A and Shearer, William T and Lyle, Robert and Orange, Jordan S and Lupski, James R} } @article {355, title = {PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.}, journal = {Brain}, volume = {140}, year = {2017}, month = {2017 Apr 01}, pages = {940-952}, abstract = {

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

}, keywords = {Adolescent, Brain, Carrier Proteins, Cell Differentiation, Cell Movement, Cerebral Cortex, Child, Child, Preschool, Cytoskeleton, Developmental Disabilities, Female, Genes, Recessive, Heredodegenerative Disorders, Nervous System, Humans, Infant, Male, Microcephaly, Microtubules, Mutation, Pedigree, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awx014}, author = {Zollo, Massimo and Ahmed, Mustafa and Ferrucci, Veronica and Salpietro, Vincenzo and Asadzadeh, Fatemeh and Carotenuto, Marianeve and Maroofian, Reza and Al-Amri, Ahmed and Singh, Royana and Scognamiglio, Iolanda and Mojarrad, Majid and Musella, Luca and Duilio, Angela and Di Somma, Angela and Karaca, Ender and Rajab, Anna and Al-Khayat, Aisha and Mohan Mohapatra, Tribhuvan and Eslahi, Atieh and Ashrafzadeh, Farah and Rawlins, Lettie E and Prasad, Rajniti and Gupta, Rashmi and Kumari, Preeti and Srivastava, Mona and Cozzolino, Flora and Kumar Rai, Sunil and Monti, Maria and Harlalka, Gaurav V and Simpson, Michael A and Rich, Philip and Al-Salmi, Fatema and Patton, Michael A and Chioza, Barry A and Efthymiou, Stephanie and Granata, Francesca and Di Rosa, Gabriella and Wiethoff, Sarah and Borgione, Eugenia and Scuderi, Carmela and Mankad, Kshitij and Hanna, Michael G and Pucci, Piero and Houlden, Henry and Lupski, James R and Crosby, Andrew H and Baple, Emma L} } @article {536, title = {Rare Genetic Variants in PARN Are Associated with Pulmonary Fibrosis in Families.}, journal = {Am J Respir Crit Care Med}, volume = {196}, year = {2017}, month = {2017 12 01}, pages = {1481-1484}, keywords = {Genetic Variation, Humans, Pulmonary Fibrosis}, issn = {1535-4970}, doi = {10.1164/rccm.201703-0635LE}, author = {Kropski, Jonathan A and Reiss, Sara and Markin, Cheryl and Brown, Kevin K and Schwartz, David A and Schwarz, Marvin I and Loyd, James E and Phillips, John A and Blackwell, Timothy S and Cogan, Joy D} } @article {334, title = {A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {343-351}, abstract = {

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who~underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p~= 1.25~{\texttimes} 10). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.

}, keywords = {Alleles, Amino Acid Sequence, Brain, Cataract, Child, Child, Preschool, Female, Genetic Variation, Genome-Wide Association Study, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Missense, Neoplasm Proteins, Pedigree, Phenotype, Repressor Proteins, Spasms, Infantile}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.12.013}, author = {Schoch, Kelly and Meng, Linyan and Szelinger, Szabolcs and Bearden, David R and Stray-Pedersen, Asbjorg and Busk, Oyvind L and Stong, Nicholas and Liston, Eriskay and Cohn, Ronald D and Scaglia, Fernando and Rosenfeld, Jill A and Tarpinian, Jennifer and Skraban, Cara M and Deardorff, Matthew A and Friedman, Jeremy N and Akdemir, Zeynep Coban and Walley, Nicole and Mikati, Mohamad A and Kranz, Peter G and Jasien, Joan and McConkie-Rosell, Allyn and McDonald, Marie and Wechsler, Stephanie Burns and Freemark, Michael and Kansagra, Sujay and Freedman, Sharon and Bali, Deeksha and Millan, Francisca and Bale, Sherri and Nelson, Stanley F and Lee, Hane and Dorrani, Naghmeh and Goldstein, David B and Xiao, Rui and Yang, Yaping and Posey, Jennifer E and Martinez-Agosto, Julian A and Lupski, James R and Wangler, Michael F and Shashi, Vandana} } @article {339, title = {Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 01 05}, pages = {21-31}, abstract = {

BACKGROUND: Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.

METHODS: We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.

RESULTS: A molecular diagnosis was rendered for 2076 of 7374 patients (28.2\%); among these patients, 101 (4.9\%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8\% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7\% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7\% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9\%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77{\texttimes}10).

CONCLUSIONS: In our study, we found multiple molecular diagnoses in 4.9\% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).

}, keywords = {Exome, Genetic Diseases, Inborn, Genetic Variation, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Phenotype, Retrospective Studies, Sequence Analysis, DNA}, issn = {1533-4406}, doi = {10.1056/NEJMoa1516767}, author = {Posey, Jennifer E and Harel, Tamar and Liu, Pengfei and Rosenfeld, Jill A and James, Regis A and Coban Akdemir, Zeynep H and Walkiewicz, Magdalena and Bi, Weimin and Xiao, Rui and Ding, Yan and Xia, Fan and Beaudet, Arthur L and Muzny, Donna M and Gibbs, Richard A and Boerwinkle, Eric and Eng, Christine M and Sutton, V Reid and Shaw, Chad A and Plon, Sharon E and Yang, Yaping and Lupski, James R} } @article {390, title = {REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Jul 06}, pages = {149-156}, abstract = {

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.

}, keywords = {Adolescent, Base Sequence, Chromosome Segregation, Exons, Family, Female, Fibromatosis, Gingival, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Pedigree, Repressor Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.06.006}, author = {Bayram, Yavuz and White, Janson J and Elcioglu, Nursel and Cho, Megan T and Zadeh, Neda and Gedikbasi, Asuman and Palanduz, Sukru and Ozturk, Sukru and Cefle, Kivanc and Kasapcopur, Ozgur and Coban Akdemir, Zeynep and Pehlivan, Davut and Begtrup, Amber and Carvalho, Claudia M B and Paine, Ingrid Sophie and Mentes, Ali and Bektas-Kayhan, Kivanc and Karaca, Ender and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R} } @article {356, title = {Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.}, journal = {Am J Med Genet B Neuropsychiatr Genet}, volume = {174}, year = {2017}, month = {2017 Jun}, pages = {381-389}, abstract = {

Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5\% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8\%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. {\textcopyright} 2017 Wiley Periodicals, Inc.

}, keywords = {Adult, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Biomarkers, Child, Exome, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Missense, Phenotype}, issn = {1552-485X}, doi = {10.1002/ajmg.b.32527}, author = {Kim, Daniel Seung and Burt, Amber A and Ranchalis, Jane E and Wilmot, Beth and Smith, Joshua D and Patterson, Karynne E and Coe, Bradley P and Li, Yatong K and Bamshad, Michael J and Nikolas, Molly and Eichler, Evan E and Swanson, James M and Nigg, Joel T and Nickerson, Deborah A and Jarvik, Gail P} } @article {448, title = {SLC13A5 is the second gene associated with Kohlsch{\"u}tter-T{\"o}nz syndrome.}, journal = {J Med Genet}, volume = {54}, year = {2017}, month = {2017 01}, pages = {54-62}, abstract = {

BACKGROUND: Kohlsch{\"u}tter-T{\"o}nz syndrome (KTZS) is a rare autosomal-recessive disease characterised by epileptic encephalopathy, intellectual disability and amelogenesis imperfecta (AI). It is frequently caused by biallelic mutations in ROGDI. Here, we report on individuals with ROGDI-negative KTZS carrying biallelic SLC13A5 mutations.

METHODS: In the present cohort study, nine individuals from four families with the clinical diagnosis of KTZS and absence of ROGDI mutations as well as one patient with unexplained epileptic encephalopathy were investigated by clinical and dental evaluation, parametric linkage analysis (one family), and exome and/or Sanger sequencing. Dental histological investigations were performed on teeth from individuals with SLC13A5-associated and ROGDI-associated KTZS.

RESULTS: Biallelic mutations in SLC13A5 were identified in 10 affected individuals. Epileptic encephalopathy usually presents in the neonatal and (less frequently) early infantile period. Yellowish to orange discolouration of both deciduous and permanent teeth, as well as wide interdental spaces and abnormal crown forms are major clinical signs of individuals with biallelic SLC13A5 mutations. Histological dental investigations confirmed the clinical diagnosis of hypoplastic AI. In comparison, the histological evaluation of a molar assessed from an individual with ROGDI-associated KTZS revealed hypocalcified AI.

CONCLUSIONS: We conclude that SLC13A5 is the second major gene associated with the clinical diagnosis of KTZS, characterised by neonatal epileptic encephalopathy and hypoplastic AI. Careful clinical and dental delineation provides clues whether ROGDI or SLC13A5 is the causative gene. Hypersensitivity of teeth as well as high caries risk requires individual dental prophylaxis and attentive dental management.

}, keywords = {Alleles, Amelogenesis Imperfecta, Brain Diseases, Cohort Studies, Dementia, Epilepsy, Exome, Female, Genetic Linkage, Genetic Predisposition to Disease, Humans, Male, Membrane Proteins, Mutation, Nuclear Proteins, Pedigree, Symporters, Tooth}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103988}, author = {Schossig, Anna and Bloch-Zupan, Agn{\`e}s and Lussi, Adrian and Wolf, Nicole I and Raskin, Salmo and Cohen, Monika and Giuliano, Fabienne and Jurgens, Julie and Krabichler, Birgit and Koolen, David A and de Macena Sobreira, Nara Lygia and Maurer, Elisabeth and Muller-Bolla, Mich{\`e}le and Penzien, Johann and Zschocke, Johannes and Kapferer-Seebacher, Ines} } @article {406, title = {SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Feb}, pages = {238-248}, abstract = {

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84\% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

}, keywords = {Adolescent, Child, Child, Preschool, Choanal Atresia, Chromosomal Proteins, Non-Histone, Female, Genetic Predisposition to Disease, Humans, Infant, Male, Microphthalmos, Muscular Dystrophies, Mutation, Nose, Phenotype}, issn = {1546-1718}, doi = {10.1038/ng.3743}, author = {Shaw, Natalie D and Brand, Harrison and Kupchinsky, Zachary A and Bengani, Hemant and Plummer, Lacey and Jones, Takako I and Erdin, Serkan and Williamson, Kathleen A and Rainger, Joe and Stortchevoi, Alexei and Samocha, Kaitlin and Currall, Benjamin B and Dunican, Donncha S and Collins, Ryan L and Willer, Jason R and Lek, Angela and Lek, Monkol and Nassan, Malik and Pereira, Shahrin and Kammin, Tammy and Lucente, Diane and Silva, Alexandra and Seabra, Catarina M and Chiang, Colby and An, Yu and Ansari, Morad and Rainger, Jacqueline K and Joss, Shelagh and Smith, Jill Clayton and Lippincott, Margaret F and Singh, Sylvia S and Patel, Nirav and Jing, Jenny W and Law, Jennifer R and Ferraro, Nalton and Verloes, Alain and Rauch, Anita and Steindl, Katharina and Zweier, Markus and Scheer, Ianina and Sato, Daisuke and Okamoto, Nobuhiko and Jacobsen, Christina and Tryggestad, Jeanie and Chernausek, Steven and Schimmenti, Lisa A and Brasseur, Benjamin and Cesaretti, Claudia and Garc{\'\i}a-Ortiz, Jose E and Buitrago, Tatiana Pineda and Silva, Orlando Perez and Hoffman, Jodi D and M{\"u}hlbauer, Wolfgang and Ruprecht, Klaus W and Loeys, Bart L and Shino, Masato and Kaindl, Angela M and Cho, Chie-Hee and Morton, Cynthia C and Meehan, Richard R and van Heyningen, Veronica and Liao, Eric C and Balasubramanian, Ravikumar and Hall, Janet E and Seminara, Stephanie B and Macarthur, Daniel and Moore, Steven A and Yoshiura, Koh-Ichiro and Gusella, James F and Marsh, Joseph A and Graham, John M and Lin, Angela E and Katsanis, Nicholas and Jones, Peter L and Crowley, William F and Davis, Erica E and FitzPatrick, David R and Talkowski, Michael E} } @article {380, title = {Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 11}, pages = {1246-1252}, abstract = {

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

}, keywords = {Adult, Aged, Antigens, CD, Cadherins, Early Detection of Cancer, Exome, Female, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Male, Middle Aged, Sequence Analysis, DNA, Stomach Neoplasms}, issn = {1476-5438}, doi = {10.1038/ejhg.2017.138}, author = {Vogelaar, Ingrid P and van der Post, Rachel S and van Krieken, J Han Jm and Spruijt, Liesbeth and van Zelst-Stams, Wendy Ag and Kets, C Marleen and Lubinski, Jan and Jakubowska, Anna and Teodorczyk, Urszula and Aalfs, Cora M and van Hest, Liselotte P and Pinheiro, Hugo and Oliveira, Carla and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and de Ligt, Joep and Vissers, Lisenka E L M and Hoischen, Alexander and Gilissen, Christian and van de Vorst, Maartje and Goeman, Jelle J and Schackert, Hans K and Ranzani, Guglielmina N and Molinaro, Valeria and G{\'o}mez Garc{\'\i}a, Encarna B and Hes, Frederik J and Holinski-Feder, Elke and Genuardi, Maurizio and Ausems, Margreet G E M and Sijmons, Rolf H and Wagner, Anja and van der Kolk, Lizet E and Bj{\o}rnevoll, Inga and H{\o}berg-Vetti, Hildegunn and van Kessel, Ad Geurts and Kuiper, Roland P and Ligtenberg, Marjolijn J L and Hoogerbrugge, Nicoline} } @article {540, title = {Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.}, journal = {JAMA Pediatr}, volume = {171}, year = {2017}, month = {2017 12 04}, pages = {e173438}, abstract = {

Importance: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.

Objective: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.

Design, Setting, and Participants: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children{\textquoteright}s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants.

Main Outcomes and Measures: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.

Results: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7\%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0\%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8\%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9\%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1\%) by exome sequencing, with implications for recurrence risk counseling.

Conclusions and Relevance: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

}, keywords = {Adult, Critical Care, Disease Management, Exome, Genetic Counseling, Genetic Diseases, Inborn, Humans, Infant, Infant Care, Infant, Newborn, Intensive Care Units, Pediatric, Length of Stay, Retrospective Studies, Texas, Whole Exome Sequencing}, issn = {2168-6211}, doi = {10.1001/jamapediatrics.2017.3438}, author = {Meng, Linyan and Pammi, Mohan and Saronwala, Anirudh and Magoulas, Pilar and Ghazi, Andrew Ray and Vetrini, Francesco and Zhang, Jing and He, Weimin and Dharmadhikari, Avinash V and Qu, Chunjing and Ward, Patricia and Braxton, Alicia and Narayanan, Swetha and Ge, Xiaoyan and Tokita, Mari J and Santiago-Sim, Teresa and Dai, Hongzheng and Chiang, Theodore and Smith, Hadley and Azamian, Mahshid S and Robak, Laurie and Bostwick, Bret L and Schaaf, Christian P and Potocki, Lorraine and Scaglia, Fernando and Bacino, Carlos A and Hanchard, Neil A and Wangler, Michael F and Scott, Daryl and Brown, Chester and Hu, Jianhong and Belmont, John W and Burrage, Lindsay C and Graham, Brett H and Sutton, Vernon Reid and Craigen, William J and Plon, Sharon E and Lupski, James R and Beaudet, Arthur L and Gibbs, Richard A and Muzny, Donna M and Miller, Marcus J and Wang, Xia and Leduc, Magalie S and Xiao, Rui and Liu, Pengfei and Shaw, Chad and Walkiewicz, Magdalena and Bi, Weimin and Xia, Fan and Lee, Brendan and Eng, Christine M and Yang, Yaping and Lalani, Seema R} } @article {425, title = {Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 10 31}, pages = {95}, abstract = {

BACKGROUND: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes.

METHODS: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs.

RESULTS: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio = 4.0, 95\% confidence interval 2.5-6.5).

CONCLUSIONS: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.

}, keywords = {Female, Genetic Heterogeneity, Heart Defects, Congenital, Humans, Inheritance Patterns, Male, Whole Exome Sequencing}, issn = {1756-994X}, doi = {10.1186/s13073-017-0482-5}, author = {Li, Alexander H and Hanchard, Neil A and Furthner, Dieter and Fernbach, Susan and Azamian, Mahshid and Nicosia, Annarita and Rosenfeld, Jill and Muzny, Donna and D{\textquoteright}Alessandro, Lisa C A and Morris, Shaine and Jhangiani, Shalini and Parekh, Dhaval R and Franklin, Wayne J and Lewin, Mark and Towbin, Jeffrey A and Penny, Daniel J and Fraser, Charles D and Martin, James F and Eng, Christine and Lupski, James R and Gibbs, Richard A and Boerwinkle, Eric and Belmont, John W} } @article {7, title = {Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 Feb}, pages = {180-192}, abstract = {

Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48\% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4\%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15\% of the interchromosomal translocation events.

}, keywords = {Base Sequence, Chromosome Breakage, Chromosome Mapping, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Genetic Association Studies, Genomics, Genotype, Homologous Recombination, Humans, In Situ Hybridization, Fluorescence, Karyotype, Male, Phenotype, Translocation, Genetic, Whole Genome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23146}, author = {Nilsson, Daniel and Pettersson, Maria and Gustavsson, Peter and F{\"o}rster, Alisa and Hofmeister, Wolfgang and Wincent, Josephine and Zachariadis, Vasilios and Anderlid, Britt-Marie and Nordgren, Ann and M{\"a}kitie, Outi and Wirta, Valtteri and K{\"a}ller, Max and Vezzi, Francesco and Lupski, James R and Nordenskj{\"o}ld, Magnus and Lundberg, Elisabeth Syk and Carvalho, Claudia M B and Lindstrand, Anna} } @article {113, title = {Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.}, journal = {Endocrine}, volume = {51}, year = {2016}, month = {2016 Feb}, pages = {236-44}, abstract = {

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 {\texttimes} 23.9 {\texttimes} 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 {\texttimes} 58.1 {\texttimes} 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

}, keywords = {Adenoma, Child, Genetic Diseases, X-Linked, Gigantism, Humans, Male, Pituitary Neoplasms, Treatment Outcome}, issn = {1559-0100}, doi = {10.1007/s12020-015-0804-6}, author = {Naves, Luciana A and Daly, Adrian F and Dias, Luiz Augusto and Yuan, Bo and Zakir, Juliano Coelho Oliveira and Barra, Gustavo Barcellos and Palmeira, Leonor and Villa, Chiara and Trivellin, Giampaolo and J{\'u}nior, Armindo Jreige and Neto, Flor{\^e}ncio Figueiredo Cavalcante and Liu, Pengfei and Pellegata, Natalia S and Stratakis, Constantine A and Lupski, James R and Beckers, Albert} } @article {77, title = {ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.}, journal = {Hum Mutat}, volume = {37}, year = {2016}, month = {2016 07}, pages = {653-60}, abstract = {

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

}, keywords = {Biomarkers, Congenital Disorders of Glycosylation, Female, Genes, Lethal, Glycosylation, Humans, Male, Mannosyltransferases, Mutation, Polysaccharides, Sequence Analysis, DNA, Survival Analysis}, issn = {1098-1004}, doi = {10.1002/humu.22983}, author = {Ng, Bobby G and Shiryaev, Sergey A and Rymen, Daisy and Eklund, Erik A and Raymond, Kimiyo and Kircher, Martin and Abdenur, Jose E and Alehan, Fusun and Midro, Alina T and Bamshad, Michael J and Barone, Rita and Berry, Gerard T and Brumbaugh, Jane E and Buckingham, Kati J and Clarkson, Katie and Cole, F Sessions and O{\textquoteright}Connor, Shawn and Cooper, Gregory M and Van Coster, Rudy and Demmer, Laurie A and Diogo, Luisa and Fay, Alexander J and Ficicioglu, Can and Fiumara, Agata and Gahl, William A and Ganetzky, Rebecca and Goel, Himanshu and Harshman, Lyndsay A and He, Miao and Jaeken, Jaak and James, Philip M and Katz, Daniel and Keldermans, Liesbeth and Kibaek, Maria and Kornberg, Andrew J and Lachlan, Katherine and Lam, Christina and Yaplito-Lee, Joy and Nickerson, Deborah A and Peters, Heidi L and Race, Valerie and R{\'e}gal, Luc and Rush, Jeffrey S and Rutledge, S Lane and Shendure, Jay and Souche, Erika and Sparks, Susan E and Trapane, Pamela and Sanchez-Valle, Amarilis and Vilain, Eric and V{\o}llo, Arve and Waechter, Charles J and Wang, Raymond Y and Wolfe, Lynne A and Wong, Derek A and Wood, Tim and Yang, Amy C and Matthijs, Gert and Freeze, Hudson H} } @article {52, title = {Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project.}, journal = {Genet Epidemiol}, volume = {40}, year = {2016}, month = {2016 09}, pages = {470-4}, abstract = {

Neutrophils are a key component of innate immunity. Individuals with low neutrophil count are susceptible to frequent infections. Linkage and association between congenital neutropenia and a single rare missense variant in TCIRG1 have been reported in a single family. Here, we report on nine rare missense variants at evolutionarily conserved sites in TCIRG1 that are associated with lower absolute neutrophil count (ANC; p = 0.005) in 1,058 participants from three cohorts: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and Jackson Heart Study (JHS) of the NHLBI Grand Opportunity Exome Sequencing Project (GO ESP). These results validate the effects of TCIRG1 coding variation on ANC and suggest that this gene may be associated with a spectrum of mild to severe effects on ANC.

}, keywords = {Adult, Aged, Aged, 80 and over, Alleles, Cohort Studies, Female, Gene Frequency, Genotype, High-Throughput Nucleotide Sequencing, Humans, Leukocyte Count, Male, Middle Aged, Mutation, Missense, National Heart, Lung, and Blood Institute (U.S.), Neutropenia, Neutrophils, Sequence Analysis, DNA, United States, Vacuolar Proton-Translocating ATPases}, issn = {1098-2272}, doi = {10.1002/gepi.21976}, author = {Rosenthal, Elisabeth A and Makaryan, Vahagn and Burt, Amber A and Crosslin, David R and Kim, Daniel Seung and Smith, Joshua D and Nickerson, Deborah A and Reiner, Alex P and Rich, Stephen S and Jackson, Rebecca D and Ganesh, Santhi K and Polfus, Linda M and Qi, Lihong and Dale, David C and Jarvik, Gail P} } @article {58, title = {Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 07 01}, pages = {836-845}, abstract = {

IMPORTANCE: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality.

OBJECTIVE: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.

DESIGN, SETTING, AND PARTICIPANTS: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children{\textquoteright}s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.

RESULTS: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.

CONCLUSIONS AND RELEVANCE: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.

}, keywords = {Adolescent, Adult, Amino Acids, Animals, Cells, Cultured, Cerebral Cortex, Child, Child, Preschool, Developmental Disabilities, Embryo, Mammalian, Female, Gene Expression Regulation, Genetic Association Studies, Humans, Intercellular Signaling Peptides and Proteins, Male, Malformations of Cortical Development, Mechanistic Target of Rapamycin Complex 1, Megalencephaly, Mosaicism, Multiprotein Complexes, Mutation, Nerve Tissue Proteins, Neurons, Rats, Retrospective Studies, TOR Serine-Threonine Kinases, Young Adult}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2016.0363}, author = {Mirzaa, Ghayda M and Campbell, Catarina D and Solovieff, Nadia and Goold, Carleton and Jansen, Laura A and Menon, Suchithra and Timms, Andrew E and Conti, Valerio and Biag, Jonathan D and Adams, Carissa and Boyle, Evan August and Collins, Sarah and Ishak, Gisele and Poliachik, Sandra and Girisha, Katta M and Yeung, Kit San and Chung, Brian Hon Yin and Rahikkala, Elisa and Gunter, Sonya A and McDaniel, Sharon S and Macmurdo, Colleen Forsyth and Bernstein, Jonathan A and Martin, Beth and Leary, Rebecca and Mahan, Scott and Liu, Shanming and Weaver, Molly and Doerschner, Michael and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Shendure, Jay and Saneto, Russell P and Novotny, Edward J and Wilson, Christopher J and Sellers, William R and Morrissey, Michael and Hevner, Robert F and Ojemann, Jeffrey G and Guerrini, Renzo and Murphy, Leon O and Winckler, Wendy and Dobyns, William B} } @article {49, title = {Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Jun 02}, pages = {1146-1158}, abstract = {

Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in~vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.

}, keywords = {Adolescent, Adult, Cerebellar Ataxia, Child, Chromosome Aberrations, Chromosomes, Human, Pair 7, Exome, Female, Genetic Linkage, Genotype, High-Throughput Nucleotide Sequencing, Humans, Intracellular Signaling Peptides and Proteins, Loss of Heterozygosity, Male, Middle Aged, Mutation, Missense, Pancytopenia, Pedigree, Proteins, Tumor Suppressor Proteins, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.009}, author = {Chen, Dong-Hui and Below, Jennifer E and Shimamura, Akiko and Keel, Sioban B and Matsushita, Mark and Wolff, John and Sul, Youngmee and Bonkowski, Emily and Castella, Maria and Taniguchi, Toshiyasu and Nickerson, Deborah and Papayannopoulou, Thalia and Bird, Thomas D and Raskind, Wendy H} } @article {99, title = {Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Jan 07}, pages = {202-9}, abstract = {

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. UNC80 is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Loss-of-function mutations of NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF). We report four individuals from three unrelated families who have homozygous missense or compound heterozygous truncating mutations in UNC80 and persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability. Compared to control cells, HEK293T cells transfected with an expression plasmid containing the c.5098C>T (p.Pro1700Ser) UNC80 mutation found in one individual showed markedly decreased NALCN channel currents. Our findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health.

}, keywords = {Adolescent, Alleles, Brain Diseases, Carrier Proteins, Child, Child, Preschool, Female, Growth Disorders, Humans, Intellectual Disability, Membrane Proteins, Muscle Hypotonia, Mutation, Severity of Illness Index}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.11.004}, author = {Stray-Pedersen, Asbj{\o}rg and Cobben, Jan-Maarten and Prescott, Trine E and Lee, Sora and Cang, Chunlei and Aranda, Kimberly and Ahmed, Sohnee and Alders, Marielle and Gerstner, Thorsten and Aslaksen, Kathinka and T{\'e}treault, Martine and Qin, Wen and Hartley, Taila and Jhangiani, Shalini N and Muzny, Donna M and Tarailo-Graovac, Maja and van Karnebeek, Clara D M and Lupski, James R and Ren, Dejian and Yoon, Grace} } @article {60, title = {The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 06}, pages = {648-56}, abstract = {

Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.

}, keywords = {Animals, Ciliopathies, Flagella, Humans, Mice, Mutation, Phenotype, Protein Binding, Protein Transport, Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3558}, author = {Toriyama, Michinori and Lee, Chanjae and Taylor, S Paige and Duran, Ivan and Cohn, Daniel H and Bruel, Ange-Line and Tabler, Jacqueline M and Drew, Kevin and Kelly, Marcus R and Kim, Sukyoung and Park, Tae Joo and Braun, Daniela A and Pierquin, Ghislaine and Biver, Armand and Wagner, Kerstin and Malfroot, Anne and Panigrahi, Inusha and Franco, Brunella and Al-Lami, Hadeel Adel and Yeung, Yvonne and Choi, Yeon Ja and Duffourd, Yannis and Faivre, Laurence and Rivi{\`e}re, Jean-Baptiste and Chen, Jiang and Liu, Karen J and Marcotte, Edward M and Hildebrandt, Friedhelm and Thauvin-Robinet, Christel and Krakow, Deborah and Jackson, Peter K and Wallingford, John B} } @article {30, title = {Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Aug 04}, pages = {318-36}, abstract = {

Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5\%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture.

}, keywords = {Adolescent, Adult, Alleles, Animals, Bardet-Biedl Syndrome, Child, Child, Preschool, Chromosome Breakpoints, Cytoskeletal Proteins, DNA Copy Number Variations, Exons, Female, Gastrulation, Genes, Recessive, Humans, Infant, Male, Mutation, Pedigree, Young Adult, Zebrafish, Zebrafish Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.04.023}, author = {Lindstrand, Anna and Frangakis, Stephan and Carvalho, Claudia M B and Richardson, Ellen B and McFadden, Kelsey A and Willer, Jason R and Pehlivan, Davut and Liu, Pengfei and Pediaditakis, Igor L and Sabo, Aniko and Lewis, Richard Alan and Banin, Eyal and Lupski, James R and Davis, Erica E and Katsanis, Nicholas} } @article {69, title = {De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Apr}, pages = {e1005963}, abstract = {

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32\% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

}, keywords = {Animals, Female, Heart Septal Defects, Heterozygote, Homozygote, Humans, Male, Mice, Mice, Knockout, Mutation, Pedigree}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1005963}, author = {Priest, James R and Osoegawa, Kazutoyo and Mohammed, Nebil and Nanda, Vivek and Kundu, Ramendra and Schultz, Kathleen and Lammer, Edward J and Girirajan, Santhosh and Scheetz, Todd and Waggott, Daryl and Haddad, Francois and Reddy, Sushma and Bernstein, Daniel and Burns, Trudy and Steimle, Jeffrey D and Yang, Xinan H and Moskowitz, Ivan P and Hurles, Matthew and Lifton, Richard P and Nickerson, Debbie and Bamshad, Michael and Eichler, Evan E and Mital, Seema and Sheffield, Val and Quertermous, Thomas and Gelb, Bruce D and Portman, Michael and Ashley, Euan A} } @article {414, title = {De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 12}, pages = {1399-1409}, abstract = {

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Exome, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heart Defects, Congenital, Humans, Intellectual Disability, Male, Mutation, Missense, Phosphorylation, Protein Phosphatase 1}, issn = {1432-1203}, doi = {10.1007/s00439-016-1731-1}, author = {Ma, Lijiang and Bayram, Yavuz and McLaughlin, Heather M and Cho, Megan T and Krokosky, Alyson and Turner, Clesson E and Lindstrom, Kristin and Bupp, Caleb P and Mayberry, Katey and Mu, Weiyi and Bodurtha, Joann and Weinstein, Veronique and Zadeh, Neda and Alcaraz, Wendy and Powis, Z{\"o}e and Shao, Yunru and Scott, Daryl A and Lewis, Andrea M and White, Janson J and Jhangiani, Shalani N and Gulec, Elif Yilmaz and Lalani, Seema R and Lupski, James R and Retterer, Kyle and Schnur, Rhonda E and Wentzensen, Ingrid M and Bale, Sherri and Chung, Wendy K} } @article {28, title = {De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Sep 01}, pages = {711-719}, abstract = {

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and~HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

}, keywords = {Animals, Brain, Developmental Disabilities, DNA-Binding Proteins, Eye Abnormalities, Female, Genes, Essential, Haploinsufficiency, Head, Heterozygote, Humans, Intellectual Disability, Male, Metabolic Diseases, Minor Histocompatibility Antigens, Mutation, Pedigree, RNA Splicing, RNA, Messenger, Spine, Syndrome, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.06.029}, author = {Kim, Jung-Hyun and Shinde, Deepali N and Reijnders, Margot R F and Hauser, Natalie S and Belmonte, Rebecca L and Wilson, Gregory R and Bosch, Dani{\"e}lle G M and Bubulya, Paula A and Shashi, Vandana and Petrovski, Slav{\'e} and Stone, Joshua K and Park, Eun Young and Veltman, Joris A and Sinnema, Margje and Stumpel, Connie T R M and Draaisma, Jos M and Nicolai, Joost and Yntema, Helger G and Lindstrom, Kristin and de Vries, Bert B A and Jewett, Tamison and Santoro, Stephanie L and Vogt, Julie and Bachman, Kristine K and Seeley, Andrea H and Krokosky, Alyson and Turner, Clesson and Rohena, Luis and Hempel, Maja and Kort{\"u}m, Fanny and Lessel, Davor and Neu, Axel and Strom, Tim M and Wieczorek, Dagmar and Bramswig, Nuria and Laccone, Franco A and Behunova, Jana and Rehder, Helga and Gordon, Christopher T and Rio, Marl{\`e}ne and Romana, Serge and Tang, Sha and El-Khechen, Dima and Cho, Megan T and McWalter, Kirsty and Douglas, Ganka and Baskin, Berivan and Begtrup, Amber and Funari, Tara and Schoch, Kelly and Stegmann, Alexander P A and Stevens, Servi J C and Zhang, Dong-Er and Traver, David and Yao, Xu and MacArthur, Daniel G and Brunner, Han G and Mancini, Grazia M and Myers, Richard M and Owen, Laurie B and Lim, Ssang-Taek and Stachura, David L and Vissers, Lisenka E L M and Ahn, Eun-Young Erin} } @article {98, title = {Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease.}, journal = {Am J Respir Crit Care Med}, volume = {193}, year = {2016}, month = {2016 06 15}, pages = {1353-63}, abstract = {

RATIONALE: Genomic regions identified by genome-wide association studies explain only a small fraction of heritability for chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin deficiency shows that rare coding variants of large effect also influence COPD susceptibility. We hypothesized that exome sequencing in families identified through a proband with severe, early-onset COPD would identify additional rare genetic determinants of large effect.

OBJECTIVES: To identify rare genetic determinants of severe COPD.

METHODS: We applied filtering approaches to identify potential causal variants for COPD in whole exomes from 347 subjects in 49 extended pedigrees from the Boston Early-Onset COPD Study. We assessed the power of this approach under different levels of genetic heterogeneity using simulations. We tested genes identified in these families using gene-based association tests in exomes of 204 cases with severe COPD and 195 resistant smokers from the COPDGene study. In addition, we examined previously described loci associated with COPD using these datasets.

MEASUREMENTS AND MAIN RESULTS: We identified 69 genes with predicted deleterious nonsynonymous, stop, or splice variants that segregated with severe COPD in at least two pedigrees. Four genes (DNAH8, ALCAM, RARS, and GBF1) also demonstrated an increase in rare nonsynonymous, stop, and/or splice mutations in cases compared with resistant smokers from the COPDGene study; however, these results were not statistically significant. We demonstrate the limitations of the power of this approach under genetic heterogeneity through simulation.

CONCLUSIONS: Rare deleterious coding variants may increase risk for COPD, but multiple genes likely contribute to COPD susceptibility.

}, keywords = {Adult, alpha 1-Antitrypsin Deficiency, Boston, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Severity of Illness Index}, issn = {1535-4970}, doi = {10.1164/rccm.201506-1223OC}, author = {Qiao, Dandi and Lange, Christoph and Beaty, Terri H and Crapo, James D and Barnes, Kathleen C and Bamshad, Michael and Hersh, Craig P and Morrow, Jarrett and Pinto-Plata, Victor M and Marchetti, Nathaniel and Bueno, Raphael and Celli, Bartolome R and Criner, Gerald J and Silverman, Edwin K and Cho, Michael H} } @article {417, title = {Exome sequencing identifies a de novo frameshift mutation in the imprinted gene ZDBF2 in a sporadic patient with Nasopalpebral Lipoma-coloboma syndrome.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 07}, pages = {1934-7}, abstract = {

Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM\%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245_6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Abnormalities, Multiple, Base Sequence, Child, Preschool, Coloboma, DNA-Binding Proteins, Exome, Eyelid Neoplasms, Female, Frameshift Mutation, Genomic Imprinting, Humans, Lipoma, Pedigree}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37683}, author = {Chac{\'o}n-Camacho, Oscar F and Sobreira, Nara and You, Jing and Pi{\~n}a-Aguilar, Raul E and Villegas-Ruiz, Vanessa and Zenteno, Juan C} } @article {32, title = {Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Aug 04}, pages = {337-51}, abstract = {

In \~{}30\% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals{\textquoteright} tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.

}, keywords = {Adenomatous Polyposis Coli, Adolescent, Adult, Alleles, Child, Preschool, Colorectal Neoplasms, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Female, Genes, Recessive, Germ-Line Mutation, Humans, Male, Middle Aged, Mismatch Repair Endonuclease PMS2, MutS Homolog 3 Protein, Pedigree}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.06.015}, author = {Adam, Ronja and Spier, Isabel and Zhao, Bixiao and Kloth, Michael and Marquez, Jonathan and Hinrichsen, Inga and Kirfel, Jutta and Tafazzoli, Aylar and Horpaopan, Sukanya and Uhlhaas, Siegfried and Stienen, Dietlinde and Friedrichs, Nicolaus and Altm{\"u}ller, Janine and Laner, Andreas and Holzapfel, Stefanie and Peters, Sophia and Kayser, Katrin and Thiele, Holger and Holinski-Feder, Elke and Marra, Giancarlo and Kristiansen, Glen and N{\"o}then, Markus M and B{\"u}ttner, Reinhard and M{\"o}slein, Gabriela and Betz, Regina C and Brieger, Angela and Lifton, Richard P and Aretz, Stefan} } @article {93, title = {Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis.}, journal = {Fam Cancer}, volume = {15}, year = {2016}, month = {2016 Apr}, pages = {281-8}, abstract = {

In up to 30\% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative genes, exome sequencing was performed using DNA from leukocytes and a total of 12 colorectal adenomas from seven unrelated patients with unexplained sporadic adenomatous polyposis. For data analysis and variant filtering, an established bioinformatics pipeline including in-house tools was applied. Variants were filtered for rare truncating point mutations and copy-number variants assuming a dominant, recessive, or tumor suppressor model of inheritance. Subsequently, targeted sequence analysis of the most promising candidate genes was performed in a validation cohort of 191 unrelated patients. All relevant variants were validated by Sanger sequencing. The analysis of exome sequencing data resulted in the identification of rare loss-of-function germline mutations in three promising candidate genes (DSC2, PIEZO1, ZSWIM7). In the validation cohort, further variants predicted to be pathogenic were identified in DSC2 and PIEZO1. According to the somatic mutation spectra, the adenomas in this patient cohort follow the classical pathways of colorectal tumorigenesis. The present study identified three candidate genes which might represent rare causes for a predisposition to colorectal adenoma formation. Especially PIEZO1 (FAM38A) and ZSWIM7 (SWS1) warrant further exploration. To evaluate the clinical relevance of these genes, investigation of larger patient cohorts and functional studies are required.

}, keywords = {Adenomatous Polyposis Coli, Adenomatous Polyps, Aged, Desmocollins, Exome, Female, Genetic Predisposition to Disease, Germ-Line Mutation, High-Throughput Nucleotide Sequencing, Humans, Ion Channels, Male, Middle Aged, Reproducibility of Results}, issn = {1573-7292}, doi = {10.1007/s10689-016-9870-z}, author = {Spier, Isabel and Kerick, Martin and Drichel, Dmitriy and Horpaopan, Sukanya and Altm{\"u}ller, Janine and Laner, Andreas and Holzapfel, Stefanie and Peters, Sophia and Adam, Ronja and Zhao, Bixiao and Becker, Tim and Lifton, Richard P and Holinski-Feder, Elke and Perner, Sven and Thiele, Holger and N{\"o}then, Markus M and Hoffmann, Per and Timmermann, Bernd and Schweiger, Michal R and Aretz, Stefan} } @article {39, title = {Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate.}, journal = {BMC Med Genomics}, volume = {9}, year = {2016}, month = {2016 Jul 19}, pages = {42}, abstract = {

BACKGROUND: Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saudi Arabia with primarily Mendelian neurologic diseases.

METHODS: We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CNVs) from WES data. Interaction/expression network and pathway analyses, as well as paralog studies were utilized to investigate potential pathogenicity and disease association of novel candidate genes. Additional cases for candidate genes were identified through the clinical WES database at Baylor Miraca Genetics Laboratories and GeneMatcher.

RESULTS: We found known pathogenic or novel variants in known disease genes with phenotypic expansion in 6 families, disease-associated CNVs in 2 families, and 12 novel disease gene candidates in 11 families, including KIF5B, GRM7, FOXP4, MLLT1, and KDM2B. Overall, a potential molecular diagnosis was provided by variants in known disease genes in 17 families (54.8~\%) and by novel candidate disease genes in an additional 11 families, making the potential molecular diagnostic rate ~90~\%.

CONCLUSIONS: Molecular diagnostic rate from WES is improved by exome-predicted CNVs. Novel candidate disease gene discovery is facilitated by paralog studies and through the use of informatics tools and available databases to identify additional evidence for pathogenicity.

TRIAL REGISTRATION: Not applicable.

}, keywords = {Arabs, Cohort Studies, Consanguinity, Data Mining, Databases, Genetic, DNA Copy Number Variations, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Molecular Diagnostic Techniques, Nervous System Diseases, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1755-8794}, doi = {10.1186/s12920-016-0208-3}, author = {Charng, Wu-Lin and Karaca, Ender and Coban Akdemir, Zeynep and Gambin, Tomasz and Atik, Mehmed M and Gu, Shen and Posey, Jennifer E and Jhangiani, Shalini N and Muzny, Donna M and Doddapaneni, Harsha and Hu, Jianhong and Boerwinkle, Eric and Gibbs, Richard A and Rosenfeld, Jill A and Cui, Hong and Xia, Fan and Manickam, Kandamurugu and Yang, Yaping and Faqeih, Eissa A and Al Asmari, Ali and Saleh, Mohammed A M and El-Hattab, Ayman W and Lupski, James R} } @article {533, title = {Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Oct}, pages = {e1006335}, abstract = {

Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.

}, keywords = {Aortic Valve, Codon, Nonsense, Constriction, Pathologic, Exome, Female, Genetic Association Studies, Genetic Linkage, Genome, Human, Heart Defects, Congenital, Humans, Male, Pedigree, Receptor, Notch1, Receptors, Notch, Sequence Deletion, Signal Transduction, Ventricular Outflow Obstruction}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006335}, author = {Preuss, Christoph and Capredon, Melanie and W{\"u}nnemann, Florian and Chetaille, Philippe and Prince, Andrea and Godard, Beatrice and Leclerc, Severine and Sobreira, Nara and Ling, Hua and Awadalla, Philip and Thibeault, Maryse and Khairy, Paul and Samuels, Mark E and Andelfinger, Gregor} } @article {45, title = {FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.}, journal = {Genet Epidemiol}, volume = {40}, year = {2016}, month = {2016 Sep}, pages = {475-85}, abstract = {

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods.

}, keywords = {Alleles, Chromosomes, Human, X, Female, Genes, X-Linked, Genetic Variation, Humans, Models, Genetic, Pedigree, Phenotype, X Chromosome Inactivation}, issn = {1098-2272}, doi = {10.1002/gepi.21979}, author = {Choi, Sungkyoung and Lee, Sungyoung and Qiao, Dandi and Hardin, Megan and Cho, Michael H and Silverman, Edwin K and Park, Taesung and Won, Sungho} } @article {80, title = {FAT1 mutations cause a glomerulotubular nephropathy.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 Feb 24}, pages = {10822}, abstract = {

Steroid-resistant nephrotic syndrome (SRNS) causes 15\% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

}, keywords = {Animals, Cadherins, cdc42 GTP-Binding Protein, Cell Adhesion, Cell Movement, Dilatation, Pathologic, Fibroblasts, Gene Knockdown Techniques, Hematuria, Humans, Kidney Tubules, Lissencephaly, Mice, Mutation, Nephrotic Syndrome, Podocytes, rac1 GTP-Binding Protein, Syndrome, Zebrafish, Zebrafish Proteins}, issn = {2041-1723}, doi = {10.1038/ncomms10822}, author = {Gee, Heon Yung and Sadowski, Carolin E and Aggarwal, Pardeep K and Porath, Jonathan D and Yakulov, Toma A and Schueler, Markus and Lovric, Svjetlana and Ashraf, Shazia and Braun, Daniela A and Halbritter, Jan and Fang, Humphrey and Airik, Rannar and Vega-Warner, Virginia and Cho, Kyeong Jee and Chan, Timothy A and Morris, Luc G T and ffrench-Constant, Charles and Allen, Nicholas and McNeill, Helen and B{\"u}scher, Rainer and Kyrieleis, Henriette and Wallot, Michael and Gaspert, Ariana and Kistler, Thomas and Milford, David V and Saleem, Moin A and Keng, Wee Teik and Alexander, Stephen I and Valentini, Rudolph P and Licht, Christoph and Teh, Jun C and Bogdanovic, Radovan and Koziell, Ania and Bierzynska, Agnieszka and Soliman, Neveen A and Otto, Edgar A and Lifton, Richard P and Holzman, Lawrence B and Sibinga, Nicholas E S and Walz, Gerd and Tufro, Alda and Hildebrandt, Friedhelm} } @article {86, title = {FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.}, journal = {J Clin Invest}, volume = {126}, year = {2016}, month = {2016 Mar 01}, pages = {948-61}, abstract = {

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

}, keywords = {Adult, Aneurysm, Dissecting, Animals, Aorta, Aortic Aneurysm, Thoracic, Apoptosis, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Female, Forkhead Transcription Factors, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Muscle, Smooth, Vascular, Mutation, Missense, Myocytes, Smooth Muscle, Pedigree, Tumor Suppressor Protein p53, Vascular Remodeling, Zebrafish}, issn = {1558-8238}, doi = {10.1172/JCI83778}, author = {Kuang, Shao-Qing and Medina-Martinez, Olga and Guo, Dong-Chuan and Gong, Limin and Regalado, Ellen S and Reynolds, Corey L and Boileau, Catherine and Jondeau, Guillaume and Prakash, Siddharth K and Kwartler, Callie S and Zhu, Lawrence Yang and Peters, Andrew M and Duan, Xue-Yan and Bamshad, Michael J and Shendure, Jay and Nickerson, Debbie A and Santos-Cortez, Regie L and Dong, Xiurong and Leal, Suzanne M and Majesky, Mark W and Swindell, Eric C and Jamrich, Milan and Milewicz, Dianna M} } @article {105, title = {Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 08}, pages = {788-95}, abstract = {

PURPOSE: The pace of Mendelian gene discovery is slowed by the "n-of-1 problem"-the difficulty of establishing the causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier, but it is often impeded by lack of a convenient or widely available way to share data on candidate variants/genes among families, clinicians, and researchers.

METHODS: Social networking among families, clinicians, and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.

RESULTS: De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.

CONCLUSION: Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with nonspecific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP; http://uwcmg.org/$\#$/family). Design and development of MyGene2 (http://www.mygene2.org), a Web-based tool that enables families, clinicians, and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP, is under way.Genet Med 18 8, 788-795.

}, keywords = {Child, Child, Preschool, Databases, Factual, Developmental Disabilities, Female, Genetic Association Studies, Histone Demethylases, Humans, Information Dissemination, Male, Mutation, Missense, Phenotype, Social Networking, Web Browser}, issn = {1530-0366}, doi = {10.1038/gim.2015.161}, author = {Chong, Jessica X and Yu, Joon-Ho and Lorentzen, Peter and Park, Karen M and Jamal, Seema M and Tabor, Holly K and Rauch, Anita and Saenz, Margarita Sifuentes and Boltshauser, Eugen and Patterson, Karynne E and Nickerson, Deborah A and Bamshad, Michael J} } @article {64, title = {Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0153864}, abstract = {

Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS.

}, keywords = {Apraxias, DNA Copy Number Variations, Exome, Female, Genetic Linkage, Genetic Predisposition to Disease, Genotype, Humans, Lod Score, Male, Pedigree, Risk, Speech}, issn = {1932-6203}, doi = {10.1371/journal.pone.0153864}, author = {Peter, Beate and Wijsman, Ellen M and Nato, Alejandro Q and Matsushita, Mark M and Chapman, Kathy L and Stanaway, Ian B and Wolff, John and Oda, Kaori and Gabo, Virginia B and Raskind, Wendy H} } @article {13, title = {A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 06 01}, pages = {2331-2341}, abstract = {

Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 {\texttimes} 10 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 {\texttimes} 10, odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 {\texttimes} 10, OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 {\texttimes} 10 for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 {\texttimes} 10 for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.

}, keywords = {Chromosome Mapping, Chromosomes, Human, Pair 20, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Defects, Congenital, Heart Ventricles, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddw071}, author = {Hanchard, Neil A and Swaminathan, Shanker and Bucasas, Kristine and Furthner, Dieter and Fernbach, Susan and Azamian, Mahshid S and Wang, Xueqing and Lewin, Mark and Towbin, Jeffrey A and D{\textquoteright}Alessandro, Lisa C A and Morris, Shaine A and Dreyer, William and Denfield, Susan and Ayres, Nancy A and Franklin, Wayne J and Justino, Henri and Lantin-Hermoso, M Regina and Ocampo, Elena C and Santos, Alexia B and Parekh, Dhaval and Moodie, Douglas and Jeewa, Aamir and Lawrence, Emily and Allen, Hugh D and Penny, Daniel J and Fraser, Charles D and Lupski, James R and Popoola, Mojisola and Wadhwa, Lalita and Brook, J David and Bu{\textquoteright}Lock, Frances A and Bhattacharya, Shoumo and Lalani, Seema R and Zender, Gloria A and Fitzgerald-Butt, Sara M and Bowman, Jessica and Corsmeier, Don and White, Peter and Lecerf, Kelsey and Zapata, Gladys and Hernandez, Patricia and Goodship, Judith A and Garg, Vidu and Keavney, Bernard D and Leal, Suzanne M and Cordell, Heather J and Belmont, John W and McBride, Kim L} } @article {65, title = {Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 05 05}, pages = {1001-1010}, abstract = {

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein~subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p~=~7.1~{\texttimes} 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Germ-Line Mutation, GTP-Binding Protein beta Subunits, Humans, Infant, Intellectual Disability, Male, Muscle Hypotonia, Phenotype, Protein Conformation, Seizures, Signal Transduction, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.011}, author = {Petrovski, Slav{\'e} and K{\"u}ry, S{\'e}bastien and Myers, Candace T and Anyane-Yeboa, Kwame and Cogn{\'e}, Benjamin and Bialer, Martin and Xia, Fan and Hemati, Parisa and Riviello, James and Mehaffey, Michele and Besnard, Thomas and Becraft, Emily and Wadley, Alexandrea and Politi, Anya Revah and Colombo, Sophie and Zhu, Xiaolin and Ren, Zhong and Andrews, Ian and Dudding-Byth, Tracy and Schneider, Amy L and Wallace, Geoffrey and Rosen, Aaron B I and Schelley, Susan and Enns, Gregory M and Corre, Pierre and Dalton, Joline and Mercier, Sandra and Latypova, X{\'e}nia and Schmitt, S{\'e}bastien and Guzman, Edwin and Moore, Christine and Bier, Louise and Heinzen, Erin L and Karachunski, Peter and Shur, Natasha and Grebe, Theresa and Basinger, Alice and Nguyen, Joanne M and B{\'e}zieau, St{\'e}phane and Wierenga, Klaas and Bernstein, Jonathan A and Scheffer, Ingrid E and Rosenfeld, Jill A and Mefford, Heather C and Isidor, Bertrand and Goldstein, David B} } @article {126, title = {Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 Jan}, pages = {156-61}, abstract = {

The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, DNA-Binding Proteins, Exome, Face, Female, Hand Deformities, Congenital, Heterozygote, Humans, Intellectual Disability, Male, Micrognathism, Mosaicism, Mutation, Neck, Pedigree, Siblings, Transcription Factors}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37405}, author = {Ben-Salem, Salma and Sobreira, Nara and Akawi, Nadia A and Al-Shamsi, Aisha M and John, Anne and Pramathan, Thachillath and Valle, David and Ali, Bassam R and Al-Gazali, Lihadh} } @article {91, title = {Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death.}, journal = {Mol Genet Genomic Med}, volume = {4}, year = {2016}, month = {2016 Jan}, pages = {77-94}, abstract = {

BACKGROUND: Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30~years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown.

METHODS: We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds.

RESULTS: Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts (LOD~=~9.62). SNP-based fine mapping within the 9.5~Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg).

CONCLUSION: We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2.

}, issn = {2324-9269}, doi = {10.1002/mgg3.181}, author = {Boone, Philip M and Yuan, Bo and Gu, Shen and Ma, Zhiwei and Gambin, Tomasz and Gonzaga-Jauregui, Claudia and Jain, Mahim and Murdock, Todd J and White, Janson J and Jhangiani, Shalini N and Walker, Kimberly and Wang, Qiaoyan and Muzny, Donna M and Gibbs, Richard A and Hejtmancik, J Fielding and Lupski, James R and Posey, Jennifer E and Lewis, Richard A} } @article {72, title = {Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.}, journal = {N Engl J Med}, volume = {374}, year = {2016}, month = {2016 Mar 17}, pages = {1032-1043}, abstract = {

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10\% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells.

METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates.

RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients.

CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

}, keywords = {Adolescent, Adult, Antigens, CD, B-Lymphocytes, Bone Marrow, Bone Marrow Examination, Child, Child, Preschool, Chromosomes, Human, Pair 7, Common Variable Immunodeficiency, Exome, Female, Heterozygote, Humans, Ikaros Transcription Factor, Immunoglobulin G, Lymphocyte Count, Male, Mutation, Pedigree, Sequence Analysis, DNA}, issn = {1533-4406}, doi = {10.1056/NEJMoa1512234}, author = {Kuehn, H S and Boisson, B and Cunningham-Rundles, C and Reichenbach, J and Stray-Pedersen, A and Gelfand, E W and Maffucci, P and Pierce, K R and Abbott, J K and Voelkerding, K V and South, S T and Augustine, N H and Bush, J S and Dolen, W K and Wray, B B and Itan, Y and Cobat, A and Sorte, H S and Ganesan, S and Prader, S and Martins, T B and Lawrence, M G and Orange, J S and Calvo, K R and Niemela, J E and Casanova, J-L and Fleisher, T A and Hill, H R and Kum{\'a}novics, A and Conley, M E and Rosenzweig, S D} } @article {354, title = {Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 05 15}, pages = {1923-1933}, abstract = {

Elevated sweat chloride levels, failure to thrive (FTT), and lung disease are characteristic features of cystic fibrosis (CF, OMIM $\#$219700). Here we describe variants in CA12 encoding carbonic anhydrase XII in two pedigrees exhibiting CF-like phenotypes. Exome sequencing of a white American adult diagnosed with CF due to elevated sweat chloride, recurrent hyponatremia, infantile FTT and lung disease identified deleterious variants in each CA12 gene: c.908-1 G>A in a splice acceptor and a novel frameshift insertion c.859_860insACCT. In an unrelated consanguineous Omani family, two children with elevated sweat chloride, infantile FTT, and recurrent hyponatremia were homozygous for a novel missense variant (p.His121Gln). Deleterious CFTR variants were absent in both pedigrees. CA XII protein was localized apically in human bronchiolar epithelia and basolaterally in the reabsorptive duct of human sweat glands. Respiratory epithelial cell RNA from the adult proband revealed only aberrant CA12 transcripts and in vitro analysis showed greatly reduced CA XII protein. Studies of ion transport across respiratory epithelial cells in vivo and in culture revealed intact CFTR-mediated chloride transport in the adult proband. CA XII protein bearing either p.His121Gln or a previously identified p.Glu143Lys missense variant localized to the basolateral membranes of polarized Madin-Darby canine kidney (MDCK) cells, but enzyme activity was severely diminished when assayed at physiologic concentrations of extracellular chloride. Our findings indicate that loss of CA XII function should be considered in individuals without CFTR mutations who exhibit CF-like features in the sweat gland and lung.

}, keywords = {Adolescent, Adult, Animals, Carbonic Anhydrases, Child, Child, Preschool, Chlorides, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Dogs, Female, Gene Expression Regulation, Enzymologic, Homozygote, Humans, Lung, Lung Diseases, Madin Darby Canine Kidney Cells, Male, Mutation, Pedigree, Phenotype, Sweat}, issn = {1460-2083}, doi = {10.1093/hmg/ddw065}, author = {Lee, Melissa and Vecchio-Pag{\'a}n, Briana and Sharma, Neeraj and Waheed, Abdul and Li, Xiaopeng and Raraigh, Karen S and Robbins, Sarah and Han, Sangwoo T and Franca, Arianna L and Pellicore, Matthew J and Evans, Taylor A and Arcara, Kristin M and Nguyen, Hien and Luan, Shan and Belchis, Deborah and Hertecant, Jozef and Zabner, Joseph and Sly, William S and Cutting, Garry R} } @article {51, title = {Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 06 02}, pages = {1249-1255}, abstract = {

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

}, keywords = {alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Brain Diseases, Electrophysiology, Epilepsy, Female, Humans, Hyperkinesis, Infant, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree, Synaptic Transmission}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.008}, author = {Madeo, Marianna and Stewart, Michelle and Sun, Yuyang and Sahir, Nadia and Wiethoff, Sarah and Chandrasekar, Indra and Yarrow, Anna and Rosenfeld, Jill A and Yang, Yaping and Cordeiro, Dawn and McCormick, Elizabeth M and Muraresku, Colleen C and Jepperson, Tyler N and McBeth, Lauren J and Seidahmed, Mohammed Zain and El Khashab, Heba Y and Hamad, Muddathir and Azzedine, Hamid and Clark, Karl and Corrochano, Silvia and Wells, Sara and Elting, Mariet W and Weiss, Marjan M and Burn, Sabrina and Myers, Angela and Landsverk, Megan and Crotwell, Patricia L and Waisfisz, Quinten and Wolf, Nicole I and Nolan, Patrick M and Padilla-Lopez, Sergio and Houlden, Henry and Lifton, Richard and Mane, Shrikant and Singh, Brij B and Falk, Marni J and Mercimek-Mahmutoglu, Saadet and Bilguvar, Kaya and Salih, Mustafa A and Acevedo-Arozena, Abraham and Kruer, Michael C} } @article {112, title = {Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 Mar}, pages = {172-9}, abstract = {

BACKGROUND: In 30-50\% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis.

METHODS: To comprehensively screen for somatic low-level APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in >= 2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods.

RESULTS: In 25\% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1\%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene.

CONCLUSIONS: The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group.

}, keywords = {Adenomatous Polyposis Coli, Adolescent, Adult, Colorectal Neoplasms, Genes, APC, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Mutation, Mutation Rate}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103468}, author = {Spier, Isabel and Drichel, Dmitriy and Kerick, Martin and Kirfel, Jutta and Horpaopan, Sukanya and Laner, Andreas and Holzapfel, Stefanie and Peters, Sophia and Adam, Ronja and Zhao, Bixiao and Becker, Tim and Lifton, Richard P and Perner, Sven and Hoffmann, Per and Kristiansen, Glen and Timmermann, Bernd and N{\"o}then, Markus M and Holinski-Feder, Elke and Schweiger, Michal R and Aretz, Stefan} } @article {119, title = {Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.}, journal = {Hum Mutat}, volume = {37}, year = {2016}, month = {2016 Feb}, pages = {160-4}, abstract = {

Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density microarray and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother, the fetus, and her later born son. This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother. We mapped two breakpoint junctions and demonstrated that both are mediated by Alu repetitive elements and identical in these four individuals. We propose a three-step process combining Alu-mediated replicative-repair-based mechanism(s) and intergenerational, intrachromosomal nonallelic homologous recombination to generate the quadruplications in this family.

}, keywords = {14-3-3 Proteins, Adult, Aged, Alu Elements, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Chromosome Duplication, Chromosomes, Human, Pair 17, DNA Copy Number Variations, Female, Genetic Loci, Genome, Human, Hand Deformities, Congenital, Humans, Infant, Male, Molecular Sequence Data, Pedigree, Sequence Alignment, Sequence Analysis, DNA}, issn = {1098-1004}, doi = {10.1002/humu.22929}, author = {Gu, Shen and Posey, Jennifer E and Yuan, Bo and Carvalho, Claudia M B and Luk, H M and Erikson, Kelly and Lo, Ivan F M and Leung, Gordon K C and Pickering, Curtis R and Chung, Brian H Y and Lupski, James R} } @article {342, title = {MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Dec 01}, pages = {1229-1244}, abstract = {

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285), c.247_250del (p.Asn83Hisfs4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

}, keywords = {Basal Ganglia, Cells, Cultured, Child, Child, Preschool, Dystonic Disorders, Fatty Acids, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Mitochondria, Mitochondrial Diseases, Models, Molecular, Mutation, Mutation, Missense, Optic Atrophy, Oxidoreductases Acting on CH-CH Group Donors, Pedigree, RNA Splice Sites, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.021}, author = {Heimer, Gali and Ker{\"a}t{\"a}r, Juha M and Riley, Lisa G and Balasubramaniam, Shanti and Eyal, Eran and Pietik{\"a}inen, Laura P and Hiltunen, J Kalervo and Marek-Yagel, Dina and Hamada, Jeffrey and Gregory, Allison and Rogers, Caleb and Hogarth, Penelope and Nance, Martha A and Shalva, Nechama and Veber, Alvit and Tzadok, Michal and Nissenkorn, Andreea and Tonduti, Davide and Renaldo, Florence and Kraoua, Ichraf and Panteghini, Celeste and Valletta, Lorella and Garavaglia, Barbara and Cowley, Mark J and Gayevskiy, Velimir and Roscioli, Tony and Silberstein, Jonathon M and Hoffmann, Chen and Raas-Rothschild, Annick and Tiranti, Valeria and Anikster, Yair and Christodoulou, John and Kastaniotis, Alexander J and Ben-Zeev, Bruria and Hayflick, Susan J} } @article {10, title = {MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Nov 01}, pages = {106}, abstract = {

BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70~\% of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease.

METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human.

RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients{\textquoteright} missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria.

CONCLUSIONS: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

}, keywords = {Adult, Amino Acid Sequence, Female, Genes, Recessive, Heart Defects, Congenital, Humans, Infant, Infant, Newborn, Male, Metalloendopeptidases, Muscle Hypotonia, Pedigree, Phenotype, Sequence Homology, Amino Acid, Sudden Infant Death, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-016-0360-6}, author = {Eldomery, Mohammad K and Akdemir, Zeynep C and V{\"o}gtle, F-Nora and Charng, Wu-Lin and Mulica, Patrycja and Rosenfeld, Jill A and Gambin, Tomasz and Gu, Shen and Burrage, Lindsay C and Al Shamsi, Aisha and Penney, Samantha and Jhangiani, Shalini N and Zimmerman, Holly H and Muzny, Donna M and Wang, Xia and Tang, Jia and Medikonda, Ravi and Ramachandran, Prasanna V and Wong, Lee-Jun and Boerwinkle, Eric and Gibbs, Richard A and Eng, Christine M and Lalani, Seema R and Hertecant, Jozef and Rodenburg, Richard J and Abdul-Rahman, Omar A and Yang, Yaping and Xia, Fan and Wang, Meng C and Lupski, James R and Meisinger, Chris and Sutton, V Reid} } @article {110, title = {Molecular diagnostic experience of whole-exome sequencing in adult patients.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 07}, pages = {678-85}, abstract = {

PURPOSE: Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults.

METHODS: We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms.

RESULTS: Molecular diagnoses were reported for 17.5\% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2\%; P = 0.0003); the diagnostic rate was higher (23.9\%) for those 18-30 years of age compared to patients older than 30 years (10.4\%; P = 0.0001). Dual Mendelian diagnoses contributed to 7\% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4\% of autosomal dominant diagnoses.

CONCLUSION: Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.Genet Med 18 7, 678-685.

}, keywords = {Adult, Exome, Female, Genetic Diseases, Inborn, Genetic Predisposition to Disease, Genetic Testing, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Male, Pathology, Molecular}, issn = {1530-0366}, doi = {10.1038/gim.2015.142}, author = {Posey, Jennifer E and Rosenfeld, Jill A and James, Regis A and Bainbridge, Matthew and Niu, Zhiyv and Wang, Xia and Dhar, Shweta and Wiszniewski, Wojciech and Akdemir, Zeynep H C and Gambin, Tomasz and Xia, Fan and Person, Richard E and Walkiewicz, Magdalena and Shaw, Chad A and Sutton, V Reid and Beaudet, Arthur L and Muzny, Donna and Eng, Christine M and Yang, Yaping and Gibbs, Richard A and Lupski, James R and Boerwinkle, Eric and Plon, Sharon E} } @article {95, title = {Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin.}, journal = {J Clin Invest}, volume = {126}, year = {2016}, month = {2016 Feb}, pages = {762-78}, abstract = {

BACKGROUND: Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases.

METHODS: We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families.

RESULTS: Affected individuals from 17 families (35.4\%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2\%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2\%) or in another disease-associated genes (6 families, 12.5\%), indicating a potential mutational burden contributing to disease expression.

CONCLUSION: In 58.3\% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis.

FUNDING: This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.

}, keywords = {Arthrogryposis, Exome, Family, Female, Genome-Wide Association Study, Humans, Male, Turkey}, issn = {1558-8238}, doi = {10.1172/JCI84457}, author = {Bayram, Yavuz and Karaca, Ender and Coban Akdemir, Zeynep and Yilmaz, Elif Ozdamar and Tayfun, Gulsen Akay and Aydin, Hatip and Torun, Deniz and Bozdogan, Sevcan Tug and Gezdirici, Alper and Isikay, Sedat and Atik, Mehmed M and Gambin, Tomasz and Harel, Tamar and El-Hattab, Ayman W and Charng, Wu-Lin and Pehlivan, Davut and Jhangiani, Shalini N and Muzny, Donna M and Karaman, Ali and Celik, Tamer and Yuregir, Ozge Ozalp and Yildirim, Timur and Bayhan, Ilhan A and Boerwinkle, Eric and Gibbs, Richard A and Elcioglu, Nursel and Tuysuz, Beyhan and Lupski, James R} } @article {75, title = {Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Mar 03}, pages = {562-570}, abstract = {

The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.

}, keywords = {Adolescent, Alleles, Amino Acid Sequence, Atrophy, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Endoplasmic Reticulum-Associated Degradation, Female, Genetic Association Studies, Genetic Variation, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Muscle Hypotonia, Mutation, Pedigree, Protein Folding, Proteins, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.01.011}, author = {Harel, Tamar and Yesil, G{\"o}zde and Bayram, Yavuz and Coban-Akdemir, Zeynep and Charng, Wu-Lin and Karaca, Ender and Al Asmari, Ali and Eldomery, Mohammad K and Hunter, Jill V and Jhangiani, Shalini N and Rosenfeld, Jill A and Pehlivan, Davut and El-Hattab, Ayman W and Saleh, Mohammed A and LeDuc, Charles A and Muzny, Donna and Boerwinkle, Eric and Gibbs, Richard A and Chung, Wendy K and Yang, Yaping and Belmont, John W and Lupski, James R} } @article {55, title = {Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 09}, pages = {608-15}, abstract = {

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene.

METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes.

RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype.

CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1\% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Cell Cycle Proteins, Cerebellar Diseases, Cerebellum, Child, Ciliopathies, Encephalocele, Eye Abnormalities, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Kidney Diseases, Cystic, Male, Mutation, Mutation Rate, Orofaciodigital Syndromes, Pedigree, Phenotype, Retina, Sequence Alignment}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103832}, author = {Roosing, Susanne and Romani, Marta and Isrie, Mala and Rosti, Rasim Ozgur and Micalizzi, Alessia and Musaev, Damir and Mazza, Tommaso and Al-Gazali, Lihadh and Altunoglu, Umut and Boltshauser, Eugen and D{\textquoteright}Arrigo, Stefano and De Keersmaecker, Bart and Kayserili, H{\"u}lya and Brandenberger, Sarah and Kraoua, Ichraf and Mark, Paul R and McKanna, Trudy and Van Keirsbilck, Joachim and Moerman, Philippe and Poretti, Andrea and Puri, Ratna and Van Esch, Hilde and Gleeson, Joseph G and Valente, Enza Maria} } @article {23, title = {Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {912-916}, abstract = {

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.

}, keywords = {Acyltransferases, Arachidonic Acid, Autistic Disorder, Child, Child, Preschool, Consanguinity, Epilepsy, Female, Homozygote, Humans, Infant, Intellectual Disability, Lysophospholipids, Male, Membrane Proteins, Mutation, Pedigree, Phosphatidylinositols}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.07.019}, author = {Johansen, Anide and Rosti, Rasim O and Musaev, Damir and Sticca, Evan and Harripaul, Ricardo and Zaki, Maha and {\c C}a{\u g}layan, Ahmet Okay and Azam, Matloob and Sultan, Tipu and Froukh, Tawfiq and Reis, Andr{\'e} and Popp, Bernt and Ahmed, Iltaf and John, Peter and Ayub, Muhammad and Ben-Omran, Tawfeg and Vincent, John B and Gleeson, Joseph G and Abou Jamra, Rami} } @article {84, title = {Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Apr}, pages = {457-65}, abstract = {

Nucleoporins are essential components of the nuclear pore complex (NPC). Only a few diseases have been attributed to NPC dysfunction. Steroid-resistant nephrotic syndrome (SRNS), a frequent cause of chronic kidney disease, is caused by dysfunction of glomerular podocytes. Here we identify in eight families with SRNS mutations in NUP93, its interaction partner NUP205 or XPO5 (encoding exportin 5) as hitherto unrecognized monogenic causes of SRNS. NUP93 mutations caused disrupted NPC assembly. NUP93 knockdown reduced the presence of NUP205 in the NPC, and, reciprocally, a NUP205 alteration abrogated NUP93 interaction. We demonstrate that NUP93 and exportin 5 interact with the signaling protein SMAD4 and that NUP93 mutations abrogated interaction with SMAD4. Notably, NUP93 mutations interfered with BMP7-induced SMAD transcriptional reporter activity. We hereby demonstrate that mutations of NUP genes cause a distinct renal disease and identify aberrant SMAD signaling as a new disease mechanism of SRNS, opening a potential new avenue for treatment.

}, keywords = {Age of Onset, Amino Acid Sequence, Animals, Cell Movement, Cell Proliferation, Cells, Cultured, Child, Child, Preschool, Drug Resistance, Female, Genes, Recessive, Genetic Association Studies, Genetic Linkage, HEK293 Cells, Humans, Infant, Karyopherins, Male, Mice, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Nuclear Pore Complex Proteins, Oxidative Stress, Podocytes, Sequence Analysis, DNA, Steroids, Xenopus laevis}, issn = {1546-1718}, doi = {10.1038/ng.3512}, author = {Braun, Daniela A and Sadowski, Carolin E and Kohl, Stefan and Lovric, Svjetlana and Astrinidis, Susanne A and Pabst, Werner L and Gee, Heon Yung and Ashraf, Shazia and Lawson, Jennifer A and Shril, Shirlee and Airik, Merlin and Tan, Weizhen and Schapiro, David and Rao, Jia and Choi, Won-Il and Hermle, Tobias and Kemper, Markus J and Pohl, Martin and Ozaltin, Fatih and Konrad, Martin and Bogdanovic, Radovan and B{\"u}scher, Rainer and Helmchen, Udo and Serdaroglu, Erkin and Lifton, Richard P and Antonin, Wolfram and Hildebrandt, Friedhelm} } @article {81, title = {Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 Feb 18}, pages = {10713}, abstract = {

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

}, keywords = {ATP Binding Cassette Transporter, Subfamily B, Member 11, ATP-Binding Cassette Transporters, Bile Acids and Salts, Cholestasis, Intrahepatic, Female, Humans, Male, Mutation, Receptors, Cytoplasmic and Nuclear, Young Adult}, issn = {2041-1723}, doi = {10.1038/ncomms10713}, author = {Gomez-Ospina, Natalia and Potter, Carol J and Xiao, Rui and Manickam, Kandamurugu and Kim, Mi-Sun and Kim, Kang Ho and Shneider, Benjamin L and Picarsic, Jennifer L and Jacobson, Theodora A and Zhang, Jing and He, Weimin and Liu, Pengfei and Knisely, A S and Finegold, Milton J and Muzny, Donna M and Boerwinkle, Eric and Lupski, James R and Plon, Sharon E and Gibbs, Richard A and Eng, Christine M and Yang, Yaping and Washington, Gabriel C and Porteus, Matthew H and Berquist, William E and Kambham, Neeraja and Singh, Ravinder J and Xia, Fan and Enns, Gregory M and Moore, David D} } @article {41, title = {Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 Oct}, pages = {1161-74}, abstract = {

Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosomes, Human, Pair 17, DNA Copy Number Variations, DNA Replication, Female, Gene Deletion, Haploinsufficiency, Homologous Recombination, Humans, Intellectual Disability, Male, Mutation, Myelin Proteins, Smith-Magenis Syndrome, Trans-Activators, Transcription Factors}, issn = {1432-1203}, doi = {10.1007/s00439-016-1703-5}, author = {Yuan, Bo and Neira, Juanita and Gu, Shen and Harel, Tamar and Liu, Pengfei and Brice{\~n}o, Ignacio and Elsea, Sarah H and G{\'o}mez, Alberto and Potocki, Lorraine and Lupski, James R} } @article {127, title = {Novel genetic causes for cerebral visual impairment.}, journal = {Eur J Hum Genet}, volume = {24}, year = {2016}, month = {2016 May}, pages = {660-5}, abstract = {

Cerebral visual impairment (CVI) is a major cause of low vision in children due to impairment in projection and/or interpretation of the visual input in the brain. Although acquired causes for CVI are well known, genetic causes underlying CVI are largely unidentified. DNAs of 25 patients with CVI and intellectual disability, but without acquired (eg, perinatal) damage, were investigated by whole-exome sequencing. The data were analyzed for de novo, autosomal-recessive, and X-linked variants, and subsequently classified into known, candidate, or unlikely to be associated with CVI. This classification was based on the Online Mendelian Inheritance in Man database, literature reports, variant characteristics, and functional relevance of the gene. After classification, variants in four genes known to be associated with CVI (AHDC1, NGLY1, NR2F1, PGAP1) in 5 patients (20\%) were identified, establishing a conclusive genetic diagnosis for CVI. In addition, in 11 patients (44\%) with CVI, variants in one or more candidate genes were identified (ACP6, AMOT, ARHGEF10L, ATP6V1A, DCAF6, DLG4, GABRB2, GRIN1, GRIN2B, KCNQ3, KCTD19, RERE, SLC1A1, SLC25A16, SLC35A2, SOX5, UFSP2, UHMK1, ZFP30). Our findings show that diverse genetic causes underlie CVI, some of which will provide insight into the biology underlying this disease process.

}, keywords = {Adolescent, Blindness, Cortical, Child, Child, Preschool, Female, Genetic Loci, Humans, Male, Polymorphism, Single Nucleotide, Young Adult}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.186}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and de Leeuw, Nicole and Pfundt, Rolph and Nillesen, Willy M and de Ligt, Joep and Gilissen, Christian and Jhangiani, Shalini and Lupski, James R and Cremers, Frans P M and de Vries, Bert B A} } @article {12, title = {Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 11}, pages = {1158-1162}, abstract = {

PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.

METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.

RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.

CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.

}, keywords = {Adolescent, Anodontia, Child, Exome, Female, Frameshift Mutation, Genetic Predisposition to Disease, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Male, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Wnt Signaling Pathway}, issn = {1530-0366}, doi = {10.1038/gim.2016.10}, author = {Ockeloen, Charlotte W and Khandelwal, Kriti D and Dreesen, Karoline and Ludwig, Kerstin U and Sullivan, Robert and van Rooij, Iris A L M and Thonissen, Michelle and Swinnen, Steven and Phan, Milien and Conte, Federica and Ishorst, Nina and Gilissen, Christian and RoaFuentes, Laury and van de Vorst, Maartje and Henkes, Arjen and Steehouwer, Marloes and van Beusekom, Ellen and Bloemen, Marjon and Vankeirsbilck, Bruno and Berg{\'e}, Stefaan and Hens, Greet and Schoenaers, Joseph and Poorten, Vincent Vander and Roosenboom, Jasmien and Verdonck, An and Devriendt, Koen and Roeleveldt, Nel and Jhangiani, Shalini N and Vissers, Lisenka E L M and Lupski, James R and de Ligt, Joep and Von den Hoff, Johannes W and Pfundt, Rolph and Brunner, Han G and Zhou, Huiqing and Dixon, Jill and Mangold, Elisabeth and van Bokhoven, Hans and Dixon, Michael J and Kleefstra, Tjitske and Hoischen, Alexander and Carels, Carine E L} } @article {82, title = {Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 May}, pages = {1165-73}, abstract = {

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

}, keywords = {Autistic Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Developmental Disabilities, DNA Copy Number Variations, Female, Genetic Association Studies, Humans, Male, Psychotic Disorders, Schizophrenia, Signal Transduction}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37595}, author = {Brownstein, Catherine A and Kleiman, Robin J and Engle, Elizabeth C and Towne, Meghan C and D{\textquoteright}Angelo, Eugene J and Yu, Timothy W and Beggs, Alan H and Picker, Jonathan and Fogler, Jason M and Carroll, Devon and Schmitt, Rachel C O and Wolff, Robert R and Shen, Yiping and Lip, Va and Bilguvar, Kaya and Kim, April and Tembulkar, Sahil and O{\textquoteright}Donnell, Kyle and Gonzalez-Heydrich, Joseph} } @article {67, title = {Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 May}, pages = {569-586}, abstract = {

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

}, keywords = {Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Female, Forkhead Transcription Factors, Genes, Lethal, Genome, Human, Genomic Imprinting, High-Throughput Nucleotide Sequencing, Humans, Infant, Newborn, Male, Pedigree, Persistent Fetal Circulation Syndrome, Pulmonary Alveoli, Pulmonary Veins, Sequence Deletion}, issn = {1432-1203}, doi = {10.1007/s00439-016-1655-9}, author = {Szafranski, Przemyslaw and Gambin, Tomasz and Dharmadhikari, Avinash V and Akdemir, Kadir Caner and Jhangiani, Shalini N and Schuette, Jennifer and Godiwala, Nihal and Yatsenko, Svetlana A and Sebastian, Jessica and Madan-Khetarpal, Suneeta and Surti, Urvashi and Abellar, Rosanna G and Bateman, David A and Wilson, Ashley L and Markham, Melinda H and Slamon, Jill and Santos-Simarro, Fernando and Palomares, Mar{\'\i}a and Nevado, Juli{\'a}n and Lapunzina, Pablo and Chung, Brian Hon-Yin and Wong, Wai-Lap and Chu, Yoyo Wing Yiu and Mok, Gary Tsz Kin and Kerem, Eitan and Reiter, Joel and Ambalavanan, Namasivayam and Anderson, Scott A and Kelly, David R and Shieh, Joseph and Rosenthal, Taryn C and Scheible, Kristin and Steiner, Laurie and Iqbal, M Anwar and McKinnon, Margaret L and Hamilton, Sara Jane and Schlade-Bartusiak, Kamilla and English, Dawn and Hendson, Glenda and Roeder, Elizabeth R and DeNapoli, Thomas S and Littlejohn, Rebecca Okashah and Wolff, Daynna J and Wagner, Carol L and Yeung, Alison and Francis, David and Fiorino, Elizabeth K and Edelman, Morris and Fox, Joyce and Hayes, Denise A and Janssens, Sandra and De Baere, Elfride and Menten, Bj{\"o}rn and Loccufier, Anne and Vanwalleghem, Lieve and Moerman, Philippe and Sznajer, Yves and Lay, Amy S and Kussmann, Jennifer L and Chawla, Jasneek and Payton, Diane J and Phillips, Gael E and Brosens, Erwin and Tibboel, Dick and de Klein, Annelies and Maystadt, Isabelle and Fisher, Richard and Sebire, Neil and Male, Alison and Chopra, Maya and Pinner, Jason and Malcolm, Girvan and Peters, Gregory and Arbuckle, Susan and Lees, Melissa and Mead, Zoe and Quarrell, Oliver and Sayers, Richard and Owens, Martina and Shaw-Smith, Charles and Lioy, Janet and McKay, Eileen and de Leeuw, Nicole and Feenstra, Ilse and Spruijt, Liesbeth and Elmslie, Frances and Thiruchelvam, Timothy and Bacino, Carlos A and Langston, Claire and Lupski, James R and Sen, Partha and Popek, Edwina and Stankiewicz, Pawe{\l}} } @article {111, title = {Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections.}, journal = {Clin Genet}, volume = {89}, year = {2016}, month = {2016 06}, pages = {719-23}, abstract = {

Marfan syndrome (MFS) due to mutations in FBN1 is a known cause of thoracic aortic aneurysms and acute aortic dissections (TAAD) associated with pleiotropic manifestations. Genetic predisposition to TAAD can also be inherited in families in the absence of syndromic features, termed familial TAAD (FTAAD), and several causative genes have been identified to date. FBN1 mutations can also be identified in FTAAD families, but the frequency of these mutations has not been established. We performed exome sequencing of 183 FTAAD families and identified pathogenic FBN1 variants in five (2.7\%) of these families. We also identified eight additional FBN1 rare variants that could not be unequivocally classified as disease-causing in six families. FBN1 sequencing should be considered in individuals with FTAAD even without significant systemic features of MFS.

}, keywords = {Adult, Aged, Aneurysm, Dissecting, Aortic Aneurysm, Thoracic, Exome, Family Health, Female, Fibrillin-1, Genetic Predisposition to Disease, Humans, Male, Marfan Syndrome, Middle Aged, Mutation, Pedigree, Sequence Analysis, DNA}, issn = {1399-0004}, doi = {10.1111/cge.12702}, author = {Regalado, E S and Guo, D C and Santos-Cortez, R L P and Hostetler, E and Bensend, T A and Pannu, H and Estrera, A and Safi, H and Mitchell, A L and Evans, J P and Leal, S M and Bamshad, M and Shendure, J and Nickerson, D A and Milewicz, D M} } @article {44, title = {PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies.}, journal = {Pediatr Neurol}, volume = {60}, year = {2016}, month = {2016 Jul}, pages = {83-7}, abstract = {

BACKGROUND: Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research.

METHODS: We enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome. All four individuals subsequently underwent whole-exome sequencing and comprehensive genomic analysis.

RESULTS: We identified disease-causing mutations in known genes associated with neurodevelopmental disorders including GNAO1 and CDKL5 in two of four individuals. One patient with PEHO syndrome and a de novoGNAO1 mutation was found to have an additional de novo mutation in HESX1 that is associated with optic atrophy.

CONCLUSIONS: We hypothesize that PEHO and PEHO-like syndrome may represent a severe end of the spectrum of the early-onset encephalopathies and, in some instances, its complex phenotype may result from an aggregated effect of mutations at two loci.

}, keywords = {Brain Edema, Child, Child, Preschool, Female, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Infant, Male, Mutation, Neurodegenerative Diseases, Optic Atrophy, Phenotype, Protein Serine-Threonine Kinases, Spasms, Infantile}, issn = {1873-5150}, doi = {10.1016/j.pediatrneurol.2016.03.011}, author = {Gawlinski, Pawel and Posmyk, Renata and Gambin, Tomasz and Sielicka, Danuta and Chorazy, Monika and Nowakowska, Beata and Jhangiani, Shalini N and Muzny, Donna M and Bekiesinska-Figatowska, Monika and Bal, Jerzy and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Wiszniewski, Wojciech} } @article {16, title = {Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Nov 03}, pages = {1005-1014}, abstract = {

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 12, Complement C1r, Complement C1s, Ehlers-Danlos Syndrome, Endoplasmic Reticulum, Exome, Female, Gene Deletion, Genetic Loci, Humans, Male, Mutation, Missense, Pedigree, Periodontitis, Protein Conformation, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.019}, author = {Kapferer-Seebacher, Ines and Pepin, Melanie and Werner, Roland and Aitman, Timothy J and Nordgren, Ann and Stoiber, Heribert and Thielens, Nicole and Gaboriaud, Christine and Amberger, Albert and Schossig, Anna and Gruber, Robert and Giunta, Cecilia and Bamshad, Michael and Bj{\"o}rck, Erik and Chen, Christina and Chitayat, David and Dorschner, Michael and Schmitt-Egenolf, Marcus and Hale, Christopher J and Hanna, David and Hennies, Hans Christian and Heiss-Kisielewsky, Irene and Lindstrand, Anna and Lundberg, Pernilla and Mitchell, Anna L and Nickerson, Deborah A and Reinstein, Eyal and Rohrbach, Marianne and Romani, Nikolaus and Schmuth, Matthias and Silver, Rachel and Taylan, Fulya and Vandersteen, Anthony and Vandrovcova, Jana and Weerakkody, Ruwan and Yang, Margaret and Pope, F Michael and Byers, Peter H and Zschocke, Johannes} } @article {140, title = {Phenotypic Expansion of Congenital Disorder of Glycosylation Due to SRD5A3 Null Mutation.}, journal = {JIMD Rep}, volume = {26}, year = {2016}, month = {2016}, pages = {7-12}, abstract = {

We present a boy, admitted at 4 months, with facial dysmorphism, hypertrichosis, loose skin, bilateral inguinal hernia, severe hypotonia, psychomotor disability, seizures with hypsarrhythmia (West syndrome), hepatosplenomegaly, increased serum transaminases, iris coloboma, glaucoma, corneal clouding and bilateral dilated lateral ventricles, and extra-axial post-cerebellar space. Serum transferrin isoelectrofocusing (IEF) showed a type 1 pattern. Whole-exome genotyping showed a previously reported homozygous nonsense mutation c.320G>A; p.Trp107X in SRD5A3. Epilepsy and glaucoma have been reported only once in the 19 described SRD5A3-congenital glycosylation defect patients, and corneal clouding not at all.

}, issn = {2192-8304}, doi = {10.1007/8904_2015_478}, author = {Tuysuz, Beyhan and Pehlivan, Davut and {\"O}zk{\"o}k, Ahmet and Jhangiani, Shalini and Yalcinkaya, Cengiz and Zeybek, {\c C}i{\u g}dem Aktu{\u g}lu and Muzny, Donna Marie and Lupski, James R and Gibbs, Richard and Jaeken, Jaak} } @article {97, title = {POGZ truncating alleles cause syndromic intellectual disability.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Jan 06}, pages = {3}, abstract = {

BACKGROUND: Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.

METHODS: Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members.

RESULTS: We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss.

CONCLUSIONS: While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.

}, keywords = {Adolescent, Adult, Alleles, Child, Preschool, Exome, Female, Heterozygote, Humans, Infant, Intellectual Disability, Male, Mutation, Sequence Analysis, DNA, Transposases}, issn = {1756-994X}, doi = {10.1186/s13073-015-0253-0}, author = {White, Janson and Beck, Christine R and Harel, Tamar and Posey, Jennifer E and Jhangiani, Shalini N and Tang, Sha and Farwell, Kelly D and Powis, Z{\"o}e and Mendelsohn, Nancy J and Baker, Janice A and Pollack, Lynda and Mason, Kati J and Wierenga, Klaas J and Arrington, Daniel K and Hall, Melissa and Psychogios, Apostolos and Fairbrother, Laura and Walkiewicz, Magdalena and Person, Richard E and Niu, Zhiyv and Zhang, Jing and Rosenfeld, Jill A and Muzny, Donna M and Eng, Christine and Beaudet, Arthur L and Lupski, James R and Boerwinkle, Eric and Gibbs, Richard A and Yang, Yaping and Xia, Fan and Sutton, V Reid} } @article {532, title = {Rapid molecular diagnostics of severe primary immunodeficiency determined by using targeted next-generation sequencing.}, journal = {J Allergy Clin Immunol}, volume = {138}, year = {2016}, month = {2016 10}, pages = {1142-1151.e2}, abstract = {

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are inherited disorders of the immune system. The most severe form, severe combined immunodeficiency (SCID), presents with profound deficiencies of T~cells, B~cells, or both at birth. If not treated promptly, affected patients usually do not live beyond infancy because of infections. Genetic heterogeneity of SCID frequently delays the diagnosis; a specific diagnosis is crucial for life-saving treatment and optimal management.

OBJECTIVE: We developed a next-generation sequencing (NGS)-based multigene-targeted panel for SCID and other severe PIDDs requiring rapid therapeutic actions in a clinical laboratory setting.

METHODS: The target gene capture/NGS assay provides an average read depth of approximately 1000{\texttimes}. The deep coverage facilitates simultaneous detection of single nucleotide variants and exonic copy number variants in one comprehensive assessment. Exons with insufficient coverage (<20{\texttimes} read depth) or high sequence homology (pseudogenes) are complemented by amplicon-based sequencing with specific primers to ensure 100\% coverage of all targeted regions.

RESULTS: Analysis of 20 patient samples with low T-cell receptor excision circle numbers on newborn screening or a positive family history or clinical suspicion of SCID or other severe PIDD identified deleterious mutations in 14 of them. Identified pathogenic variants included both single nucleotide variants and exonic copy number variants, such as hemizygous nonsense, frameshift, and missense changes in IL2RG; compound heterozygous changes in ATM, RAG1, and CIITA; homozygous changes in DCLRE1C and IL7R; and a heterozygous nonsense mutation in CHD7.

CONCLUSION: High-throughput deep sequencing analysis with complete clinical validation greatly increases the diagnostic yield of severe primary immunodeficiency. Establishing a molecular diagnosis enables early immune reconstitution through prompt therapeutic intervention and guides management for improved long-term quality of life.

}, keywords = {Adolescent, Child, Female, Genetic Variation, Humans, Male, Pathology, Molecular, Sequence Analysis, DNA, Severe Combined Immunodeficiency}, issn = {1097-6825}, doi = {10.1016/j.jaci.2016.05.035}, author = {Yu, Hui and Zhang, Victor Wei and Stray-Pedersen, Asbj{\o}rg and Hanson, Imelda Celine and Forbes, Lisa R and de la Morena, M Teresa and Chinn, Ivan K and Gorman, Elizabeth and Mendelsohn, Nancy J and Pozos, Tamara and Wiszniewski, Wojciech and Nicholas, Sarah K and Yates, Anne B and Moore, Lindsey E and Berge, Knut Erik and Sorte, Hanne and Bayer, Diana K and ALZahrani, Daifulah and Geha, Raif S and Feng, Yanming and Wang, Guoli and Orange, Jordan S and Lupski, James R and Wang, Jing and Wong, Lee-Jun} } @article {70, title = {Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Apr 07}, pages = {772-81}, abstract = {

Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, dysgenesis of the corpus callosum, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1-domain-containing kinase) were independently identified by whole-exome sequencing as the cause of this condition in four unrelated families. Matching these families was facilitated by the sharing of phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin-cytoskeleton dynamics, and mTOR signaling. Two of the three mutations (c.376C>T [p.Arg126(*)] and c.1363A>T [p.Lys455(*)]) are predicted to truncate the protein, and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A (p.Arg511His), alters a conserved residue within the TBC1 domain. Structural analysis implicated Arg511 as a required residue for Rab-GAP function, and in~silico homology modeling predicted impaired GAP function in the corresponding mutant. These results suggest that loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.

}, keywords = {Adolescent, Alleles, Amino Acid Sequence, Brain Diseases, Child, Child, Preschool, Corpus Callosum, Female, GTPase-Activating Proteins, Humans, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Protein-Serine-Threonine Kinases, Signal Transduction, TOR Serine-Threonine Kinases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.01.016}, author = {Chong, Jessica X and Caputo, Viviana and Phelps, Ian G and Stella, Lorenzo and Worgan, Lisa and Dempsey, Jennifer C and Nguyen, Alina and Leuzzi, Vincenzo and Webster, Richard and Pizzuti, Antonio and Marvin, Colby T and Ishak, Gisele E and Ardern-Holmes, Simone and Richmond, Zara and Bamshad, Michael J and Ortiz-Gonzalez, Xilma R and Tartaglia, Marco and Chopra, Maya and Doherty, Dan} } @article {21, title = {Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {831-845}, abstract = {

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

}, keywords = {Adenosine Triphosphatases, Adult, Alleles, Animals, ATPases Associated with Diverse Cellular Activities, Axons, Cardiomyopathies, Child, Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Drosophila melanogaster, Female, Fibroblasts, Homozygote, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Muscle Hypotonia, Muscles, Mutation, Nervous System Diseases, Neurons, Optic Atrophy, Phenotype, Polymorphism, Single Nucleotide, Syndrome, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.007}, author = {Harel, Tamar and Yoon, Wan Hee and Garone, Caterina and Gu, Shen and Coban-Akdemir, Zeynep and Eldomery, Mohammad K and Posey, Jennifer E and Jhangiani, Shalini N and Rosenfeld, Jill A and Cho, Megan T and Fox, Stephanie and Withers, Marjorie and Brooks, Stephanie M and Chiang, Theodore and Duraine, Lita and Erdin, Serkan and Yuan, Bo and Shao, Yunru and Moussallem, Elie and Lamperti, Costanza and Donati, Maria A and Smith, Joshua D and McLaughlin, Heather M and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Pippucci, Tommaso and Magini, Pamela and Seri, Marco and Zeviani, Massimo and Hirano, Michio and Hunter, Jill V and Srour, Myriam and Zanigni, Stefano and Lewis, Richard Alan and Muzny, Donna M and Lotze, Timothy E and Boerwinkle, Eric and Gibbs, Richard A and Hickey, Scott E and Graham, Brett H and Yang, Yaping and Buhas, Daniela and Martin, Donna M and Potocki, Lorraine and Graziano, Claudio and Bellen, Hugo J and Lupski, James R} } @article {90, title = {Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Feb 04}, pages = {347-57}, abstract = {

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous \~{}34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

}, keywords = {Alleles, Arabs, Arrhythmias, Cardiac, Base Sequence, Child, Child, Preschool, Endoplasmic Reticulum Stress, European Continental Ancestry Group, Exome, Exons, Female, Gene Deletion, Golgi Apparatus, Hispanic Americans, Homozygote, Humans, Infant, Male, Molecular Sequence Data, Muscle Weakness, Pedigree, Rhabdomyolysis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.12.008}, author = {Lalani, Seema R and Liu, Pengfei and Rosenfeld, Jill A and Watkin, Levi B and Chiang, Theodore and Leduc, Magalie S and Zhu, Wenmiao and Ding, Yan and Pan, Shujuan and Vetrini, Francesco and Miyake, Christina Y and Shinawi, Marwan and Gambin, Tomasz and Eldomery, Mohammad K and Akdemir, Zeynep Hande Coban and Emrick, Lisa and Wilnai, Yael and Schelley, Susan and Koenig, Mary Kay and Memon, Nada and Farach, Laura S and Coe, Bradley P and Azamian, Mahshid and Hernandez, Patricia and Zapata, Gladys and Jhangiani, Shalini N and Muzny, Donna M and Lotze, Timothy and Clark, Gary and Wilfong, Angus and Northrup, Hope and Adesina, Adekunle and Bacino, Carlos A and Scaglia, Fernando and Bonnen, Penelope E and Crosson, Jane and Duis, Jessica and Maegawa, Gustavo H B and Coman, David and Inwood, Anita and McGill, Jim and Boerwinkle, Eric and Graham, Brett and Beaudet, Art and Eng, Christine M and Hanchard, Neil A and Xia, Fan and Orange, Jordan S and Gibbs, Richard A and Lupski, James R and Yang, Yaping} } @article {345, title = {The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 05}, pages = {443-51}, abstract = {

PURPOSE: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders of the peripheral nervous system. Copy-number variants (CNVs) contribute significantly to CMT, as duplication of PMP22 underlies the majority of CMT1 cases. We hypothesized that CNVs and/or single-nucleotide variants (SNVs) might exist in patients with CMT with an unknown molecular genetic etiology.

METHODS: Two hundred patients with CMT, negative for both SNV mutations in several CMT genes and for CNVs involving PMP22, were screened for CNVs by high-resolution oligonucleotide array comparative genomic hybridization. Whole-exome sequencing was conducted on individuals with rare, potentially pathogenic CNVs.

RESULTS: Putatively causative CNVs were identified in five subjects (~2.5\%); four of the five map to known neuropathy genes. Breakpoint sequencing revealed Alu-Alu-mediated junctions as a predominant contributor. Exome sequencing identified MFN2 SNVs in two of the individuals.

CONCLUSION: Neuropathy-associated CNV outside of the PMP22 locus is rare in CMT. Nevertheless, there is potential clinical utility in testing for CNVs and exome sequencing in CMT cases negative for the CMT1A duplication. These findings suggest that complex phenotypes including neuropathy can potentially be caused by a combination of SNVs and CNVs affecting more than one disease-associated locus and contributing to a mutational burden.Genet Med 18 5, 443-451.

}, keywords = {Adult, Age of Onset, Charcot-Marie-Tooth Disease, Child, Preschool, Comparative Genomic Hybridization, DNA Copy Number Variations, Exome, Female, Genetic Predisposition to Disease, GTP Phosphohydrolases, High-Throughput Nucleotide Sequencing, Humans, Male, Mitochondrial Proteins, Motor Neurons, Myelin P0 Protein, Myelin Proteins, Neural Conduction, Polymorphism, Single Nucleotide, Polyneuropathies}, issn = {1530-0366}, doi = {10.1038/gim.2015.124}, author = {Pehlivan, Davut and Beck, Christine R and Okamoto, Yuji and Harel, Tamar and Akdemir, Zeynep H C and Jhangiani, Shalini N and Withers, Marjorie A and Goksungur, Meryem Tuba and Carvalho, Claudia M B and Czesnik, Dirk and Gonzaga-Jauregui, Claudia and Wiszniewski, Wojciech and Muzny, Donna M and Gibbs, Richard A and Rautenstrauss, Bernd and Sereda, Michael W and Lupski, James R} } @article {76, title = {Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.}, journal = {Endocr Relat Cancer}, volume = {23}, year = {2016}, month = {2016 04}, pages = {221-33}, abstract = {

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8\%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

}, keywords = {Adult, Female, Genetic Diseases, X-Linked, Gigantism, Humans, Male, Middle Aged, Mosaicism, Polymerase Chain Reaction, Syndrome, Young Adult}, issn = {1479-6821}, doi = {10.1530/ERC-16-0082}, author = {Daly, Adrian F and Yuan, Bo and Fina, Frederic and Caberg, Jean-Hubert and Trivellin, Giampaolo and Rostomyan, Liliya and de Herder, Wouter W and Naves, Luciana A and Metzger, Daniel and Cuny, Thomas and Rabl, Wolfgang and Shah, Nalini and Jaffrain-Rea, Marie-Lise and Zatelli, Maria Chiara and Faucz, Fabio R and Castermans, Emilie and Nanni-Metellus, Isabelle and Lodish, Maya and Muhammad, Ammar and Palmeira, Leonor and Potorac, Iulia and Mantovani, Giovanna and Neggers, Sebastian J and Klein, Marc and Barlier, Anne and Liu, Pengfei and Ouafik, L{\textquoteright}Houcine and Bours, Vincent and Lupski, James R and Stratakis, Constantine A and Beckers, Albert} } @article {31, title = {SRD5A3-CDG: Expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 Dec}, pages = {3165-3171}, abstract = {

Increasing numbers of congenital disorders of glycosylation (CDG) have been reported recently resulting in an expansion of the phenotypes associated with this group of disorders. SRD5A3 codes for polyprenol reductase which converts polyprenol to dolichol. This is a major pathway for dolichol biosynthesis for N-glycosylation, O-mannosylation, C-mannosylation, and GPI anchor synthesis. We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement. We compare that to 13 affected individuals from the literature including five adults allowing us to delineate the features that may develop over time with this disorder including kyphosis, retinitis pigmentosa, and cataracts. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Adult, Child, Congenital Disorders of Glycosylation, Dolichols, Eye, Female, Glycosylation, Homozygote, Humans, Male, Membrane Proteins, Mutation, Phenotype, Skin, Tretinoin}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37875}, author = {Wheeler, Patricia G and Ng, Bobby G and Sanford, Laura and Sutton, V Reid and Bartholomew, Dennis W and Pastore, Matthew T and Bamshad, Michael J and Kircher, Martin and Buckingham, Kati J and Nickerson, Deborah A and Shendure, Jay and Freeze, Hudson H} } @article {11, title = {Two locus inheritance of non-syndromic midline craniosynostosis via rare and common alleles.}, journal = {Elife}, volume = {5}, year = {2016}, month = {2016 Sep 08}, abstract = {

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7\%) had damaging de novo or rare transmitted mutations in , an inhibitor of BMP - induced osteoblast differentiation (p<10). mutations nonetheless showed striking incomplete penetrance (<60\%). Genotypes of a common variant near that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

}, keywords = {Alleles, Bone Morphogenetic Protein 2, Craniosynostoses, Exome, Genetic Association Studies, Humans, Infant, Mutation, Penetrance, Sequence Analysis, DNA, Smad6 Protein}, issn = {2050-084X}, doi = {10.7554/eLife.20125}, author = {Timberlake, Andrew T and Choi, Jungmin and Zaidi, Samir and Lu, Qiongshi and Nelson-Williams, Carol and Brooks, Eric D and Bilguvar, Kaya and Tikhonova, Irina and Mane, Shrikant and Yang, Jenny F and Sawh-Martinez, Rajendra and Persing, Sarah and Zellner, Elizabeth G and Loring, Erin and Chuang, Carolyn and Galm, Amy and Hashim, Peter W and Steinbacher, Derek M and DiLuna, Michael L and Duncan, Charles C and Pelphrey, Kevin A and Zhao, Hongyu and Persing, John A and Lifton, Richard P} } @article {73, title = {Two novel germline DDX41 mutations in a family with inherited myelodysplasia/acute myeloid leukemia.}, journal = {Haematologica}, volume = {101}, year = {2016}, month = {2016 06}, pages = {e228-31}, keywords = {DEAD-box RNA Helicases, Family, Female, Germ-Line Mutation, Humans, Leukemia, Myeloid, Acute, Male, Myelodysplastic Syndromes, Neoplasm Proteins}, issn = {1592-8721}, doi = {10.3324/haematol.2015.139790}, author = {Li, Ruijuan and Sobreira, Nara and Witmer, P Dane and Pratz, Keith W and Braunstein, Evan M} } @article {430, title = {Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1-q35.3 susceptibility locus identified by whole-exome sequencing.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2016}, month = {2016 01}, pages = {73-78}, abstract = {

Keratoconus (KTCN) is a protrusion and thinning of the cornea, resulting in impairment of visual function. The extreme genetic heterogeneity makes it difficult to discover factors unambiguously influencing the KTCN phenotype. In this study, we used whole-exome sequencing (WES) and Sanger sequencing to reduce the number of candidate genes at the 5q31.1-q35.3 locus and to prioritize other potentially relevant variants in an Ecuadorian family with KTCN. We applied WES in two affected KTCN individuals from the Ecuadorian family that showed a suggestive linkage between the KTCN phenotype and the 5q31.1-q35.3 locus. Putative variants identified by WES were further evaluated in this family using Sanger sequencing. Exome capture discovered a total of 173 rare (minor allele frequency <0.001 in control population) nonsynonymous variants in both affected individuals. Among them, 16 SNVs were selected for further evaluation. Segregation analysis revealed that variants c.475T>G in SKP1, c.671G>A in PROB1, and c.527G>A in IL17B in the 5q31.1-q35.3 linkage region, and c.850G>A in HKDC1 in the 10q22 locus completely segregated with the phenotype in the studied KTCN family. We demonstrate that a combination of various techniques significantly narrowed the studied genomic region and reduced the list of the putative exonic variants. Moreover, since this locus overlapped two other chromosomal regions previously recognized in distinct KTCN studies, our findings suggest that this 5q31.1-q35.3 locus might be linked with KTCN.

}, keywords = {Chromosomes, Human, Pair 5, Exome, Female, Gene Frequency, Genetic Linkage, Genetic Predisposition to Disease, Genome, Human, Hexokinase, High-Throughput Nucleotide Sequencing, Humans, Interleukin-17, Keratoconus, Male, Pedigree, Phenotype, Proteins, S-Phase Kinase-Associated Proteins}, issn = {1476-5438}, doi = {10.1038/ejhg.2016.130}, author = {Karolak, Justyna A and Gambin, Tomasz and Pitarque, Jose A and Molinari, Andrea and Jhangiani, Shalini and Stankiewicz, Pawel and Lupski, James R and Gajecka, Marzena} } @article {534, title = {Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome.}, journal = {Neurology}, volume = {87}, year = {2016}, month = {2016 Oct 04}, pages = {1442-1448}, abstract = {

OBJECTIVE: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3.

METHODS: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing.

RESULTS: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures.

CONCLUSIONS: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.

}, keywords = {Adolescent, Child, Diagnosis, Differential, Female, Genetic Variation, Humans, Male, Myasthenic Syndromes, Congenital, Vesicular Acetylcholine Transport Proteins}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000003179}, author = {O{\textquoteright}Grady, Gina L and Verschuuren, Corien and Yuen, Michaela and Webster, Richard and Menezes, Manoj and Fock, Johanna M and Pride, Natalie and Best, Heather A and Benavides Damm, Tatiana and Turner, Christian and Lek, Monkol and Engel, Andrew G and North, Kathryn N and Clarke, Nigel F and MacArthur, Daniel G and Kamsteeg, Erik-Jan and Cooper, Sandra T} } @article {455, title = {Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Nov 03}, pages = {1086-1105}, abstract = {

This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking glutathione reductase glr1 show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease.

}, keywords = {Amino Acid Sequence, Animals, Cell Nucleus, Cercopithecus aethiops, Cohort Studies, COS Cells, Creatine Kinase, Cytoplasm, Distal Myopathies, ELAV-Like Protein 4, Female, Flavoproteins, Gene Deletion, Genetic Variation, Genome-Wide Association Study, Glutathione Reductase, HEK293 Cells, Humans, Male, Muscle, Skeletal, Mutation, Missense, Myopathies, Structural, Congenital, Oxidoreductases, Pedigree, Protein Conformation, Saccharomyces cerevisiae Proteins, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.005}, author = {O{\textquoteright}Grady, Gina L and Best, Heather A and Sztal, Tamar E and Schartner, Vanessa and Sanjuan-Vazquez, Myriam and Donkervoort, Sandra and Abath Neto, Osorio and Sutton, Roger Bryan and Ilkovski, Biljana and Romero, Norma Beatriz and Stojkovic, Tanya and Dastgir, Jahannaz and Waddell, Leigh B and Boland, Anne and Hu, Ying and Williams, Caitlin and Ruparelia, Avnika A and Maisonobe, Thierry and Peduto, Anthony J and Reddel, Stephen W and Lek, Monkol and Tukiainen, Taru and Cummings, Beryl B and Joshi, Himanshu and Nectoux, Juliette and Brammah, Susan and Deleuze, Jean-Fran{\c c}ois and Ing, Viola Oorschot and Ramm, Georg and Ardicli, Didem and Nowak, Kristen J and Talim, Beril and Topaloglu, Haluk and Laing, Nigel G and North, Kathryn N and MacArthur, Daniel G and Friant, Sylvie and Clarke, Nigel F and Bryson-Richardson, Robert J and B{\"o}nnemann, Carsten G and Laporte, Jocelyn and Cooper, Sandra T} } @article {88, title = {A visual and curatorial approach to clinical variant prioritization and disease gene discovery in genome-wide diagnostics.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Feb 02}, pages = {13}, abstract = {

BACKGROUND: Genome-wide data are increasingly important in the clinical evaluation of human disease. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. Recent work has shown that systematic integration of clinical phenotype data with genotype information can improve diagnostic workflows and prioritization of filtered rare variants. We have developed visually interactive, analytically transparent analysis software that leverages existing disease catalogs, such as the Online Mendelian Inheritance in Man database (OMIM) and the Human Phenotype Ontology (HPO), to integrate patient phenotype and variant data into ranked diagnostic alternatives.

METHODS: Our tool, "OMIM Explorer" ( http://www.omimexplorer.com ), extends the biomedical application of semantic similarity methods beyond those reported in previous studies. The tool also provides a simple interface for translating free-text clinical notes into HPO terms, enabling clinical providers and geneticists to contribute phenotypes to the diagnostic process. The visual approach uses semantic similarity with multidimensional scaling to collapse high-dimensional phenotype and genotype data from an individual into a graphical format that contextualizes the patient within a low-dimensional disease map. The map proposes a differential diagnosis and algorithmically suggests potential alternatives for phenotype queries--in essence, generating a computationally assisted differential diagnosis informed by the individual{\textquoteright}s personal genome. Visual interactivity allows the user to filter and update variant rankings by interacting with intermediate results. The tool also implements an adaptive approach for disease gene discovery based on patient phenotypes.

RESULTS: We retrospectively analyzed pilot cohort data from the Baylor Miraca Genetics Laboratory, demonstrating performance of the tool and workflow in the re-analysis of clinical exomes. Our tool assigned to clinically reported variants a median rank of 2, placing causal variants in the top 1 \% of filtered candidates across the 47 cohort cases with reported molecular diagnoses of exome variants in OMIM Morbidmap genes. Our tool outperformed Phen-Gen, eXtasy, PhenIX, PHIVE, and hiPHIVE in the prioritization of these clinically reported variants.

CONCLUSIONS: Our integrative paradigm can improve efficiency and, potentially, the quality of genomic medicine by more effectively utilizing available phenotype information, catalog data, and genomic knowledge.

}, keywords = {Computational Biology, Diagnosis, Differential, Disease, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Pilot Projects, Retrospective Studies, Software}, issn = {1756-994X}, doi = {10.1186/s13073-016-0261-8}, author = {James, Regis A and Campbell, Ian M and Chen, Edward S and Boone, Philip M and Rao, Mitchell A and Bainbridge, Matthew N and Lupski, James R and Yang, Yaping and Eng, Christine M and Posey, Jennifer E and Shaw, Chad A} } @article {124, title = {Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity.}, journal = {Kidney Int}, volume = {89}, year = {2016}, month = {2016 Feb}, pages = {468-475}, abstract = {

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.

}, keywords = {Age of Onset, Cohort Studies, DNA Mutational Analysis, Exome, Humans, Kidney Diseases, Cystic, Renal Insufficiency, Chronic}, issn = {1523-1755}, doi = {10.1038/ki.2015.317}, author = {Braun, Daniela A and Schueler, Markus and Halbritter, Jan and Gee, Heon Yung and Porath, Jonathan D and Lawson, Jennifer A and Airik, Rannar and Shril, Shirlee and Allen, Susan J and Stein, Deborah and Al Kindy, Adila and Beck, Bodo B and Cengiz, Nurcan and Moorani, Khemchand N and Ozaltin, Fatih and Hashmi, Seema and Sayer, John A and Bockenhauer, Detlef and Soliman, Neveen A and Otto, Edgar A and Lifton, Richard P and Hildebrandt, Friedhelm} } @article {115, title = {Whole-Exome Sequencing in Familial Parkinson Disease.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 Jan}, pages = {68-75}, abstract = {

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD.

DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5\% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6\% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

}, keywords = {Adult, Aged, Cohort Studies, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Middle Aged, Parkinsonian Disorders, Protein-Tyrosine Kinases, Sequence Analysis, DNA, Tenascin}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2015.3266}, author = {Farlow, Janice L and Robak, Laurie A and Hetrick, Kurt and Bowling, Kevin and Boerwinkle, Eric and Coban-Akdemir, Zeynep H and Gambin, Tomasz and Gibbs, Richard A and Gu, Shen and Jain, Preti and Jankovic, Joseph and Jhangiani, Shalini and Kaw, Kaveeta and Lai, Dongbing and Lin, Hai and Ling, Hua and Liu, Yunlong and Lupski, James R and Muzny, Donna and Porter, Paula and Pugh, Elizabeth and White, Janson and Doheny, Kimberly and Myers, Richard M and Shulman, Joshua M and Foroud, Tatiana} } @article {185, title = {Absence of heterozygosity due to template switching during replicative rearrangements.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 Apr 02}, pages = {555-64}, abstract = {

We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

}, keywords = {Base Sequence, DNA Copy Number Variations, DNA Repair, DNA Replication, Gene Rearrangement, Humans, In Situ Hybridization, Fluorescence, Loss of Heterozygosity, Models, Genetic, Molecular Sequence Data, Netherlands, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Uniparental Disomy}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.01.021}, author = {Carvalho, Claudia M B and Pfundt, Rolph and King, Daniel A and Lindsay, Sarah J and Zuccherato, Luciana W and Macville, Merryn V E and Liu, Pengfei and Johnson, Diana and Stankiewicz, Pawel and Brown, Chester W and Shaw, Chad A and Hurles, Matthew E and Ira, Grzegorz and Hastings, P J and Brunner, Han G and Lupski, James R} } @article {147, title = {Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Nov}, pages = {1080-7}, abstract = {

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80\% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

}, keywords = {Adolescent, Adult, Alleles, Amino Acid Substitution, Child, DNA Mutational Analysis, Exome, Facies, Female, Genetic Association Studies, Genotype, Humans, Male, Models, Molecular, Mutation, Noonan Syndrome, Phenotype, Protein Conformation, Protein Interaction Domains and Motifs, Son of Sevenless Proteins, Young Adult}, issn = {1098-1004}, doi = {10.1002/humu.22834}, author = {Cordeddu, Viviana and Yin, Jiani C and Gunnarsson, Cecilia and Virtanen, Carl and Drunat, S{\'e}verine and Lepri, Francesca and De Luca, Alessandro and Rossi, Cesare and Ciolfi, Andrea and Pugh, Trevor J and Bruselles, Alessandro and Priest, James R and Pennacchio, Len A and Lu, Zhibin and Danesh, Arnavaz and Quevedo, Rene and Hamid, Alaa and Martinelli, Simone and Pantaleoni, Francesca and Gnazzo, Maria and Daniele, Paola and Lissewski, Christina and Bocchinfuso, Gianfranco and Stella, Lorenzo and Odent, Sylvie and Philip, Nicole and Faivre, Laurence and Vlckova, Marketa and Seemanova, Eva and Digilio, Cristina and Zenker, Martin and Zampino, Giuseppe and Verloes, Alain and Dallapiccola, Bruno and Roberts, Amy E and Cav{\'e}, H{\'e}l{\`e}ne and Gelb, Bruce D and Neel, Benjamin G and Tartaglia, Marco} } @article {122, title = {Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {647-60}, abstract = {

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In~vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In~vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

}, keywords = {Alleles, Animals, Female, Fluorescent Antibody Technique, Genetic Linkage, Hearing Loss, Unilateral, Humans, Male, Mice, Mutation, NIH 3T3 Cells, Pedigree, Phenotype, Prognosis, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Stem Cell Factor, Waardenburg Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.09.011}, author = {Zazo Seco, Celia and Serr{\~a}o de Castro, Luciana and van Nierop, Josephine W and Mor{\'\i}n, Mat{\'\i}as and Jhangiani, Shalini and Verver, Eva J J and Schraders, Margit and Maiwald, Nadine and Wesdorp, Mieke and Venselaar, Hanka and Spruijt, Liesbeth and Oostrik, Jaap and Schoots, Jeroen and van Reeuwijk, Jeroen and Lelieveld, Stefan H and Huygen, Patrick L M and Insenser, Mar{\'\i}a and Admiraal, Ronald J C and Pennings, Ronald J E and Hoefsloot, Lies H and Arias-V{\'a}squez, Alejandro and de Ligt, Joep and Yntema, Helger G and Jansen, Joop H and Muzny, Donna M and Huls, Gerwin and van Rossum, Michelle M and Lupski, James R and Moreno-Pelayo, Miguel Angel and Kunst, Henricus P M and Kremer, Hannie} } @article {170, title = {Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jul 15}, pages = {4061-77}, abstract = {

Alu repetitive elements are known to be major contributors to genome instability by generating Alu-mediated copy-number variants (CNVs). Most of the reported Alu-mediated CNVs are simple deletions and duplications, and the mechanism underlying Alu-Alu-mediated rearrangement has been attributed to non-allelic homologous recombination (NAHR). Chromosome 17 at the p13.3 genomic region lacks extensive low-copy repeat architecture; however, it is highly enriched for Alu repetitive elements, with a fraction of 30\% of total sequence annotated in the human reference genome, compared with the 10\% genome-wide and 18\% on chromosome 17. We conducted mechanistic studies of the 17p13.3 CNVs by performing high-density oligonucleotide array comparative genomic hybridization, specifically interrogating the 17p13.3 region with \~{}150 bp per probe density; CNV breakpoint junctions were mapped to nucleotide resolution by polymerase chain reaction and Sanger sequencing. Studied rearrangements include 5 interstitial deletions, 14 tandem duplications, 7 terminal deletions and 13 complex genomic rearrangements (CGRs). Within the 17p13.3 region, Alu-Alu-mediated rearrangements were identified in 80\% of the interstitial deletions, 46\% of the tandem duplications and 50\% of the CGRs, indicating that this mechanism was a major contributor for formation of breakpoint junctions. Our studies suggest that Alu repetitive elements facilitate formation of non-recurrent CNVs, CGRs and other structural aberrations of chromosome 17 at p13.3. The common observation of Alu-mediated rearrangement in CGRs and breakpoint junction sequences analysis further demonstrates that this type of mechanism is unlikely attributed to NAHR, but rather may be due to a recombination-coupled DNA replicative repair process.

}, keywords = {Alleles, Alu Elements, Base Sequence, Chromosomes, Human, Pair 17, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Gene Duplication, Gene Rearrangement, Genome, Human, Genomic Instability, Genomics, Homologous Recombination, Humans, Male, Molecular Sequence Data, Segmental Duplications, Genomic, Sequence Deletion}, issn = {1460-2083}, doi = {10.1093/hmg/ddv146}, author = {Gu, Shen and Yuan, Bo and Campbell, Ian M and Beck, Christine R and Carvalho, Claudia M B and Nagamani, Sandesh C S and Erez, Ayelet and Patel, Ankita and Bacino, Carlos A and Shaw, Chad A and Stankiewicz, Pawe{\l} and Cheung, Sau Wai and Bi, Weimin and Lupski, James R} } @article {641, title = {An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Jan}, pages = {159-63}, abstract = {

We describe a boy who has an anadysplasia-like spondylometaphyseal dysplasia. By whole exome sequencing he was shown to have compound heterozygous mutations of LBR that codes for the lamin B receptor. He shares many similarities with a case previously described, but in whom the early natural history could not be established [Borovik et al., 2013]. Thus, in addition to Greenberg dysplasia (a perinatal lethal disorder), homozygosity or compound heterozygosity of mutations in LBR can result in a mild, spontaneously regressing bone dysplasia.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phenotype, Pregnancy, Radiography, Receptors, Cytoplasmic and Nuclear, Spine}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36808}, author = {Sobreira, Nara and Modaff, Peggy and Steel, Gary and You, Jing and Nanda, Sonia and Hoover-Fong, Julie and Valle, David and Pauli, Richard M} } @article {199, title = {Assessment of incidental findings in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.}, journal = {Genet Med}, volume = {17}, year = {2015}, month = {2015 Oct}, pages = {782-8}, abstract = {

PURPOSE: In March 2013 the American College of Medical Genetics and Genomics published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.

METHODS: We identified rare, nonsynonymous, and splicing single-nucleotide variants and insertions/deletions and assessed variant classification using the Human Gene Mutation, Emory, and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients.

RESULTS: Our filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the three reference databases. Of 101 variants listed in the Human Gene Mutation Database, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86\% of individuals had a reportable incidental variant.

CONCLUSION: These observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.

}, keywords = {Databases, Nucleic Acid, Exome, Female, Genetic Diseases, Inborn, Genomics, High-Throughput Nucleotide Sequencing, Humans, Incidental Findings, Male, Mutation, Polymorphism, Single Nucleotide}, issn = {1530-0366}, doi = {10.1038/gim.2014.196}, author = {Jurgens, Julie and Ling, Hua and Hetrick, Kurt and Pugh, Elizabeth and Schiettecatte, Fran{\c c}ois and Doheny, Kimberly and Hamosh, Ada and Avramopoulos, Dimitri and Valle, David and Sobreira, Nara} } @article {197, title = {Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.}, journal = {Circ Cardiovasc Genet}, volume = {8}, year = {2015}, month = {2015 Apr}, pages = {351-5}, abstract = {

BACKGROUND: Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.

METHODS AND RESULTS: By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2{\texttimes}10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1\%; P=1.2{\texttimes}10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9{\texttimes}10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.

CONCLUSIONS: Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.

}, keywords = {Adult, African Americans, Alleles, Coronary Disease, European Continental Ancestry Group, Female, Histidine, Histidine Ammonia-Lyase, Humans, Male, Mutation}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.114.000697}, author = {Yu, Bing and Li, Alexander H and Muzny, Donna and Veeraraghavan, Narayanan and de Vries, Paul S and Bis, Joshua C and Musani, Solomon K and Alexander, Danny and Morrison, Alanna C and Franco, Oscar H and Uitterlinden, Andr{\'e} and Hofman, Albert and Dehghan, Abbas and Wilson, James G and Psaty, Bruce M and Gibbs, Richard and Wei, Peng and Boerwinkle, Eric} } @article {640, title = {Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Jun 05}, pages = {1011-9}, abstract = {

BACKGROUND AND OBJECTIVES: Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.

RESULTS: Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A>G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.

CONCLUSIONS: This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process next-generation sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases.

}, keywords = {Adolescent, Atypical Hemolytic Uremic Syndrome, Base Sequence, Blotting, Western, Child, Diacylglycerol Kinase, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Infant, Introns, Male, Molecular Sequence Data, Mutation, Phenotype, Predictive Value of Tests, Risk Factors}, issn = {1555-905X}, doi = {10.2215/CJN.08520814}, author = {Mele, Caterina and Lemaire, Mathieu and Iatropoulos, Paraskevas and Piras, Rossella and Bresin, Elena and Bettoni, Serena and Bick, David and Helbling, Daniel and Veith, Regan and Valoti, Elisabetta and Donadelli, Roberta and Murer, Luisa and Neunh{\"a}userer, Maria and Breno, Matteo and Fremeaux-Bacchi, Veronique and Lifton, Richard and Remuzzi, Giuseppe and Noris, Marina} } @article {153, title = {Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Sep}, pages = {612-6}, abstract = {

BACKGROUND: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30\%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus.

METHODS: Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu).

RESULTS: The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site.

CONCLUSIONS: Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life.

}, keywords = {Diabetes Mellitus, Humans, Infant, Insulin, Regular, Human, Introns, Mutation, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103220}, author = {Carmody, David and Park, Soo-Young and Ye, Honggang and Perrone, Marie E and Alkorta-Aranburu, G and Highland, Heather M and Hanis, Craig L and Philipson, Louis H and Bell, Graeme I and Greeley, Siri Atma W} } @article {173, title = {COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jun}, pages = {654-60}, abstract = {

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.

}, keywords = {Amino Acid Sequence, Arthritis, Autoimmune Diseases, Child, Preschool, Coatomer Protein, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Genetic Association Studies, Genetic Predisposition to Disease, Golgi Apparatus, HEK293 Cells, Humans, Infant, Lod Score, Lung Diseases, Interstitial, Male, Molecular Sequence Data, Pedigree, Protein Transport}, issn = {1546-1718}, doi = {10.1038/ng.3279}, author = {Watkin, Levi B and Jessen, Birthe and Wiszniewski, Wojciech and Vece, Timothy J and Jan, Max and Sha, Youbao and Thamsen, Maike and Santos-Cortez, Regie L P and Lee, Kwanghyuk and Gambin, Tomasz and Forbes, Lisa R and Law, Christopher S and Stray-Pedersen, Asbj{\o}rg and Cheng, Mickie H and Mace, Emily M and Anderson, Mark S and Liu, Dongfang and Tang, Ling Fung and Nicholas, Sarah K and Nahmod, Karen and Makedonas, George and Canter, Debra L and Kwok, Pui-Yan and Hicks, John and Jones, Kirk D and Penney, Samantha and Jhangiani, Shalini N and Rosenblum, Michael D and Dell, Sharon D and Waterfield, Michael R and Papa, Feroz R and Muzny, Donna M and Zaitlen, Noah and Leal, Suzanne M and Gonzaga-Jauregui, Claudia and Boerwinkle, Eric and Eissa, N Tony and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Shum, Anthony K} } @article {108, title = {De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Dec 03}, pages = {904-13}, abstract = {

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5{\textquoteright} end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(*)) and c.35_38delTCAA (p.Ile12Lysfs(*)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5{\textquoteright} end of the geminin protein. All three GMNN mutations identified alter sites 5{\textquoteright} to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

}, keywords = {Adolescent, Amino Acid Sequence, Base Sequence, Cell Cycle, Child, Preschool, Congenital Microtia, Dwarfism, Exons, Female, Geminin, Gene Expression, Genes, Dominant, Growth Disorders, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Inheritance Patterns, Male, Micrognathism, Molecular Sequence Data, Mutation, Patella, Pedigree, Protein Stability, Proteolysis, RNA Splicing, Sequence Alignment}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.11.006}, author = {Burrage, Lindsay C and Charng, Wu-Lin and Eldomery, Mohammad K and Willer, Jason R and Davis, Erica E and Lugtenberg, Dorien and Zhu, Wenmiao and Leduc, Magalie S and Akdemir, Zeynep C and Azamian, Mahshid and Zapata, Gladys and Hernandez, Patricia P and Schoots, Jeroen and de Munnik, Sonja A and Roepman, Ronald and Pearring, Jillian N and Jhangiani, Shalini and Katsanis, Nicholas and Vissers, Lisenka E L M and Brunner, Han G and Beaudet, Arthur L and Rosenfeld, Jill A and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Xia, Fan and Lalani, Seema R and Lupski, James R and Bongers, Ernie M H F and Yang, Yaping} } @article {213, title = {Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.}, journal = {J Invest Dermatol}, volume = {135}, year = {2015}, month = {2015 Jun}, pages = {1540-1547}, abstract = {

Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.

}, keywords = {Amino Acid Sequence, Cell Membrane, Child, Child, Preschool, Connexin 43, Connexins, Craniofacial Abnormalities, Disease Progression, Erythrokeratodermia Variabilis, Exome, Eye Abnormalities, Female, Foot Deformities, Congenital, Golgi Apparatus, HeLa Cells, Humans, Immunohistochemistry, Male, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Phenotype, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Skin Diseases, Syndactyly, Tooth Abnormalities}, issn = {1523-1747}, doi = {10.1038/jid.2014.485}, author = {Boyden, Lynn M and Craiglow, Brittany G and Zhou, Jing and Hu, Ronghua and Loring, Erin C and Morel, Kimberly D and Lauren, Christine T and Lifton, Richard P and Bilguvar, Kaya and Paller, Amy S and Choate, Keith A} } @article {183, title = {DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 Apr 02}, pages = {612-22}, abstract = {

Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects{\textquoteright} leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS.

}, keywords = {Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Base Sequence, Craniofacial Abnormalities, Dishevelled Proteins, DNA Primers, Dwarfism, Exome, Exons, Frameshift Mutation, Gene Components, Humans, Limb Deformities, Congenital, Molecular Sequence Data, Phosphoproteins, Sequence Analysis, DNA, Urogenital Abnormalities}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.02.015}, author = {White, Janson and Mazzeu, Juliana F and Hoischen, Alexander and Jhangiani, Shalini N and Gambin, Tomasz and Alcino, Michele Calijorne and Penney, Samantha and Saraiva, Jorge M and Hove, Hanne and Skovby, Flemming and Kayserili, H{\"u}lya and Estrella, Elicia and Vulto-van Silfhout, Anneke T and Steehouwer, Marloes and Muzny, Donna M and Sutton, V Reid and Gibbs, Richard A and Lupski, James R and Brunner, Han G and van Bon, Bregje W M and Carvalho, Claudia M B} } @article {215, title = {Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.}, journal = {Blood}, volume = {125}, year = {2015}, month = {2015 Jan 22}, pages = {591-9}, abstract = {

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as $\#$NCT00001350.

}, keywords = {Adolescent, Adult, Autoimmune Diseases, Child, Child, Preschool, Female, Genetic Diseases, Inborn, Humans, Infant, Lymphoproliferative Disorders, Male, Mutation, Phosphorylation, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, T-Lymphocytes, Regulatory}, issn = {1528-0020}, doi = {10.1182/blood-2014-09-602763}, author = {Milner, Joshua D and Vogel, Tiphanie P and Forbes, Lisa and Ma, Chi A and Stray-Pedersen, Asbj{\o}rg and Niemela, Julie E and Lyons, Jonathan J and Engelhardt, Karin R and Zhang, Yu and Topcagic, Nermina and Roberson, Elisha D O and Matthews, Helen and Verbsky, James W and Dasu, Trivikram and Vargas-Hernandez, Alexander and Varghese, Nidhy and McClain, Kenneth L and Karam, Lina B and Nahmod, Karen and Makedonas, George and Mace, Emily M and Sorte, Hanne S and Perminow, G{\o}ri and Rao, V Koneti and O{\textquoteright}Connell, Michael P and Price, Susan and Su, Helen C and Butrick, Morgan and McElwee, Joshua and Hughes, Jason D and Willet, Joseph and Swan, David and Xu, Yaobo and Santibanez-Koref, Mauro and Slowik, Voytek and Dinwiddie, Darrell L and Ciaccio, Christina E and Saunders, Carol J and Septer, Seth and Kingsmore, Stephen F and White, Andrew J and Cant, Andrew J and Hambleton, Sophie and Cooper, Megan A} } @article {135, title = {Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.}, journal = {Cell Rep}, volume = {12}, year = {2015}, month = {2015 Aug 18}, pages = {1169-83}, abstract = {

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in \~{} 45\% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

}, keywords = {Animals, Charcot-Marie-Tooth Disease, Exome, Female, Genetic Load, Genetic Variation, HSP40 Heat-Shock Proteins, Humans, Male, Mutation, Myelin P2 Protein, Pedigree, Penetrance, Peripheral Nervous System Diseases, Phenotype, Serine C-Palmitoyltransferase, Suppression, Genetic, Zebrafish}, issn = {2211-1247}, doi = {10.1016/j.celrep.2015.07.023}, author = {Gonzaga-Jauregui, Claudia and Harel, Tamar and Gambin, Tomasz and Kousi, Maria and Griffin, Laurie B and Francescatto, Ludmila and Ozes, Burcak and Karaca, Ender and Jhangiani, Shalini N and Bainbridge, Matthew N and Lawson, Kim S and Pehlivan, Davut and Okamoto, Yuji and Withers, Marjorie and Mancias, Pedro and Slavotinek, Anne and Reitnauer, Pamela J and Goksungur, Meryem T and Shy, Michael and Crawford, Thomas O and Koenig, Michel and Willer, Jason and Flores, Brittany N and Pediaditrakis, Igor and Us, Onder and Wiszniewski, Wojciech and Parman, Yesim and Antonellis, Anthony and Muzny, Donna M and Katsanis, Nicholas and Battaloglu, Esra and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R} } @article {181, title = {Exome sequencing identifies a homozygous C5orf42 variant in a Turkish kindred with oral-facial-digital syndrome type VI.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Sep}, pages = {2132-7}, abstract = {

Oral-facial-digital syndrome type VI (OFDVI) is a rare ciliopathy in the spectrum of Joubert syndrome (JS) and distinguished from other oral-facial-digital syndromes by metacarpal abnormalities with central polydactyly and by a molar tooth sign on cranial MRI. Additional characteristic features include short stature, micrognathia, posteriorly rotated low-set ears, hypertelorism, epicanthal folds, broad nasal tip, tongue hamartoma, upper lip notch, intraoral frenula, cleft lip/palate, and renal anomalies. Recently, novel mutations in C5orf42 were identified in 9 out of 11 OFDVI families. In a subsequent study C5orf42 was found to be mutated in only 2 out of 17 OFDVI probands while 28 patients with a pure JS phenotype also had pathogenic mutations of C5orf42. We report on two affected cousins diagnosed with OFDVI who were born from first degree cousin marriages. Whole exome sequencing (WES) identified a homozygous predicted damaging missense mutation (c.4034A > G; p.Gln1345Arg) in the C5orf42 gene. Our data contribute to the evidence that C5orf42 is one of the causative genes for OFDVI.

}, keywords = {Abnormalities, Multiple, Cerebellar Diseases, Cerebellum, Child, Cleft Palate, Exome, Eye Abnormalities, Female, Genetic Predisposition to Disease, Hamartoma, Homozygote, Humans, Kidney Diseases, Cystic, Magnetic Resonance Imaging, Male, Membrane Proteins, Middle Aged, Mutation, Orofaciodigital Syndromes, Phenotype, Retina, Turkey}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37092}, author = {Bayram, Yavuz and Aydin, Hatip and Gambin, Tomasz and Akdemir, Zeynep Coban and Atik, Mehmed M and Karaca, Ender and Karaman, Ali and Pehlivan, Davut and Jhangiani, Shalini N and Gibbs, Richard A and Lupski, James R} } @article {174, title = {Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis.}, journal = {Hum Genet}, volume = {134}, year = {2015}, month = {2015 Jun}, pages = {671-3}, abstract = {

Charcot-Marie-Tooth disease is a heterogeneous group of inherited distal symmetric polyneuropathies associated with mutations in genes encoding components essential for normal functioning of the Schwann cell and axon. TRIM2, encoding a ligase that ubiquitinates the neurofilament light chain, was recently associated with early-onset neuropathy in a single patient. We report a TRIM2 homozygous missense mutation (c.2000A>C; p.D667A) in a patient with peripheral neuropathy and bilateral vocal cord paralysis, allowing for further delineation of the associated phenotypic spectrum.

}, keywords = {Adult, Charcot-Marie-Tooth Disease, Exome, Female, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Infant, Newborn, Male, Mutation, Missense, Nuclear Proteins, Vocal Cord Paralysis}, issn = {1432-1203}, doi = {10.1007/s00439-015-1548-3}, author = {Pehlivan, Davut and Coban Akdemir, Zeynep and Karaca, Ender and Bayram, Yavuz and Jhangiani, Shalini and Yildiz, Edibe Pembegul and Muzny, Donna and Uluc, Kayihan and Gibbs, Richard A and Elcioglu, Nursel and Lupski, James R and Harel, Tamar} } @article {168, title = {Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders.}, journal = {Genome Res}, volume = {25}, year = {2015}, month = {2015 Jul}, pages = {948-57}, abstract = {

Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53\%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole-genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing.

}, keywords = {Animals, Exome, Female, Genetic Diseases, Inborn, Genetic Linkage, Genetic Variation, Genome-Wide Association Study, Genomics, High-Throughput Nucleotide Sequencing, Male, Mice, Mutation, Phenotype, Reproducibility of Results}, issn = {1549-5469}, doi = {10.1101/gr.186882.114}, author = {Fairfield, Heather and Srivastava, Anuj and Ananda, Guruprasad and Liu, Rangjiao and Kircher, Martin and Lakshminarayana, Anuradha and Harris, Belinda S and Karst, Son Yong and Dionne, Louise A and Kane, Coleen C and Curtain, Michelle and Berry, Melissa L and Ward-Bailey, Patricia F and Greenstein, Ian and Byers, Candice and Czechanski, Anne and Sharp, Jocelyn and Palmer, Kristina and Gudis, Polyxeni and Martin, Whitney and Tadenev, Abby and Bogdanik, Laurent and Pratt, C Herbert and Chang, Bo and Schroeder, David G and Cox, Gregory A and Cliften, Paul and Milbrandt, Jeffrey and Murray, Stephen and Burgess, Robert and Bergstrom, David E and Donahue, Leah Rae and Hamamy, Hanan and Masri, Amira and Santoni, Federico A and Makrythanasis, Periklis and Antonarakis, Stylianos E and Shendure, Jay and Reinholdt, Laura G} } @article {202, title = {Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.}, journal = {Int J Cancer}, volume = {137}, year = {2015}, month = {2015 Jul 15}, pages = {320-31}, abstract = {

In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5\% (4/266) of all patients, 4\% (3/77) of all familial cases and 7\% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes.

}, keywords = {Adenoma, Adolescent, Adult, Aged, Aged, 80 and over, Child, Colorectal Neoplasms, DNA Polymerase II, DNA-Directed DNA Polymerase, Family Health, Female, Gene Frequency, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Isoenzymes, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Phospholipase D, Poly-ADP-Ribose Binding Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Young Adult}, issn = {1097-0215}, doi = {10.1002/ijc.29396}, author = {Spier, Isabel and Holzapfel, Stefanie and Altm{\"u}ller, Janine and Zhao, Bixiao and Horpaopan, Sukanya and Vogt, Stefanie and Chen, Sophia and Morak, Monika and Raeder, Susanne and Kayser, Katrin and Stienen, Dietlinde and Adam, Ronja and N{\"u}rnberg, Peter and Plotz, Guido and Holinski-Feder, Elke and Lifton, Richard P and Thiele, Holger and Hoffmann, Per and Steinke, Verena and Aretz, Stefan} } @article {187, title = {Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.}, journal = {J Clin Invest}, volume = {125}, year = {2015}, month = {2015 Apr}, pages = {1703-7}, abstract = {

Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.

}, keywords = {Adult, Age of Onset, Amino Acid Sequence, Cell Line, Tumor, Cell Nucleus, Child, Child, Preschool, Chromosomes, Human, Pair 12, Cytoskeleton, Frameshift Mutation, Humans, Ichthyosis, Intermediate Filaments, Keratin-1, Keratinocytes, Loss of Heterozygosity, Male, Molecular Sequence Data, Mosaicism, Phenotype, Polymorphism, Single Nucleotide, Protein Transport, Transfection}, issn = {1558-8238}, doi = {10.1172/JCI64415}, author = {Choate, Keith A and Lu, Yin and Zhou, Jing and Elias, Peter M and Zaidi, Samir and Paller, Amy S and Farhi, Anita and Nelson-Williams, Carol and Crumrine, Debra and Milstone, Leonard M and Lifton, Richard P} } @article {146, title = {GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {1009-1014}, abstract = {

We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, Craniofacial Abnormalities, Databases, Genetic, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein K, Humans, Information Dissemination, Intellectual Disability, Male, Muscular Atrophy, Phenotype, Polymorphism, Single Nucleotide, Ribonucleoproteins, Software, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22837}, author = {Au, P Y Billie and You, Jing and Caluseriu, Oana and Schwartzentruber, Jeremy and Majewski, Jacek and Bernier, Francois P and Ferguson, Marcia and Valle, David and Parboosingh, Jillian S and Sobreira, Nara and Innes, A Micheil and Kline, Antonie D} } @article {121, title = {Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.}, journal = {Neuron}, volume = {88}, year = {2015}, month = {2015 Nov 04}, pages = {499-513}, abstract = {

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85\% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

}, keywords = {Brain, Cohort Studies, Databases, Genetic, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Variation, Humans, Male, Mendelian Randomization Analysis, Nervous System Diseases, Pedigree}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.09.048}, author = {Karaca, Ender and Harel, Tamar and Pehlivan, Davut and Jhangiani, Shalini N and Gambin, Tomasz and Coban Akdemir, Zeynep and Gonzaga-Jauregui, Claudia and Erdin, Serkan and Bayram, Yavuz and Campbell, Ian M and Hunter, Jill V and Atik, Mehmed M and Van Esch, Hilde and Yuan, Bo and Wiszniewski, Wojciech and Isikay, Sedat and Yesil, G{\"o}zde and Yuregir, Ozge O and Tug Bozdogan, Sevcan and Aslan, Huseyin and Aydin, Hatip and Tos, Tulay and Aksoy, Ayse and De Vivo, Darryl C and Jain, Preti and Geckinli, B Bilge and Sezer, Ozlem and Gul, Davut and Durmaz, Burak and Cogulu, Ozgur and Ozkinay, Ferda and Topcu, Vehap and Candan, Sukru and Cebi, Alper Han and Ikbal, Mevlit and Yilmaz Gulec, Elif and Gezdirici, Alper and Koparir, Erkan and Ekici, Fatma and Coskun, Salih and Cicek, Salih and Karaer, Kadri and Koparir, Asuman and Duz, Mehmet Bugrahan and Kirat, Emre and Fenercioglu, Elif and Ulucan, Hakan and Seven, Mehmet and Guran, Tulay and Elcioglu, Nursel and Yildirim, Mahmut Selman and Aktas, Dilek and Alika{\c s}ifo{\u g}lu, Mehmet and Ture, Mehmet and Yakut, Tahsin and Overton, John D and Yuksel, Adnan and Ozen, Mustafa and Muzny, Donna M and Adams, David R and Boerwinkle, Eric and Chung, Wendy K and Gibbs, Richard A and Lupski, James R} } @article {149, title = {The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Aug 06}, pages = {199-215}, abstract = {

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying \~{}50\% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

}, keywords = {Genetic Diseases, Inborn, Genetics, Medical, Humans, Phenotype, Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.06.009}, author = {Chong, Jessica X and Buckingham, Kati J and Jhangiani, Shalini N and Boehm, Corinne and Sobreira, Nara and Smith, Joshua D and Harrell, Tanya M and McMillin, Margaret J and Wiszniewski, Wojciech and Gambin, Tomasz and Coban Akdemir, Zeynep H and Doheny, Kimberly and Scott, Alan F and Avramopoulos, Dimitri and Chakravarti, Aravinda and Hoover-Fong, Julie and Mathews, Debra and Witmer, P Dane and Ling, Hua and Hetrick, Kurt and Watkins, Lee and Patterson, Karynne E and Reinier, Frederic and Blue, Elizabeth and Muzny, Donna and Kircher, Martin and Bilguvar, Kaya and L{\'o}pez-Gir{\'a}ldez, Francesc and Sutton, V Reid and Tabor, Holly K and Leal, Suzanne M and G{\"u}nel, Murat and Mane, Shrikant and Gibbs, Richard A and Boerwinkle, Eric and Hamosh, Ada and Shendure, Jay and Lupski, James R and Lifton, Richard P and Valle, David and Nickerson, Deborah A and Bamshad, Michael J} } @article {198, title = {Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.}, journal = {J Clin Invest}, volume = {125}, year = {2015}, month = {2015 Feb}, pages = {636-51}, abstract = {

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65\% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.

}, keywords = {Adolescent, Adult, Cell Cycle Proteins, Child, Child, Preschool, Chondroitin Sulfate Proteoglycans, Chromosomal Proteins, Non-Histone, Codon, Nonsense, De Lange Syndrome, Exome, Exonucleases, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Heterozygote, Histone Deacetylases, Histone-Lysine N-Methyltransferase, Humans, Infant, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Proteins, Repressor Proteins, Transcriptome}, issn = {1558-8238}, doi = {10.1172/JCI77435}, author = {Yuan, Bo and Pehlivan, Davut and Karaca, Ender and Patel, Nisha and Charng, Wu-Lin and Gambin, Tomasz and Gonzaga-Jauregui, Claudia and Sutton, V Reid and Yesil, G{\"o}zde and Bozdogan, Sevcan Tug and Tos, Tulay and Koparir, Asuman and Koparir, Erkan and Beck, Christine R and Gu, Shen and Aslan, Huseyin and Yuregir, Ozge Ozalp and Al Rubeaan, Khalid and Alnaqeb, Dhekra and Alshammari, Muneera J and Bayram, Yavuz and Atik, Mehmed M and Aydin, Hatip and Geckinli, B Bilge and Seven, Mehmet and Ulucan, Hakan and Fenercioglu, Elif and Ozen, Mustafa and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Tuysuz, Beyhan and Alkuraya, Fowzan S and Gibbs, Richard A and Lupski, James R} } @article {186, title = {Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 May}, pages = {E808-14}, abstract = {

CONTEXT: Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hypergonadotropic hypogonadism. Responsible genes include those with roles in gonadal development or maintenance, sex steroid synthesis, or end-organ resistance to gonadotropins. Identification of novel causative genes in this disorder will contribute to our understanding of the regulation of human reproductive function.

OBJECTIVES: The aim of this study was to identify and report the gene responsible for autosomal-recessive hypergonadotropic hypogonadism in two unrelated families.

DESIGN AND PARTICIPANTS: Clinical evaluation and whole-exome sequencing were performed in two pairs of sisters with nonsyndromic hypergonadotropic hypogonadism from two unrelated families.

RESULTS: Exome sequencing analysis revealed two different truncating mutations in the same gene: SOHLH1 c.705delT (p.Pro235fs*4) and SOHLH1 c.27C>G (p.Tyr9stop). Both mutations were unique to the families and segregation was consistent with Mendelian expectations for an autosomal-recessive mode of inheritance.

CONCLUSIONS: Sohlh1 was known from previous mouse studies to be a transcriptional regulator that functions in the maintenance and survival of primordial ovarian follicles, but loss-of-function mutations in human females have not been reported. Our results provide evidence that homozygous-truncating mutations in SOHLH1 cause female nonsyndromic hypergonadotropic hypogonadism.

}, keywords = {Adolescent, Basic Helix-Loop-Helix Transcription Factors, Child, Exome, Female, Homozygote, Humans, Hypogonadism, Mutation}, issn = {1945-7197}, doi = {10.1210/jc.2015-1150}, author = {Bayram, Yavuz and Gulsuner, Suleyman and Guran, Tulay and Abaci, Ayhan and Yesil, G{\"o}zde and Gulsuner, Hilal Unal and Atay, Zeynep and Pierce, Sarah B and Gambin, Tomasz and Lee, Ming and Turan, Serap and Bober, Ece and Atik, Mehmed M and Walsh, Tom and Karaca, Ender and Pehlivan, Davut and Jhangiani, Shalini N and Muzny, Donna and Bereket, Abdullah and Buyukgebiz, Atilla and Boerwinkle, Eric and Gibbs, Richard A and King, Mary-Claire and Lupski, James R} } @article {155, title = {Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Aug}, pages = {514-22}, abstract = {

BACKGROUND: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS.

METHODS: We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off.

RESULTS: We identified presumed causal variants in 62\% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34\% of individuals have a {\textquoteright}pure JS{\textquoteright} phenotype. Retinal disease is present in 30\% of individuals, renal disease in 25\%, coloboma in 17\%, polydactyly in 15\%, liver fibrosis in 14\% and encephalocele in 8\%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes.

CONCLUSIONS: This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.

}, keywords = {Abnormalities, Multiple, Cerebellum, Cohort Studies, DNA Mutational Analysis, Eye Abnormalities, Genetic Association Studies, Genetic Heterogeneity, Humans, Kidney Diseases, Cystic, Models, Theoretical, Pedigree, Retina, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103087}, author = {Bachmann-Gagescu, R and Dempsey, J C and Phelps, I G and O{\textquoteright}Roak, B J and Knutzen, D M and Rue, T C and Ishak, G E and Isabella, C R and Gorden, N and Adkins, J and Boyle, E A and de Lacy, N and O{\textquoteright}Day, D and Alswaid, A and Ramadevi A, Radha and Lingappa, L and Louren{\c c}o, C and Martorell, L and Garcia-Cazorla, {\`A} and Ozy{\"u}rek, H and Halilo{\u g}lu, G and Tuysuz, B and Top{\c c}u, M and Chance, P and Parisi, M A and Glass, I A and Shendure, J and Doherty, D} } @article {154, title = {KIAA0586 is Mutated in Joubert Syndrome.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Sep}, pages = {831-5}, abstract = {

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62\% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5\% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Alternative Splicing, Brain, Cell Cycle Proteins, Cerebellum, Child, Child, Preschool, DNA Mutational Analysis, Eye Abnormalities, Gene Order, Genetic Association Studies, Humans, Kidney Diseases, Cystic, Magnetic Resonance Imaging, Mutation, Phenotype, Retina, Young Adult}, issn = {1098-1004}, doi = {10.1002/humu.22821}, author = {Bachmann-Gagescu, Ruxandra and Phelps, Ian G and Dempsey, Jennifer C and Sharma, Vivek A and Ishak, Gisele E and Boyle, Evan A and Wilson, Meredith and Marques Louren{\c c}o, Charles and Arslan, Mutluay and Shendure, Jay and Doherty, Dan} } @article {131, title = {The Matchmaker Exchange: a platform for rare disease gene discovery.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {915-21}, abstract = {

There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

}, keywords = {Database Management Systems, Databases, Genetic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Information Dissemination, Rare Diseases, Software}, issn = {1098-1004}, doi = {10.1002/humu.22858}, author = {Philippakis, Anthony A and Azzariti, Danielle R and Beltran, Sergi and Brookes, Anthony J and Brownstein, Catherine A and Brudno, Michael and Brunner, Han G and Buske, Orion J and Carey, Knox and Doll, Cassie and Dumitriu, Sergiu and Dyke, Stephanie O M and den Dunnen, Johan T and Firth, Helen V and Gibbs, Richard A and Girdea, Marta and Gonzalez, Michael and Haendel, Melissa A and Hamosh, Ada and Holm, Ingrid A and Huang, Lijia and Hurles, Matthew E and Hutton, Ben and Krier, Joel B and Misyura, Andriy and Mungall, Christopher J and Paschall, Justin and Paten, Benedict and Robinson, Peter N and Schiettecatte, Fran{\c c}ois and Sobreira, Nara L and Swaminathan, Ganesh J and Taschner, Peter E and Terry, Sharon F and Washington, Nicole L and Z{\"u}chner, Stephan and Boycott, Kym M and Rehm, Heidi L} } @article {237, title = {Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Mar}, pages = {342-6}, abstract = {

Osteochondrodysplasias represent a large group of developmental structural disorders that can be caused by mutations in a variety of genes responsible for chondrocyte development, differentiation, mineralization and early ossification. The application of whole-exome sequencing to disorders apparently segregating as Mendelian traits has proven to be an effective approach to disease gene identification for conditions with unknown molecular etiology. We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity. Interestingly, the identified variant seems to have arisen as a founder mutation in the Puerto Rican population.

}, keywords = {Amino Acid Sequence, Child, Preschool, Comparative Genomic Hybridization, Exome, Female, Fibrillar Collagens, Follow-Up Studies, Founder Effect, Genotype, Hispanic Americans, Humans, Infant, Male, Molecular Sequence Data, Mutation, Osteochondrodysplasias, Pedigree, Polymorphism, Single Nucleotide, Prostaglandins F, Puerto Rico, Sequence Alignment}, issn = {1476-5438}, doi = {10.1038/ejhg.2014.107}, author = {Gonzaga-Jauregui, Claudia and Gamble, Candace N and Yuan, Bo and Penney, Samantha and Jhangiani, Shalini and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and Hecht, Jacqueline T} } @article {196, title = {Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.}, journal = {Gastroenterology}, volume = {148}, year = {2015}, month = {2015 Apr}, pages = {771-782.e11}, abstract = {

BACKGROUND \& AIMS: Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no~evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers.

METHODS: We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed.

RESULTS: We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens.

CONCLUSIONS: Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.

}, keywords = {Adult, Animals, Apolipoprotein B-100, Case-Control Studies, Cell Cycle Proteins, Chronic Disease, Core Binding Factor Alpha 2 Subunit, Enteric Nervous System, Female, Gastrointestinal Motility, Gene Expression Profiling, Gene Knockdown Techniques, HEK293 Cells, Humans, Intestinal Pseudo-Obstruction, Male, Middle Aged, Nuclear Proteins, Phosphoproteins, RNA, Messenger, Sequence Analysis, DNA, Young Adult, Zebrafish, Zebrafish Proteins}, issn = {1528-0012}, doi = {10.1053/j.gastro.2014.12.034}, author = {Bonora, Elena and Bianco, Francesca and Cordeddu, Lina and Bamshad, Michael and Francescatto, Ludmila and Dowless, Dustin and Stanghellini, Vincenzo and Cogliandro, Rosanna F and Lindberg, Greger and Mungan, Zeynel and Cefle, Kivanc and Ozcelik, Tayfun and Palanduz, Sukru and Ozturk, Sukru and Gedikbasi, Asuman and Gori, Alessandra and Pippucci, Tommaso and Graziano, Claudio and Volta, Umberto and Caio, Giacomo and Barbara, Giovanni and D{\textquoteright}Amato, Mauro and Seri, Marco and Katsanis, Nicholas and Romeo, Giovanni and De Giorgio, Roberto} } @article {130, title = {Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Sep 03}, pages = {457-64}, abstract = {

Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, ATPases Associated with Diverse Cellular Activities, Base Sequence, Exome, Female, Gene Frequency, Genes, Recessive, Hearing Loss, Homeodomain Proteins, Humans, Intellectual Disability, Male, Microcephaly, Molecular Sequence Data, Mutation, Seizures, Sequence Alignment, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.07.014}, author = {Tanaka, Akemi J and Cho, Megan T and Millan, Francisca and Juusola, Jane and Retterer, Kyle and Joshi, Charuta and Niyazov, Dmitriy and Garnica, Adolfo and Gratz, Edward and Deardorff, Matthew and Wilkins, Alisha and Ortiz-Gonzalez, Xilma and Mathews, Katherine and Panzer, Karin and Brilstra, Eva and van Gassen, Koen L I and Volker-Touw, Catharina M L and van Binsbergen, Ellen and Sobreira, Nara and Hamosh, Ada and McKnight, Dianalee and Monaghan, Kristin G and Chung, Wendy K} } @article {216, title = {New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.}, journal = {JAMA Ophthalmol}, volume = {133}, year = {2015}, month = {2015 Feb}, pages = {133-9}, abstract = {

IMPORTANCE: The families evaluated in this study represent the second report of cone-rod dystrophy (CRD) cases caused by mutations in RAB28, a recently discovered gene associated with CRD.

OBJECTIVE: To determine the disease-causing gene in 2 families of Spanish descent presenting with CRD who do not have ABCA4 mutations.

DESIGN, SETTING, AND PARTICIPANTS: Molecular genetics and observational case studies of 2 families, each with 1 affected proband with CRD and 3 or 5 unaffected family members. The affected individual from each family received a complete ophthalmic examination including assessment of refractive errors and best-corrected visual acuity, biomicroscopy, color fundus photography, electroretinography analysis, and visual-evoked potential analysis. After complete sequencing of the ABCA4 gene with negative results, the screening for disease-causing mutations was performed by whole-exome sequencing. Possible disease-associated variants were determined by filtering based on minor allele frequency, predicted pathogenicity, and segregation analysis in all family members.

MAIN OUTCOMES AND MEASURES: The appearance of the macula was evaluated by clinical examination, fundus photography, and fundus autofluorescence imaging, and visual function was assessed by electroretinography. Disease-causing mutations were assessed by sequence analyses.

RESULTS: Ophthalmologic findings included markedly reduced visual acuity, bull{\textquoteright}s eye maculopathy, foveal hyperpigmentation, peripapillary atrophy, dyschromatopsia, extinguished photopic responses, and reduced scotopic responses observed on electroretinography consistent with the CRD phenotype often associated with ABCA4 mutations. Although no ABCA4 mutations were detected in either patient, whole-exome sequencing analysis identified 2 new homozygous mutations in the recently described RAB28 gene, the c.172 + 1G>C splice site variant in IVS2 and the missense c.T651G:p.C217W substitution. Both variants were determined as deleterious by predictive programs and were segregated with the disease in both families. Sequencing of 107 additional patients of Spanish descent with CRD did not reveal other cases with RAB28 mutations.

CONCLUSIONS AND RELEVANCE: Deleterious mutations in RAB28 result in a classic CRD phenotype and are an infrequent cause of CRD in the Spanish population.

}, keywords = {Adolescent, Adult, Child, Diagnosis, Differential, DNA Mutational Analysis, Female, Follow-Up Studies, Genetic Predisposition to Disease, Hispanic Americans, Humans, Male, Microscopy, Acoustic, Mutation, Pedigree, Phenotype, rab GTP-Binding Proteins, Retinitis Pigmentosa, Retrospective Studies, Young Adult}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2014.4266}, author = {Riveiro-{\'A}lvarez, Rosa and Xie, Yajing Angela and L{\'o}pez-Mart{\'\i}nez, Miguel-{\'A}ngel and Gambin, Tomasz and P{\'e}rez-Carro, Raquel and {\'A}vila-Fern{\'a}ndez, Almudena and L{\'o}pez-Molina, Mar{\'\i}a-Isabel and Zernant, Jana and Jhangiani, Shalini and Muzny, Donna and Yuan, Bo and Boerwinkle, Eric and Gibbs, Richard and Lupski, James R and Ayuso, Carmen and Allikmets, Rando} } @article {223, title = {NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy.}, journal = {Eur J Med Genet}, volume = {58}, year = {2015}, month = {2015 Jan}, pages = {39-43}, abstract = {

N-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteasome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson{\textquoteright}s disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA, p.Asn511LysfsX51). We hypothesize that this mutation likely limits the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, Corneal Opacity, Developmental Disabilities, Female, Frameshift Mutation, Genotype, Humans, Intellectual Disability, Male, Movement Disorders, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, Peripheral Nervous System Diseases}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2014.08.008}, author = {{\c C}a{\u g}layan, Ahmet Okay and Comu, Sinan and Baranoski, Jacob F and Parman, Yesim and Kaymak{\c c}alan, Hande and Akg{\"u}m{\"u}{\c s}, G{\"o}zde Tu{\u g}ce and Caglar, Caner and D{\"o}len, Duygu and Erson-Omay, Emine Zeynep and Harmanci, Akdes Serin and Mishra-Gorur, Ketu and Freeze, Hudson H and Yasuno, Katsuhito and Bilguvar, Kaya and G{\"u}nel, Murat} } @article {120, title = {Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {691-707}, abstract = {

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.

}, keywords = {Abnormalities, Multiple, Charcot-Marie-Tooth Disease, Child, Child, Preschool, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 17, Comparative Genomic Hybridization, Female, Follow-Up Studies, Gene Duplication, Gene Rearrangement, Genome, Human, Genomics, Humans, Infant, Male, Models, Genetic, Myelin Proteins, Phenotype, Prognosis, Recombination, Genetic, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.10.003}, author = {Yuan, Bo and Harel, Tamar and Gu, Shen and Liu, Pengfei and Burglen, Lydie and Chantot-Bastaraud, Sandra and Gelowani, Violet and Beck, Christine R and Carvalho, Claudia M B and Cheung, Sau Wai and Coe, Andrew and Malan, Val{\'e}rie and Munnich, Arnold and Magoulas, Pilar L and Potocki, Lorraine and Lupski, James R} } @article {144, title = {Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {1004-8}, abstract = {

Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.

}, keywords = {Adolescent, Adult, Child, Collagen Type II, Exome, Female, Humans, Joint Diseases, Male, Osteochondrodysplasias, Pedigree, Polymorphism, Single Nucleotide, Radiography, Sequence Analysis, DNA}, issn = {1098-1004}, doi = {10.1002/humu.22839}, author = {Jurgens, Julie and Sobreira, Nara and Modaff, Peggy and Reiser, Catherine A and Seo, Soo Hyun and Seong, Moon-Woo and Park, Sung Sup and Kim, Ok Hwa and Cho, Tae-Joon and Pauli, Richard M} } @article {152, title = {Rare A2ML1 variants confer susceptibility to otitis media.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Aug}, pages = {917-20}, abstract = {

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

}, keywords = {alpha-Macroglobulins, Animals, Base Sequence, Child, Cochlea, Exome, Family Health, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Otitis Media, Pedigree, Principal Component Analysis, Protein Conformation, Sequence Analysis, DNA}, issn = {1546-1718}, doi = {10.1038/ng.3347}, author = {Santos-Cortez, Regie Lyn P and Chiong, Charlotte M and Reyes-Quintos, Ma Rina T and Tantoco, Ma Leah C and Wang, Xin and Acharya, Anushree and Abbe, Izoduwa and Giese, Arnaud P and Smith, Joshua D and Allen, E Kaitlynn and Li, Biao and Cutiongco-de la Paz, Eva Maria and Garcia, Marieflor Cristy and Llanes, Erasmo Gonzalo D V and Labra, Patrick John and Gloria-Cruz, Teresa Luisa I and Chan, Abner L and Wang, Gao T and Daly, Kathleen A and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Patel, Janak A and Riazuddin, Saima and Sale, Michele M and Chonmaitree, Tasnee and Ahmed, Zubair M and Abes, Generoso T and Leal, Suzanne M} } @article {195, title = {Rare variants in RTEL1 are associated with familial interstitial pneumonia.}, journal = {Am J Respir Crit Care Med}, volume = {191}, year = {2015}, month = {2015 Mar 15}, pages = {646-55}, abstract = {

RATIONALE: Up to 20\% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.

OBJECTIVES: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.

METHODS: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds.

MEASUREMENTS AND MAIN RESULTS: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7\%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10\% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function.

CONCLUSIONS: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

}, keywords = {Aged, Aged, 80 and over, DNA Helicases, Female, Genetic Variation, Heterozygote, Humans, Lung, Lung Diseases, Interstitial, Male, Middle Aged, Pedigree, Telomere}, issn = {1535-4970}, doi = {10.1164/rccm.201408-1510OC}, author = {Cogan, Joy D and Kropski, Jonathan A and Zhao, Min and Mitchell, Daphne B and Rives, Lynette and Markin, Cheryl and Garnett, Errine T and Montgomery, Keri H and Mason, Wendi R and McKean, David F and Powers, Julia and Murphy, Elissa and Olson, Lana M and Choi, Leena and Cheng, Dong-Sheng and Blue, Elizabeth Marchani and Young, Lisa R and Lancaster, Lisa H and Steele, Mark P and Brown, Kevin K and Schwarz, Marvin I and Fingerlin, Tasha E and Schwartz, David A and Lawson, William E and Loyd, James E and Zhao, Zhongming and Phillips, John A and Blackwell, Timothy S} } @article {137, title = {Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Nov}, pages = {2795-9}, abstract = {

Klippel-Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel-Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel-Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left-right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel-Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel{\textquoteright}s deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel-Feil syndrome, and in addition-from a mechanistic standpoint-suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy. {\textcopyright} 2015 Wiley Periodicals, Inc.

}, keywords = {Adolescent, Base Sequence, Female, Humans, Klippel-Feil Syndrome, Male, Molecular Sequence Data, Mutation, Pedigree, Radiography, Receptors, Notch, Signal Transduction, Spine}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37263}, author = {Karaca, Ender and Yuregir, Ozge O and Bozdogan, Sevcan T and Aslan, Huseyin and Pehlivan, Davut and Jhangiani, Shalini N and Akdemir, Zeynep C and Gambin, Tomasz and Bayram, Yavuz and Atik, Mehmed M and Erdin, Serkan and Muzny, Donna and Gibbs, Richard A and Lupski, James R} } @article {171, title = {Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.}, journal = {Elife}, volume = {4}, year = {2015}, month = {2015 Apr 24}, pages = {e06315}, abstract = {

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5\%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

}, keywords = {Adolescent, Adult, Age of Onset, Aldosterone, Amino Acid Sequence, Calcium, Calcium Channels, T-Type, Calcium Signaling, Child, Child, Preschool, Female, Gene Expression, Genotype, Heterozygote, Humans, Hyperaldosteronism, Hypertension, Infant, Male, Membrane Potentials, Middle Aged, Molecular Sequence Data, Mutation, Phenotype, Recurrence, Sequence Alignment, Zona Glomerulosa}, issn = {2050-084X}, doi = {10.7554/eLife.06315}, author = {Scholl, Ute I and St{\"o}lting, Gabriel and Nelson-Williams, Carol and Vichot, Alfred A and Choi, Murim and Loring, Erin and Prasad, Manju L and Goh, Gerald and Carling, Tobias and Juhlin, C Christofer and Quack, Ivo and Rump, Lars C and Thiel, Anne and Lande, Marc and Frazier, Britney G and Rasoulpour, Majid and Bowlin, David L and Sethna, Christine B and Trachtman, Howard and Fahlke, Christoph and Lifton, Richard P} } @article {143, title = {Secondary findings and carrier test frequencies in a large multiethnic sample.}, journal = {Genome Med}, volume = {7}, year = {2015}, month = {2015}, pages = {54}, abstract = {

BACKGROUND: Besides its growing importance in clinical diagnostics and understanding the genetic basis of Mendelian and complex diseases, whole exome sequencing (WES) is a rich source of additional information of potential clinical utility for physicians, patients and their families. We analyzed the frequency and nature of single nucleotide variants (SNVs) considered secondary findings and recessive disease allele carrier status in the exomes of 8554 individuals from a large, randomly sampled cohort study and 2514 patients from a study of presumed Mendelian disease having undergone WES.

METHODS: We used the same sequencing platform and data processing pipeline to analyze all samples and characterized the distributions of reported pathogenic (ClinVar, Human Gene Mutation Database (HGMD)) and predicted deleterious variants in the pre-specified American College of Medical Genetics and Genomics (ACMG) secondary findings and recessive disease genes in different ethnic groups.

RESULTS: In the 56 ACMG secondary findings genes, the average number of predicted deleterious variants per individual was 0.74, and the mean number of ClinVar reported pathogenic variants was 0.06. We observed an average of 10 deleterious and 0.78 ClinVar reported pathogenic variants per individual in 1423 autosomal recessive disease genes. By repeatedly sampling pairs of exomes, 0.5~\% of the randomly generated couples were at 25~\% risk of having an affected offspring for an autosomal recessive disorder based on the ClinVar variants.

CONCLUSIONS: By investigating reported pathogenic and novel, predicted deleterious variants we estimated the lower and upper limits of the population fraction for which exome sequencing may reveal additional medically relevant information. We suggest that the observed wide range for the lower and upper limits of these frequency numbers will be gradually reduced due to improvement in classification databases and prediction algorithms.

}, issn = {1756-994X}, doi = {10.1186/s13073-015-0171-1}, author = {Gambin, Tomasz and Jhangiani, Shalini N and Below, Jennifer E and Campbell, Ian M and Wiszniewski, Wojciech and Muzny, Donna M and Staples, Jeffrey and Morrison, Alanna C and Bainbridge, Matthew N and Penney, Samantha and McGuire, Amy L and Gibbs, Richard A and Lupski, James R and Boerwinkle, Eric} } @article {148, title = {An siRNA-based functional genomics screen for the~identification of regulators of ciliogenesis and ciliopathy~genes.}, journal = {Nat Cell Biol}, volume = {17}, year = {2015}, month = {2015 Aug}, pages = {1074-1087}, abstract = {

Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

}, keywords = {Abnormalities, Multiple, Animals, Caenorhabditis elegans, Cerebellar Diseases, Cerebellum, Cilia, Ciliary Motility Disorders, Databases, Genetic, Ellis-Van Creveld Syndrome, Eye Abnormalities, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Genomics, HEK293 Cells, High-Throughput Nucleotide Sequencing, Humans, Kidney Diseases, Cystic, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Photoreceptor Cells, Pregnancy Proteins, Proteins, Reproducibility of Results, Retina, RNA Interference, Suppressor Factors, Immunologic, Transfection, Zebrafish}, issn = {1476-4679}, doi = {10.1038/ncb3201}, author = {Wheway, Gabrielle and Schmidts, Miriam and Mans, Dorus A and Szymanska, Katarzyna and Nguyen, Thanh-Minh T and Racher, Hilary and Phelps, Ian G and Toedt, Grischa and Kennedy, Julie and Wunderlich, Kirsten A and Sorusch, Nasrin and Abdelhamed, Zakia A and Natarajan, Subaashini and Herridge, Warren and van Reeuwijk, Jeroen and Horn, Nicola and Boldt, Karsten and Parry, David A and Letteboer, Stef J F and Roosing, Susanne and Adams, Matthew and Bell, Sandra M and Bond, Jacquelyn and Higgins, Julie and Morrison, Ewan E and Tomlinson, Darren C and Slaats, Gisela G and van Dam, Teunis J P and Huang, Lijia and Kessler, Kristin and Giessl, Andreas and Logan, Clare V and Boyle, Evan A and Shendure, Jay and Anazi, Shamsa and Aldahmesh, Mohammed and Al Hazzaa, Selwa and Hegele, Robert A and Ober, Carole and Frosk, Patrick and Mhanni, Aizeddin A and Chodirker, Bernard N and Chudley, Albert E and Lamont, Ryan and Bernier, Francois P and Beaulieu, Chandree L and Gordon, Paul and Pon, Richard T and Donahue, Clem and Barkovich, A James and Wolf, Louis and Toomes, Carmel and Thiel, Christian T and Boycott, Kym M and McKibbin, Martin and Inglehearn, Chris F and Stewart, Fiona and Omran, Heymut and Huynen, Martijn A and Sergouniotis, Panagiotis I and Alkuraya, Fowzan S and Parboosingh, Jillian S and Innes, A Micheil and Willoughby, Colin E and Giles, Rachel H and Webster, Andrew R and Ueffing, Marius and Blacque, Oliver and Gleeson, Joseph G and Wolfrum, Uwe and Beales, Philip L and Gibson, Toby and Doherty, Dan and Mitchison, Hannah M and Roepman, Ronald and Johnson, Colin A} } @article {201, title = {TBX6 null variants and a common hypomorphic allele in congenital scoliosis.}, journal = {N Engl J Med}, volume = {372}, year = {2015}, month = {2015 Jan 22}, pages = {341-50}, abstract = {

BACKGROUND: Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.

METHODS: We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions.

RESULTS: We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11\%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8{\texttimes}10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1{\texttimes}10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis.

CONCLUSIONS: Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11\% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.).

}, keywords = {Adolescent, Asian Continental Ancestry Group, Child, Child, Preschool, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Mutation, Pedigree, Phenotype, Radiography, Scoliosis, Sequence Deletion, Spine, T-Box Domain Proteins}, issn = {1533-4406}, doi = {10.1056/NEJMoa1406829}, author = {Wu, N and Ming, X and Xiao, J and Wu, Z and Chen, X and Shinawi, M and Shen, Y and Yu, G and Liu, J and Xie, H and Gucev, Z S and Liu, S and Yang, N and Al-Kateb, H and Chen, J and Zhang, J and Hauser, N and Zhang, T and Tasic, V and Liu, P and Su, X and Pan, X and Liu, C and Wang, L and Shen, J and Shen, J and Chen, Y and Zhang, T and Zhang, J and Choy, K W and Wang, J and Wang, Q and Li, S and Zhou, W and Guo, J and Wang, Y and Zhang, C and Zhao, Hong and An, Yu and Zhao, Yu and Wang, J and Liu, Z and Zuo, Y and Tian, Y and Weng, X and Sutton, V R and Wang, H and Ming, Y and Kulkarni, S and Zhong, T P and Giampietro, P F and Dunwoodie, S L and Cheung, S W and Zhang, X and Jin, L and Lupski, J R and Qiu, G and Zhang, F} } @article {218, title = {Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 Jan}, pages = {E140-7}, abstract = {

CONTEXT: Pituitary stalk interruption syndrome (PSIS) is a rare, congenital anomaly of the pituitary gland characterized by pituitary gland insufficiency, thin or discontinuous pituitary stalk, anterior pituitary hypoplasia, and ectopic positioning of the posterior pituitary gland (neurohypophysis). The clinical presentation of patients with PSIS varies from isolated growth hormone (GH) deficiency to combined pituitary insufficiency and accompanying extrapituitary findings. Mutations in HESX1, LHX4, OTX2, SOX3, and PROKR2 have been associated with PSIS in less than 5\% of cases; thus, the underlying genetic etiology for the vast majority of cases remains to be determined.

OBJECTIVE: We applied whole-exome sequencing (WES) to a consanguineous family with two affected siblings who have pituitary gland insufficiency and radiographic findings of hypoplastic (thin) pituitary gland, empty sella, ectopic neurohypophysis, and interrupted pitiutary stalk-characteristic clinical diagnostic findings of PSIS.

DESIGN AND PARTICIPANTS: WES was applied to two affected and one unaffected siblings.

RESULTS: WES of two affected and one unaffected sibling revealed a unique homozygous missense mutation in GPR161, which encodes the orphan G protein-coupled receptor 161, a protein responsible for transducing extracellular signals across the plasma membrane into the cell.

CONCLUSION: Mutations of GPR161 may be implicated as a potential novel cause of PSIS.

}, keywords = {Adolescent, Child, Preschool, Exome, Female, Genome-Wide Association Study, Humans, Hypopituitarism, Mutation, Pituitary Gland, Receptors, G-Protein-Coupled}, issn = {1945-7197}, doi = {10.1210/jc.2014-1984}, author = {Karaca, Ender and Buyukkaya, Ramazan and Pehlivan, Davut and Charng, Wu-Lin and Yaykasli, Kursat O and Bayram, Yavuz and Gambin, Tomasz and Withers, Marjorie and Atik, Mehmed M and Arslanoglu, Ilknur and Bolu, Semih and Erdin, Serkan and Buyukkaya, Ayla and Yaykasli, Emine and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R} } @article {189, title = {X-linked acrogigantism syndrome: clinical profile and therapeutic responses.}, journal = {Endocr Relat Cancer}, volume = {22}, year = {2015}, month = {2015 Jun}, pages = {353-67}, abstract = {

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Chromosomes, Human, X, Female, Gigantism, Humans, Infant, Male, Pituitary Neoplasms, Young Adult}, issn = {1479-6821}, doi = {10.1530/ERC-15-0038}, author = {Beckers, Albert and Lodish, Maya Beth and Trivellin, Giampaolo and Rostomyan, Liliya and Lee, Misu and Faucz, Fabio R and Yuan, Bo and Choong, Catherine S and Caberg, Jean-Hubert and Verrua, Elisa and Naves, Luciana Ansaneli and Cheetham, Tim D and Young, Jacques and Lysy, Philippe A and Petrossians, Patrick and Cotterill, Andrew and Shah, Nalini Samir and Metzger, Daniel and Castermans, Emilie and Ambrosio, Maria Rosaria and Villa, Chiara and Strebkova, Natalia and Mazerkina, Nadia and Gaillard, St{\'e}phan and Barra, Gustavo Barcelos and Casulari, Luis Augusto and Neggers, Sebastian J and Salvatori, Roberto and Jaffrain-Rea, Marie-Lise and Zacharin, Margaret and Santamaria, Beatriz Lecumberri and Zacharieva, Sabina and Lim, Ee Mun and Mantovani, Giovanna and Zatelli, Maria Chaira and Collins, Michael T and Bonneville, Jean-Fran{\c c}ois and Quezado, Martha and Chittiboina, Prashant and Oldfield, Edward H and Bours, Vincent and Liu, Pengfei and W de Herder, Wouter and Pellegata, Natalia and Lupski, James R and Daly, Adrian F and Stratakis, Constantine A} } @article {231, title = {The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {143-61}, abstract = {

Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70\%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22\%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects{\textquoteright} genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci.

}, keywords = {Adenosine Triphosphatases, Alu Elements, Base Sequence, Cation Transport Proteins, Cell Line, Transformed, DNA Copy Number Variations, Genotype, Humans, Protein Isoforms, Recombinant Fusion Proteins, Sequence Analysis, DNA, Sequence Deletion, Spastic Paraplegia, Hereditary, Spastin}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.06.014}, author = {Boone, Philip M and Yuan, Bo and Campbell, Ian M and Scull, Jennifer C and Withers, Marjorie A and Baggett, Brett C and Beck, Christine R and Shaw, Christine J and Stankiewicz, Pawel and Moretti, Paolo and Goodwin, Wendy E and Hein, Nichole and Fink, John K and Seong, Moon-Woo and Seo, Soo Hyun and Park, Sung Sup and Karbassi, Izabela D and Batish, Sat Dev and Ord{\'o}{\~n}ez-Ugalde, Andr{\'e}s and Quint{\'a}ns, Beatriz and Sobrido, Mar{\'\i}a-Jes{\'u}s and Stemmler, Susanne and Lupski, James R} } @article {251, title = {Clinical utility of whole-exome sequencing in rare diseases: Galactosialidosis.}, journal = {Eur J Med Genet}, volume = {57}, year = {2014}, month = {2014 Jul}, pages = {339-344}, abstract = {

Rare genetic disorders can go undiagnosed for years as the entire spectrum of phenotypic variation is not well characterized given the reduced number of patients reported in the literature and the low frequency at which these occur. Moreover, the current paradigm for clinical diagnostics defines disease diagnosis by a specified spectrum of phenotypic findings; when such parameters are either missing, or other findings not usually observed are seen, the phenotype driven approach to diagnosis may result in a specific etiological diagnosis not even being considered within the differential diagnosis. The novel implementation of genomic sequencing approaches to investigate rare genetic disorders is allowing not only the discovery of new genes, but also the phenotypic expansion of known Mendelian genetic disorders. Here we report the detailed clinical assessment of a patient with a rare genetic disorder with undefined molecular diagnosis. We applied whole-exome sequencing to this patient and unaffected parents in order to identify the molecular cause of her disorder. We identified compound heterozygous mutations in the CTSA gene, responsible for causing galactosialidosis; the molecular diagnosis was further confirmed by biochemical studies. This report expands on the clinical spectrum of this rare lysosomal disorder and exemplifies how genomic approaches are further elucidating the characterization and understanding of genetic diseases.

}, keywords = {Adult, Cathepsin A, Exome, Female, Humans, Lysosomal Storage Diseases, Mutation, Rare Diseases, Sequence Analysis, DNA, Young Adult}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2014.04.005}, author = {Prada, Carlos E and Gonzaga-Jauregui, Claudia and Tannenbaum, Rebecca and Penney, Samantha and Lupski, James R and Hopkin, Robert J and Sutton, V Reid} } @article {248, title = {De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {784-9}, abstract = {

Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25\% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.

}, keywords = {Child, Child, Preschool, DNA-Binding Proteins, Exome, Female, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Muscle Hypotonia, Mutation, Sleep Apnea Syndromes, Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.04.006}, author = {Xia, Fan and Bainbridge, Matthew N and Tan, Tiong Yang and Wangler, Michael F and Scheuerle, Angela E and Zackai, Elaine H and Harr, Margaret H and Sutton, V Reid and Nalam, Roopa L and Zhu, Wenmiao and Nash, Margot and Ryan, Monique M and Yaplito-Lee, Joy and Hunter, Jill V and Deardorff, Matthew A and Penney, Samantha J and Beaudet, Arthur L and Plon, Sharon E and Boerwinkle, Eric A and Lupski, James R and Eng, Christine M and Muzny, Donna M and Yang, Yaping and Gibbs, Richard A} } @article {240, title = {Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2240-9}, abstract = {

Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dysostosis (MFD) and macrocytic anemia diagnostic of Diamond-Blackfan anemia (DBA) have been reported. Disease-causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease-causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from six unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies. {\textcopyright} 2014 Wiley Periodicals, Inc.

}, keywords = {Adult, Anemia, Diamond-Blackfan, Apoptosis Regulatory Proteins, Child, Preschool, Exome, Family, Female, Genetic Heterogeneity, Humans, Infant, Infant, Newborn, Male, Mandibulofacial Dysostosis, Pedigree, Phenotype, Pregnancy, Ribosomal Proteins, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36633}, author = {Gripp, Karen W and Curry, Cynthia and Olney, Ann Haskins and Sandoval, Claudio and Fisher, Jamie and Chong, Jessica Xiao-Ling and Pilchman, Lisa and Sahraoui, Rebecca and Stabley, Deborah L and Sol-Church, Katia} } @article {277, title = {DIAMUND: direct comparison of genomes to detect mutations.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Mar}, pages = {283-8}, abstract = {

DNA sequencing has become a powerful method to discover the genetic basis of disease. Standard, widely used protocols for analysis usually begin by comparing each individual to the human reference genome. When applied to a set of related individuals, this approach reveals millions of differences, most of which are shared among the individuals and unrelated to the disease being investigated. We have developed a novel algorithm for variant detection, one that compares DNA sequences directly to one another, without aligning them to the reference genome. When used to find de novo mutations in exome sequences from family trios, or to compare normal and diseased samples from the same individual, the new method, direct alignment for mutation discovery (DIAMUND), produces a dramatically smaller list of candidate mutations than previous methods, without losing sensitivity to detect the true cause of a genetic disease. We demonstrate our results on several example cases, including two family trios in which it correctly found the disease-causing variant while excluding thousands of harmless variants that standard methods had identified.

}, keywords = {Algorithms, Computational Biology, Exome, Genetic Loci, Genetic Variation, Genome, Human, Humans, Mutation, Sequence Alignment, Sequence Analysis, DNA, Software}, issn = {1098-1004}, doi = {10.1002/humu.22503}, author = {Salzberg, Steven L and Pertea, Mihaela and Fahrner, Jill A and Sobreira, Nara} } @article {209, title = {Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Nov 06}, pages = {565-78}, abstract = {

The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in~vitro. Moreover, epistatic analyses in~vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.

}, keywords = {Abnormalities, Multiple, Acyl-CoA Dehydrogenase, Long-Chain, Adaptor Proteins, Signal Transducing, Animals, Asialoglycoprotein Receptor, Base Sequence, Cell Line, Chromosome Breakpoints, Chromosome Deletion, Chromosomes, Human, Pair 17, Dishevelled Proteins, Flow Cytometry, Gene Dosage, Humans, Immunohistochemistry, Intellectual Disability, Microcephaly, Microtubule-Associated Proteins, Molecular Sequence Data, Phosphoproteins, Retrospective Studies, Sequence Analysis, DNA, Smith-Magenis Syndrome, Syndrome, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.10.006}, author = {Carvalho, Claudia M B and Vasanth, Shivakumar and Shinawi, Marwan and Russell, Chad and Ramocki, Melissa B and Brown, Chester W and Graakjaer, Jesper and Skytte, Anne-Bine and Vianna-Morgante, Angela M and Krepischi, Ana C V and Patel, Gayle S and Immken, LaDonna and Aleck, Kyrieckos and Lim, Cynthia and Cheung, Sau Wai and Rosenberg, Carla and Katsanis, Nicholas and Lupski, James R} } @article {220, title = {A drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases.}, journal = {Cell}, volume = {159}, year = {2014}, month = {2014 Sep 25}, pages = {200-214}, abstract = {

Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health.

}, keywords = {Animals, Disease, Disease Models, Animal, Drosophila melanogaster, Genetic Testing, Humans, Inheritance Patterns, RNA Interference, X Chromosome}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.09.002}, author = {Yamamoto, Shinya and Jaiswal, Manish and Charng, Wu-Lin and Gambin, Tomasz and Karaca, Ender and Mirzaa, Ghayda and Wiszniewski, Wojciech and Sandoval, Hector and Haelterman, Nele A and Xiong, Bo and Zhang, Ke and Bayat, Vafa and David, Gabriela and Li, Tongchao and Chen, Kuchuan and Gala, Upasana and Harel, Tamar and Pehlivan, Davut and Penney, Samantha and Vissers, Lisenka E L M and de Ligt, Joep and Jhangiani, Shalini N and Xie, Yajing and Tsang, Stephen H and Parman, Yesim and Sivaci, Merve and Battaloglu, Esra and Muzny, Donna and Wan, Ying-Wooi and Liu, Zhandong and Lin-Moore, Alexander T and Clark, Robin D and Curry, Cynthia J and Link, Nichole and Schulze, Karen L and Boerwinkle, Eric and Dobyns, William B and Allikmets, Rando and Gibbs, Richard A and Chen, Rui and Lupski, James R and Wangler, Michael F and Bellen, Hugo J} } @article {227, title = {Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {235-40}, abstract = {

Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Base Sequence, Craniofacial Abnormalities, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Face, Hedgehog Proteins, Humans, Intellectual Disability, Limb Deformities, Congenital, Mandibulofacial Dysostosis, Mice, Molecular Sequence Data, Mutation, Protein Structure, Tertiary, Zebrafish, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.008}, author = {Smith, Joshua D and Hing, Anne V and Clarke, Christine M and Johnson, Nathan M and Perez, Francisco A and Park, Sarah S and Horst, Jeremy A and Mecham, Brig and Maves, Lisa and Nickerson, Deborah A and Cunningham, Michael L} } @article {285, title = {Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D.}, journal = {Genet Med}, volume = {16}, year = {2014}, month = {2014 May}, pages = {386-394}, abstract = {

PURPOSE: Copy-number variations as a mutational mechanism contribute significantly to human disease. Approximately one-half of the patients with Charcot-Marie-Tooth (CMT) disease have a 1.4 Mb duplication copy-number variation as the cause of their neuropathy. However, non-CMT1A neuropathy patients rarely have causative copy-number variations, and to date, autosomal-recessive disease has not been associated with copy-number variation as a mutational mechanism.

METHODS: We performed Agilent 8 {\texttimes} 60 K array comparative genomic hybridization on DNA from 12 recessive Turkish families with CMT disease. Additional molecular studies were conducted to detect breakpoint junctions and to evaluate gene expression levels in a family in which we detected an intragenic duplication copy-number variation.

RESULTS: We detected an ~6.25 kb homozygous intragenic duplication in NDRG1, a gene known to be causative for recessive HMSNL/CMT4D, in three individuals from a Turkish family with CMT neuropathy. Further studies showed that this intragenic copy-number variation resulted in a homozygous duplication of exons 6-8 that caused decreased mRNA expression of NDRG1.

CONCLUSION: Exon-focused high-resolution array comparative genomic hybridization enables the detection of copy-number variation carrier states in recessive genes, particularly small copy-number variations encompassing or disrupting single genes. In families for whom a molecular diagnosis has not been elucidated by conventional clinical assays, an assessment for copy-number variations in known CMT genes might be considered.

}, keywords = {Adult, Base Sequence, Cell Cycle Proteins, Charcot-Marie-Tooth Disease, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Gene Duplication, Gene Expression, Genes, Recessive, Humans, Intracellular Signaling Peptides and Proteins, Male, Mutation, Refsum Disease, Sequence Analysis, DNA, Turkey, Young Adult}, issn = {1530-0366}, doi = {10.1038/gim.2013.155}, author = {Okamoto, Yuji and Goksungur, Meryem Tuba and Pehlivan, Davut and Beck, Christine R and Gonzaga-Jauregui, Claudia and Muzny, Donna M and Atik, Mehmed M and Carvalho, Claudia M B and Matur, Zeliha and Bayraktar, Serife and Boone, Philip M and Akyuz, Kaya and Gibbs, Richard A and Battaloglu, Esra and Parman, Yesim and Lupski, James R} } @article {258, title = {Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency.}, journal = {Orphanet J Rare Dis}, volume = {9}, year = {2014}, month = {2014 Mar 27}, pages = {43}, abstract = {

BACKGROUND: Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism.

METHODS/RESULTS: High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S1 phase. Based on the patient{\textquoteright}s distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them.

CONCLUSIONS: This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency.

}, keywords = {Abnormalities, Multiple, Cell Cycle, Chromatin Assembly and Disassembly, DNA-Binding Proteins, Face, Female, Hand Deformities, Congenital, Haploinsufficiency, Humans, Intellectual Disability, Male, Micrognathism, Neck, Transcription Factors}, issn = {1750-1172}, doi = {10.1186/1750-1172-9-43}, author = {Sim, Joe C H and White, Susan M and Fitzpatrick, Elizabeth and Wilson, Gabrielle R and Gillies, Greta and Pope, Kate and Mountford, Hayley S and Torring, Pernille M and McKee, Shane and Vulto-van Silfhout, Anneke T and Jhangiani, Shalini N and Muzny, Donna M and Leventer, Richard J and Delatycki, Martin B and Amor, David J and Lockhart, Paul J} } @article {281, title = {The genetic basis of DOORS syndrome: an exome-sequencing study.}, journal = {Lancet Neurol}, volume = {13}, year = {2014}, month = {2014 Jan}, pages = {44-58}, abstract = {

BACKGROUND: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.

METHODS: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.

FINDINGS: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.

INTERPRETATION: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.

FUNDING: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

}, keywords = {Adolescent, Carrier Proteins, Child, Child, Preschool, Craniofacial Abnormalities, Exome, Female, Hand Deformities, Congenital, Hearing Loss, Sensorineural, Humans, Infant, Intellectual Disability, Internationality, Male, Nails, Malformed, Phenotype, Sequence Analysis, DNA, Young Adult}, issn = {1474-4465}, doi = {10.1016/S1474-4422(13)70265-5}, author = {Campeau, Philippe M and Kasperaviciute, Dalia and Lu, James T and Burrage, Lindsay C and Kim, Choel and Hori, Mutsuki and Powell, Berkley R and Stewart, Fiona and F{\'e}lix, T{\^e}mis Maria and van den Ende, Jenneke and Wisniewska, Marzena and Kayserili, H{\"u}lya and Rump, Patrick and Nampoothiri, Sheela and Aftimos, Salim and Mey, Antje and Nair, Lal D V and Begleiter, Michael L and De Bie, Isabelle and Meenakshi, Girish and Murray, Mitzi L and Repetto, Gabriela M and Golabi, Mahin and Blair, Edward and Male, Alison and Giuliano, Fabienne and Kariminejad, Ariana and Newman, William G and Bhaskar, Sanjeev S and Dickerson, Jonathan E and Kerr, Bronwyn and Banka, Siddharth and Giltay, Jacques C and Wieczorek, Dagmar and Tostevin, Anna and Wiszniewska, Joanna and Cheung, Sau Wai and Hennekam, Raoul C and Gibbs, Richard A and Lee, Brendan H and Sisodiya, Sanjay M} } @article {234, title = {Germ-line and somatic DICER1 mutations in pineoblastoma.}, journal = {Acta Neuropathol}, volume = {128}, year = {2014}, month = {2014 Oct}, pages = {583-95}, abstract = {

Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.

}, keywords = {Adolescent, Brain Neoplasms, Child, Child, Preschool, DEAD-box RNA Helicases, DNA Mutational Analysis, Family Health, Female, Germ-Line Mutation, Humans, Infant, Male, Pineal Gland, Pinealoma, Ribonuclease III, Young Adult}, issn = {1432-0533}, doi = {10.1007/s00401-014-1318-7}, author = {de Kock, Leanne and Sabbaghian, Nelly and Druker, Harriet and Weber, Evan and Hamel, Nancy and Miller, Suzanne and Choong, Catherine S and Gottardo, Nicholas G and Kees, Ursula R and Rednam, Surya P and van Hest, Liselotte P and Jongmans, Marjolijn C and Jhangiani, Shalini and Lupski, James R and Zacharin, Margaret and Bouron-Dal Soglio, Doroth{\'e}e and Huang, Annie and Priest, John R and Perry, Arie and Mueller, Sabine and Albrecht, Steffen and Malkin, David and Grundy, Richard G and Foulkes, William D} } @article {207, title = {Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Dec 18}, pages = {2363-74}, abstract = {

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.

METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.

RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients{\textquoteright} pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.

CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

}, keywords = {Acromegaly, Adolescent, Adult, Age of Onset, Child, Child, Preschool, Chromosome Duplication, Chromosomes, Human, X, Female, Gigantism, Human Growth Hormone, Humans, Infant, Male, Mutation, Phenotype, Protein Conformation, Receptors, G-Protein-Coupled}, issn = {1533-4406}, doi = {10.1056/NEJMoa1408028}, author = {Trivellin, Giampaolo and Daly, Adrian F and Faucz, Fabio R and Yuan, Bo and Rostomyan, Liliya and Larco, Darwin O and Schernthaner-Reiter, Marie Helene and Szarek, Eva and Leal, Let{\'\i}cia F and Caberg, Jean-Hubert and Castermans, Emilie and Villa, Chiara and Dimopoulos, Aggeliki and Chittiboina, Prashant and Xekouki, Paraskevi and Shah, Nalini and Metzger, Daniel and Lysy, Philippe A and Ferrante, Emanuele and Strebkova, Natalia and Mazerkina, Nadia and Zatelli, Maria Chiara and Lodish, Maya and Horvath, Anelia and de Alexandre, Rodrigo Bertollo and Manning, Allison D and Levy, Isaac and Keil, Margaret F and Sierra, Maria de la Luz and Palmeira, Leonor and Coppieters, Wouter and Georges, Michel and Naves, Luciana A and Jamar, Mauricette and Bours, Vincent and Wu, T John and Choong, Catherine S and Bertherat, Jerome and Chanson, Philippe and Kamenick{\'y}, Peter and Farrell, William E and Barlier, Anne and Quezado, Martha and Bjelobaba, Ivana and Stojilkovic, Stanko S and Wess, Jurgen and Costanzi, Stefano and Liu, Pengfei and Lupski, James R and Beckers, Albert and Stratakis, Constantine A} } @article {257, title = {Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Mar}, pages = {e1004258}, abstract = {

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon{\textquoteright}s initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.

}, keywords = {Abnormalities, Multiple, Actins, Adolescent, Adult, Child, Child, Preschool, Colon, Exome, Female, Heterozygote, Humans, Intestinal Pseudo-Obstruction, Male, Muscle, Smooth, Mutation, Urinary Bladder}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004258}, author = {Wangler, Michael F and Gonzaga-Jauregui, Claudia and Gambin, Tomasz and Penney, Samantha and Moss, Timothy and Chopra, Atul and Probst, Frank J and Xia, Fan and Yang, Yaping and Werlin, Steven and Eglite, Ieva and Kornejeva, Liene and Bacino, Carlos A and Baldridge, Dustin and Neul, Jeff and Lehman, Efrat Lev and Larson, Austin and Beuten, Joke and Muzny, Donna M and Jhangiani, Shalini and Gibbs, Richard A and Lupski, James R and Beaudet, Arthur} } @article {253, title = {Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.}, journal = {Cell}, volume = {157}, year = {2014}, month = {2014 Apr 24}, pages = {636-50}, abstract = {

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.

}, keywords = {Abnormalities, Multiple, Animals, Central Nervous System Diseases, Cerebrum, Child, Preschool, Endoribonucleases, Female, Fibroblasts, Humans, Infant, Male, Mice, Mice, Inbred CBA, Microcephaly, Mutation, Missense, Nuclear Proteins, Peripheral Nervous System Diseases, Phosphotransferases, RNA, Transfer, Transcription Factors}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.02.058}, author = {Karaca, Ender and Weitzer, Stefan and Pehlivan, Davut and Shiraishi, Hiroshi and Gogakos, Tasos and Hanada, Toshikatsu and Jhangiani, Shalini N and Wiszniewski, Wojciech and Withers, Marjorie and Campbell, Ian M and Erdin, Serkan and Isikay, Sedat and Franco, Luis M and Gonzaga-Jauregui, Claudia and Gambin, Tomasz and Gelowani, Violet and Hunter, Jill V and Yesil, G{\"o}zde and Koparir, Erkan and Yilmaz, Sarenur and Brown, Miguel and Briskin, Daniel and Hafner, Markus and Morozov, Pavel and Farazi, Thalia A and Bernreuther, Christian and Glatzel, Markus and Trattnig, Siegfried and Friske, Joachim and Kronnerwetter, Claudia and Bainbridge, Matthew N and Gezdirici, Alper and Seven, Mehmet and Muzny, Donna M and Boerwinkle, Eric and Ozen, Mustafa and Clausen, Tim and Tuschl, Thomas and Yuksel, Adnan and Hess, Andreas and Gibbs, Richard A and Martinez, Javier and Penninger, Josef M and Lupski, James R} } @article {236, title = {Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.}, journal = {J Hepatol}, volume = {61}, year = {2014}, month = {2014 Nov}, pages = {1056-63}, abstract = {

BACKGROUND \& AIMS: In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology.

METHODS: Patient 1 was a 10 year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2 day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown aetiology since age 3 months.

RESULTS: Unbiased whole-exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations.

CONCLUSIONS: Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.

}, keywords = {Amino Acid Sequence, Base Sequence, Carboxylic Ester Hydrolases, Child, Cholestasis, DNA Mutational Analysis, End Stage Liver Disease, Exome, Fatal Outcome, Female, Genes, Recessive, Hepatolenticular Degeneration, Heterozygote, Homozygote, Humans, Infant, Newborn, Liver Failure, Liver Failure, Acute, Male, Membrane Proteins, Mitochondrial Proteins, Molecular Sequence Data, Pedigree, Receptor, Notch2, RNA Splice Sites, Sequence Homology, Amino Acid}, issn = {1600-0641}, doi = {10.1016/j.jhep.2014.06.038}, author = {Vilarinho, S{\'\i}lvia and Choi, Murim and Jain, Dhanpat and Malhotra, Ajay and Kulkarni, Sanjay and Pashankar, Dinesh and Phatak, Uma and Patel, Mohini and Bale, Allen and Mane, Shrikant and Lifton, Richard P and Mistry, Pramod K} } @article {273, title = {Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jun 01}, pages = {2888-900}, abstract = {

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80\% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for \~{}5\% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

}, keywords = {Amino Acid Sequence, Child, Child, Preschool, Cohort Studies, Cranial Fontanelles, De Lange Syndrome, Eye Abnormalities, Female, Genes, X-Linked, Histone Deacetylases, Humans, Hypertelorism, Infant, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Repressor Proteins, Sequence Alignment}, issn = {1460-2083}, doi = {10.1093/hmg/ddu002}, author = {Kaiser, Frank J and Ansari, Morad and Braunholz, Diana and Concepci{\'o}n Gil-Rodr{\'\i}guez, Mar{\'\i}a and Decroos, Christophe and Wilde, Jonathan J and Fincher, Christopher T and Kaur, Maninder and Bando, Masashige and Amor, David J and Atwal, Paldeep S and Bahlo, Melanie and Bowman, Christine M and Bradley, Jacquelyn J and Brunner, Han G and Clark, Dinah and Del Campo, Miguel and Di Donato, Nataliya and Diakumis, Peter and Dubbs, Holly and Dyment, David A and Eckhold, Juliane and Ernst, Sarah and Ferreira, Jose C and Francey, Lauren J and Gehlken, Ulrike and Guill{\'e}n-Navarro, Encarna and Gyftodimou, Yolanda and Hall, Bryan D and Hennekam, Raoul and Hudgins, Louanne and Hullings, Melanie and Hunter, Jennifer M and Yntema, Helger and Innes, A Micheil and Kline, Antonie D and Krumina, Zita and Lee, Hane and Leppig, Kathleen and Lynch, Sally Ann and Mallozzi, Mark B and Mannini, Linda and McKee, Shane and Mehta, Sarju G and Micule, Ieva and Mohammed, Shehla and Moran, Ellen and Mortier, Geert R and Moser, Joe-Ann S and Noon, Sarah E and Nozaki, Naohito and Nunes, Luis and Pappas, John G and Penney, Lynette S and P{\'e}rez-Ayt{\'e}s, Antonio and Petersen, Michael B and Puisac, Beatriz and Revencu, Nicole and Roeder, Elizabeth and Saitta, Sulagna and Scheuerle, Angela E and Schindeler, Karen L and Siu, Victoria M and Stark, Zornitza and Strom, Samuel P and Thiese, Heidi and Vater, Inga and Willems, Patrick and Williamson, Kathleen and Wilson, Louise C and Hakonarson, Hakon and Quintero-Rivera, Fabiola and Wierzba, Jolanta and Musio, Antonio and Gillessen-Kaesbach, Gabriele and Ramos, Feliciano J and Jackson, Laird G and Shirahige, Katsuhiko and Pi{\'e}, Juan and Christianson, David W and Krantz, Ian D and FitzPatrick, David R and Deardorff, Matthew A} } @article {284, title = {Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder.}, journal = {Pediatr Diabetes}, volume = {15}, year = {2014}, month = {2014 May}, pages = {252-6}, abstract = {

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases.

}, keywords = {Amino Acid Substitution, Blindness, Cortical, Carrier Proteins, Developmental Disabilities, Diabetes Mellitus, Epilepsy, Generalized, Fatal Outcome, Frameshift Mutation, Heterozygote, Humans, Infant, Newborn, Infant, Newborn, Diseases, Male, Membrane Proteins, Microcephaly, Neurologic Manifestations, Point Mutation, Severity of Illness Index}, issn = {1399-5448}, doi = {10.1111/pedi.12086}, author = {Shalev, Stavit A and Tenenbaum-Rakover, Yardena and Horovitz, Yoseph and Paz, Veronica P and Ye, Honggang and Carmody, David and Highland, Heather M and Boerwinkle, Eric and Hanis, Craig L and Muzny, Donna M and Gibbs, Richard A and Bell, Graeme I and Philipson, Louis H and Greeley, Siri Atma W} } @article {217, title = {Molecular findings among patients referred for clinical whole-exome sequencing.}, journal = {JAMA}, volume = {312}, year = {2014}, month = {2014 Nov 12}, pages = {1870-9}, abstract = {

IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.

OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.

DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient{\textquoteright}s physician. The patients were primarily pediatric (1756 [88\%]; mean age, 6 years; 888 females [44\%], 1101 males [55\%], and 11 fetuses [1\% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.

RESULTS: A molecular diagnosis was reported for 504 patients (25.2\%) with 58\% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2\%; 95\% CI, 23.5\%-31.2\%) for the neurological group, 282/1147 (24.6\%; 95\% CI, 22.1\%-27.2\%) for the neurological plus other organ systems group, 30/83 (36.1\%; 95\% CI, 26.1\%-47.5\%) for the specific neurological group, and 49/244 (20.1\%; 95\% CI, 15.6\%-25.8\%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1\%) autosomal dominant, 181 (34.3\%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3\%) X-linked, and 1 (0.2\%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6\%) had blended phenotypes resulting from 2 single gene defects. About 30\% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6\%), including 59 patients (3\%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.

CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25\% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Exome, Female, Fetus, Genetic Diseases, Inborn, Genetic Testing, Genomics, Humans, Incidental Findings, Infant, Infant, Newborn, Male, Molecular Diagnostic Techniques, Mutation, Phenotype, Referral and Consultation, Sequence Analysis, DNA}, issn = {1538-3598}, doi = {10.1001/jama.2014.14601}, author = {Yang, Yaping and Muzny, Donna M and Xia, Fan and Niu, Zhiyv and Person, Richard and Ding, Yan and Ward, Patricia and Braxton, Alicia and Wang, Min and Buhay, Christian and Veeraraghavan, Narayanan and Hawes, Alicia and Chiang, Theodore and Leduc, Magalie and Beuten, Joke and Zhang, Jing and He, Weimin and Scull, Jennifer and Willis, Alecia and Landsverk, Megan and Craigen, William J and Bekheirnia, Mir Reza and Stray-Pedersen, Asbjorg and Liu, Pengfei and Wen, Shu and Alcaraz, Wendy and Cui, Hong and Walkiewicz, Magdalena and Reid, Jeffrey and Bainbridge, Matthew and Patel, Ankita and Boerwinkle, Eric and Beaudet, Arthur L and Lupski, James R and Plon, Sharon E and Gibbs, Richard A and Eng, Christine M} } @article {243, title = {Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jun 05}, pages = {915-23}, abstract = {

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in~vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

}, keywords = {Adult, Alleles, Animals, Anophthalmos, Brain Diseases, Metabolic, Inborn, Coloboma, Corneal Opacity, Exome, Eye Proteins, Female, Gene Expression, HEK293 Cells, Heterozygote, Homozygote, Humans, Intellectual Disability, Intracellular Signaling Peptides and Proteins, Male, Mice, Microcephaly, Microphthalmos, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Signal Transduction}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.005}, author = {Rainger, Joe and Pehlivan, Davut and Johansson, Stefan and Bengani, Hemant and Sanchez-Pulido, Luis and Williamson, Kathleen A and Ture, Mehmet and Barker, Heather and Rosendahl, Karen and Spranger, J{\"u}rgen and Horn, Denise and Meynert, Alison and Floyd, James A B and Prescott, Trine and Anderson, Carl A and Rainger, Jacqueline K and Karaca, Ender and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Muzny, Donna M and Seawright, Anne and Soares, Dinesh C and Kharbanda, Mira and Murday, Victoria and Finch, Andrew and Gibbs, Richard A and van Heyningen, Veronica and Taylor, Martin S and Yakut, Tahsin and Knappskog, Per M and Hurles, Matthew E and Ponting, Chris P and Lupski, James R and Houge, Gunnar and FitzPatrick, David R} } @article {224, title = {Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Oct}, pages = {1135-1139}, abstract = {

Upon detection of pathogen-associated molecular patterns, innate immune receptors initiate inflammatory responses. These receptors include cytoplasmic NOD-like receptors (NLRs) whose stimulation recruits and proteolytically activates caspase-1 within the inflammasome, a multiprotein complex. Caspase-1 mediates the production of interleukin-1 family cytokines (IL1FCs), leading to fever and inflammatory cell death (pyroptosis). Mutations that constitutively activate these pathways underlie several autoinflammatory diseases with diverse clinical features. We describe a family with a previously unreported syndrome featuring neonatal-onset enterocolitis, periodic fever, and fatal or near-fatal episodes of autoinflammation. We show that the disease is caused by a de novo gain-of-function mutation in NLRC4 encoding a p.Val341Ala substitution in the HD1 domain of the protein that cosegregates with disease. Mutant NLRC4 causes constitutive IL1FC production and macrophage cell death. Infected macrophages from affected individuals are polarized toward pyroptosis and exhibit abnormal staining for inflammasome components. These findings identify and describe the cause of a life-threatening but treatable autoinflammatory disease that underscores the divergent roles of the NLRC4 inflammasome.

}, keywords = {Calcium-Binding Proteins, CARD Signaling Adaptor Proteins, Enterocolitis, Exome, Family Health, Fatal Outcome, Female, Humans, Inflammation, Male, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Syndrome}, issn = {1546-1718}, doi = {10.1038/ng.3066}, author = {Romberg, Neil and Al Moussawi, Khatoun and Nelson-Williams, Carol and Stiegler, Amy L and Loring, Erin and Choi, Murim and Overton, John and Meffre, Eric and Khokha, Mustafa K and Huttner, Anita J and West, Brian and Podoltsev, Nikolai A and Boggon, Titus J and Kazmierczak, Barbara I and Lifton, Richard P} } @article {278, title = {Mutations in CSPP1 lead to classical Joubert syndrome.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {80-6}, abstract = {

Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in~vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.

}, keywords = {Abnormalities, Multiple, Brain, Cell Cycle Proteins, Centrosome, Cerebellar Diseases, Cerebellum, Cilia, Cohort Studies, Eye Abnormalities, Fibroblasts, Gene Deletion, Humans, Image Processing, Computer-Assisted, Kidney Diseases, Cystic, Microtubule-Associated Proteins, Polymorphism, Single Nucleotide, Retina}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.015}, author = {Akizu, Naiara and Silhavy, Jennifer L and Rosti, Rasim Ozgur and Scott, Eric and Fenstermaker, Ali G and Schroth, Jana and Zaki, Maha S and Sanchez, Henry and Gupta, Neerja and Kabra, Madhulika and Kara, Majdi and Ben-Omran, Tawfeg and Rosti, Basak and Guemez-Gamboa, Alicia and Spencer, Emily and Pan, Roger and Cai, Na and Abdellateef, Mostafa and Gabriel, Stacey and Halbritter, Jan and Hildebrandt, Friedhelm and van Bokhoven, Hans and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {203, title = {Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.}, journal = {Neuron}, volume = {84}, year = {2014}, month = {2014 Dec 17}, pages = {1226-39}, abstract = {

Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.

}, keywords = {Adenosine Triphosphatases, Animals, Brain, Cell Count, Cell Division, Dendrites, Drosophila, Drosophila Proteins, Humans, Katanin, Mice, Microcephaly, Microtubule-Associated Proteins, Mutation, Neural Stem Cells, Neurogenesis, Optic Lobe, Nonmammalian, Spindle Apparatus, Zebrafish}, issn = {1097-4199}, doi = {10.1016/j.neuron.2014.12.014}, author = {Mishra-Gorur, Ketu and {\c C}a{\u g}layan, Ahmet Okay and Schaffer, Ashleigh E and Chabu, Chiswili and Henegariu, Octavian and Vonhoff, Fernando and Akg{\"u}m{\"u}{\c s}, G{\"o}zde Tu{\u g}ce and Nishimura, Sayoko and Han, Wenqi and Tu, Shu and Baran, Bur{\c c}in and G{\"u}m{\"u}{\c s}, Hakan and Dilber, Cengiz and Zaki, Maha S and Hossni, Heba A A and Rivi{\`e}re, Jean-Baptiste and Kayserili, H{\"u}lya and Spencer, Emily G and Rosti, Rasim O and Schroth, Jana and Per, H{\"u}seyin and Caglar, Caner and {\c C}a{\u g}lar, {\c C}a{\u g}ri and D{\"o}len, Duygu and Baranoski, Jacob F and Kumanda{\c s}, Sefer and Minja, Frank J and Erson-Omay, E Zeynep and Mane, Shrikant M and Lifton, Richard P and Xu, Tian and Keshishian, Haig and Dobyns, William B and Chi, Neil C and {\v S}estan, Nenad and Louvi, Angeliki and Bilguvar, Kaya and Yasuno, Katsuhito and Gleeson, Joseph G and G{\"u}nel, Murat} } @article {228, title = {Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {227-34}, abstract = {

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes.

}, keywords = {Adult, Alleles, Base Sequence, Cerebellar Cortex, Cerebellar Diseases, Child, Child, Preschool, Cysts, Exome, Female, Humans, Laminin, Male, Muscular Dystrophies, Retinal Dystrophies, Sequence Analysis, DNA, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.007}, author = {Aldinger, Kimberly A and Mosca, Stephen J and T{\'e}treault, Martine and Dempsey, Jennifer C and Ishak, Gisele E and Hartley, Taila and Phelps, Ian G and Lamont, Ryan E and O{\textquoteright}Day, Diana R and Basel, Donald and Gripp, Karen W and Baker, Laura and Stephan, Mark J and Bernier, Francois P and Boycott, Kym M and Majewski, Jacek and Parboosingh, Jillian S and Innes, A Micheil and Doherty, Dan} } @article {275, title = {Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {105-12}, keywords = {Alleles, Child, Preschool, Choline-Phosphate Cytidylyltransferase, Female, Humans, Infant, Male, Middle Aged, Mutation, Missense, Osteochondrodysplasias, Pedigree, Phosphatidylcholines, Retinitis Pigmentosa}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.018}, author = {Hoover-Fong, Julie and Sobreira, Nara and Jurgens, Julie and Modaff, Peggy and Blout, Carrie and Moser, Ann and Kim, Ok-Hwa and Cho, Tae-Joon and Cho, Sung Yoon and Kim, Sang Jin and Jin, Dong-Kyu and Kitoh, Hiroshi and Park, Woong-Yang and Ling, Hua and Hetrick, Kurt N and Doheny, Kimberly F and Valle, David and Pauli, Richard M} } @article {256, title = {Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {734-44}, abstract = {

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83\%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82\%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher{\textquoteright}s exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

}, keywords = {Abnormalities, Multiple, Arachnodactyly, Arthrogryposis, Blepharophimosis, Child, Child, Preschool, Cleft Palate, Clubfoot, Connective Tissue Diseases, Contracture, Exome, Female, Hand Deformities, Congenital, Humans, Ion Channels, Male, Mutation, Ophthalmoplegia, Pedigree, Retinal Diseases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.03.015}, author = {McMillin, Margaret J and Beck, Anita E and Chong, Jessica X and Shively, Kathryn M and Buckingham, Kati J and Gildersleeve, Heidi I S and Aracena, Mariana I and Aylsworth, Arthur S and Bitoun, Pierre and Carey, John C and Clericuzio, Carol L and Crow, Yanick J and Curry, Cynthia J and Devriendt, Koenraad and Everman, David B and Fryer, Alan and Gibson, Kate and Giovannucci Uzielli, Maria Luisa and Graham, John M and Hall, Judith G and Hecht, Jacqueline T and Heidenreich, Randall A and Hurst, Jane A and Irani, Sarosh and Krapels, Ingrid P C and Leroy, Jules G and Mowat, David and Plant, Gordon T and Robertson, Stephen P and Schorry, Elizabeth K and Scott, Richard H and Seaver, Laurie H and Sherr, Elliott and Splitt, Miranda and Stewart, Helen and Stumpel, Constance and Temel, Sehime G and Weaver, David D and Whiteford, Margo and Williams, Marc S and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {211, title = {Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Nov 06}, pages = {579-83}, abstract = {

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Base Sequence, Caenorhabditis elegans, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, Pair 5, DNA-Binding Proteins, Humans, Molecular Sequence Data, Muscle Hypotonia, Mutation, Seizures, Sequence Analysis, DNA, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.09.014}, author = {Lalani, Seema R and Zhang, Jing and Schaaf, Christian P and Brown, Chester W and Magoulas, Pilar and Tsai, Anne Chun-Hui and El-Gharbawy, Areeg and Wierenga, Klaas J and Bartholomew, Dennis and Fong, Chin-To and Barbaro-Dieber, Tina and Kukolich, Mary K and Burrage, Lindsay C and Austin, Elise and Keller, Kory and Pastore, Matthew and Fernandez, Fabio and Lotze, Timothy and Wilfong, Angus and Purcarin, Gabriela and Zhu, Wenmiao and Craigen, William J and McGuire, Marianne and Jain, Mahim and Cooney, Erin and Azamian, Mahshid and Bainbridge, Matthew N and Muzny, Donna M and Boerwinkle, Eric and Person, Richard E and Niu, Zhiyv and Eng, Christine M and Lupski, James R and Gibbs, Richard A and Beaudet, Arthur L and Yang, Yaping and Wang, Meng C and Xia, Fan} } @article {263, title = {Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.}, journal = {Am J Respir Crit Care Med}, volume = {189}, year = {2014}, month = {2014 Mar 15}, pages = {707-17}, abstract = {

RATIONALE: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD.

OBJECTIVES: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.

METHODS: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis.

MEASUREMENTS AND MAIN RESULTS: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85\% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 \% predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 {\textpm} Hz at 25{\textdegree}C), but an abnormal, circular beat pattern.

CONCLUSIONS: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.

}, keywords = {Adolescent, Adult, Child, Cilia, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Female, Genetic Association Studies, Genetic Markers, Genetic Testing, Homozygote, Humans, Kartagener Syndrome, Linear Models, Male, Middle Aged, Mutation, Nasal Mucosa, Sequence Analysis, DNA, Young Adult}, issn = {1535-4970}, doi = {10.1164/rccm.201311-2047OC}, author = {Knowles, Michael R and Ostrowski, Lawrence E and Leigh, Margaret W and Sears, Patrick R and Davis, Stephanie D and Wolf, Whitney E and Hazucha, Milan J and Carson, Johnny L and Olivier, Kenneth N and Sagel, Scott D and Rosenfeld, Margaret and Ferkol, Thomas W and Dell, Sharon D and Milla, Carlos E and Randell, Scott H and Yin, Weining and Sannuti, Aruna and Metjian, Hilda M and Noone, Peadar G and Noone, Peter J and Olson, Christina A and Patrone, Michael V and Dang, Hong and Lee, Hye-Seung and Hurd, Toby W and Gee, Heon Yung and Otto, Edgar A and Halbritter, Jan and Kohl, Stefan and Kircher, Martin and Krischer, Jeffrey and Bamshad, Michael J and Nickerson, Deborah A and Hildebrandt, Friedhelm and Shendure, Jay and Zariwala, Maimoona A} } @article {260, title = {Mutations in TJP2 cause progressive cholestatic liver disease.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Apr}, pages = {326-8}, abstract = {

Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.

}, keywords = {Animals, Base Sequence, Cholestasis, Intrahepatic, High-Throughput Nucleotide Sequencing, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Models, Biological, Molecular Sequence Data, Mutation, Pedigree, Real-Time Polymerase Chain Reaction, Sequence Alignment, Species Specificity, Tight Junctions, Zonula Occludens-2 Protein}, issn = {1546-1718}, doi = {10.1038/ng.2918}, author = {Sambrotta, Melissa and Strautnieks, Sandra and Papouli, Efterpi and Rushton, Peter and Clark, Barnaby E and Parry, David A and Logan, Clare V and Newbury, Lucy J and Kamath, Binita M and Ling, Simon and Grammatikopoulos, Tassos and Wagner, Bart E and Magee, John C and Sokol, Ronald J and Mieli-Vergani, Giorgina and Smith, Joshua D and Johnson, Colin A and McClean, Patricia and Simpson, Michael A and Knisely, A S and Bull, Laura N and Thompson, Richard J} } @article {292, title = {Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6.}, journal = {Pediatr Diabetes}, volume = {15}, year = {2014}, month = {2014 Feb}, pages = {67-72}, abstract = {

Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446 mg/dL) within 24 h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5{\textquoteright} splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost-effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case.

}, keywords = {Abnormalities, Multiple, Congenital Abnormalities, Diabetes Mellitus, Type 1, Digestive System Abnormalities, DNA-Binding Proteins, Duodenal Obstruction, Fatal Outcome, Gallbladder, Humans, Infant, Infant, Newborn, Infant, Newborn, Diseases, Intestinal Atresia, Intestinal Volvulus, Male, Pancreas, Pancreatic Diseases, Regulatory Factor X Transcription Factors, Transcription Factors}, issn = {1399-5448}, doi = {10.1111/pedi.12063}, author = {Concepcion, Jennifer P and Reh, Christina S and Daniels, Mark and Liu, Xiaoming and Paz, Veronica P and Ye, Honggang and Highland, Heather M and Hanis, Craig L and Greeley, Siri Atma W} } @article {200, title = {Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families.}, journal = {Mol Syndromol}, volume = {5}, year = {2014}, month = {2014 Dec}, pages = {268-75}, abstract = {

Autosomal recessive osteogenesis imperfecta (OI) accounts for 10\% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed.

}, issn = {1661-8769}, doi = {10.1159/000369108}, author = {Minillo, Renata Moldenhauer and Sobreira, Nara and de Faria Soares, Maria de Fatima and Jurgens, Julie and Ling, Hua and Hetrick, Kurt N and Doheny, Kimberly F and Valle, David and Brunoni, Decio and Perez, Ana B Alvarez} } @article {271, title = {NR2F1 mutations cause optic atrophy with intellectual disability.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {303-9}, abstract = {

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Child, Child, Preschool, COUP Transcription Factor I, DNA-Binding Proteins, Female, Genotype, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Optic Atrophy, Phenotype, Young Adult, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.002}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and Gonzaga-Jauregui, Claudia and Xu, Mafei and de Ligt, Joep and Jhangiani, Shalini and Wiszniewski, Wojciech and Muzny, Donna M and Yntema, Helger G and Pfundt, Rolph and Vissers, Lisenka E L M and Spruijt, Liesbeth and Blokland, Ellen A W and Chen, Chun-An and Lewis, Richard A and Tsai, Sophia Y and Gibbs, Richard A and Tsai, Ming-Jer and Lupski, James R and Zoghbi, Huda Y and Cremers, Frans P M and de Vries, Bert B A and Schaaf, Christian P} } @article {229, title = {Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {173-82}, abstract = {

New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.

}, keywords = {Cell Division, DNA Copy Number Variations, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Male, Models, Genetic, Mosaicism, Mutation, Pedigree, Prospective Studies, Recurrence, Risk, Sex Characteristics, Smith-Magenis Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.003}, author = {Campbell, Ian M and Yuan, Bo and Robberecht, Caroline and Pfundt, Rolph and Szafranski, Przemyslaw and McEntagart, Meriel E and Nagamani, Sandesh C S and Erez, Ayelet and Bartnik, Magdalena and Wi{\'s}niowiecka-Kowalnik, Barbara and Plunkett, Katie S and Pursley, Amber N and Kang, Sung-Hae L and Bi, Weimin and Lalani, Seema R and Bacino, Carlos A and Vast, Mala and Marks, Karen and Patton, Michael and Olofsson, Peter and Patel, Ankita and Veltman, Joris A and Cheung, Sau Wai and Shaw, Chad A and Vissers, Lisenka E L M and Vermeesch, Joris R and Lupski, James R and Stankiewicz, Pawe{\l}} } @article {241, title = {PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Jul 03}, pages = {96-107}, abstract = {

Human phosphoglucomutase 3 (PGM3) catalyzes the conversion of N-acetyl-glucosamine (GlcNAc)-6-phosphate into GlcNAc-1-phosphate during the synthesis of uridine diphosphate (UDP)-GlcNAc, a sugar nucleotide critical to multiple glycosylation pathways. We identified three unrelated children with recurrent infections, congenital leukopenia including neutropenia, B and T~cell lymphopenia, and progression to bone marrow failure. Whole-exome sequencing demonstrated deleterious mutations in PGM3 in all three subjects, delineating their disease to be due to an unsuspected congenital disorder of glycosylation (CDG). Functional studies of the disease-associated PGM3 variants in E.~coli cells demonstrated reduced PGM3 activity for all mutants tested. Two of the three children had skeletal anomalies resembling Desbuquois dysplasia: short stature, brachydactyly, dysmorphic facial features, and intellectual disability. However, these additional features were absent in the third child, showing the clinical variability of the disease. Two children received hematopoietic stem cell transplantation of cord blood and bone marrow from matched related donors; both had successful engraftment and correction of neutropenia and lymphopenia. We define PGM3-CDG as a treatable immunodeficiency, document the power of whole-exome sequencing in gene discoveries for rare disorders, and illustrate the utility of genomic analyses in studying combined and variable phenotypes.

}, keywords = {Bone Diseases, Developmental, Congenital Disorders of Glycosylation, Female, Humans, Immunologic Deficiency Syndromes, Male, Mutation, Pedigree, Phosphoglucomutase}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.007}, author = {Stray-Pedersen, Asbj{\o}rg and Backe, Paul H and Sorte, Hanne S and M{\o}rkrid, Lars and Chokshi, Niti Y and Erichsen, Hans Christian and Gambin, Tomasz and Elgst{\o}en, Katja B P and Bj{\o}r{\r a}s, Magnar and Wlodarski, Marcin W and Kr{\"u}ger, Marcus and Jhangiani, Shalini N and Muzny, Donna M and Patel, Ankita and Raymond, Kimiyo M and Sasa, Ghadir S and Krance, Robert A and Martinez, Caridad A and Abraham, Shirley M and Speckmann, Carsten and Ehl, Stephan and Hall, Patricia and Forbes, Lisa R and Merckoll, Else and Westvik, Jostein and Nishimura, Gen and Rustad, Cecilie F and Abrahamsen, Tore G and R{\o}nnestad, Arild and Osnes, Liv T and Egeland, Torstein and R{\o}dningen, Olaug K and Beck, Christine R and Boerwinkle, Eric A and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Lausch, Ekkehart and Hanson, I Celine} } @article {250, title = {Power analysis and sample size estimation for sequence-based association studies.}, journal = {Bioinformatics}, volume = {30}, year = {2014}, month = {2014 Aug 15}, pages = {2377-8}, abstract = {

MOTIVATION: Statistical methods have been developed to test for complex trait rare variant (RV) associations, in which variants are aggregated across a region, which is typically a gene. Power analysis and sample size estimation for sequence-based RV association studies are challenging because of the necessity to realistically model the underlying allelic architecture of complex diseases within a suitable analytical framework to assess the performance of a variety of RV association methods in an unbiased manner.

SUMMARY: We developed SEQPower, a software package to perform statistical power analysis for sequence-based association data under a variety of genetic variant and disease phenotype models. It aids epidemiologists in determining the best study design, sample size and statistical tests for sequence-based association studies. It also provides biostatisticians with a platform to fairly compare RV association methods and to validate and assess novel association tests.

AVAILABILITY AND IMPLEMENTATION: The SEQPower program, source code, multi-platform executables, documentation, list of association tests, examples and tutorials are available at http://bioinformatics.org/spower.

}, keywords = {Alleles, Data Interpretation, Statistical, Disease, Genetic Association Studies, Genetic Variation, Humans, Phenotype, Sample Size, Sequence Analysis, DNA, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu296}, author = {Wang, Gao T and Li, Biao and Santos-Cortez, Regie P Lyn and Peng, Bo and Leal, Suzanne M} } @article {255, title = {Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Jun}, pages = {613-7}, abstract = {

Adrenal tumors autonomously producing cortisol cause Cushing{\textquoteright}s syndrome. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin) or GNAS (Gαs). Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35\% of adenomas with overt Cushing{\textquoteright}s syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.

}, keywords = {Adolescent, Adrenal Gland Neoplasms, Adult, Aged, Amino Acid Sequence, Base Sequence, cdc42 GTP-Binding Protein, Cell Proliferation, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, Cyclin-Dependent Kinase Inhibitor p16, DNA Copy Number Variations, Exome, Female, Gene Deletion, Gene Dosage, HEK293 Cells, Humans, Hydrocortisone, Male, Middle Aged, Molecular Sequence Data, Mutation, Phosphorylation, Sequence Analysis, DNA, Sequence Homology, Amino Acid}, issn = {1546-1718}, doi = {10.1038/ng.2956}, author = {Goh, Gerald and Scholl, Ute I and Healy, James M and Choi, Murim and Prasad, Manju L and Nelson-Williams, Carol and Kunstman, John W and Kuntsman, John W and Korah, Reju and Suttorp, Anna-Carinna and Dietrich, Dimo and Haase, Matthias and Willenberg, Holger S and St{\r a}lberg, Peter and Hellman, Per and Akerstr{\"o}m, G{\"o}ran and Bj{\"o}rklund, Peyman and Carling, Tobias and Lifton, Richard P} } @article {219, title = {RNF213 rare variants in an ethnically diverse population with Moyamoya disease.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Nov}, pages = {3200-7}, abstract = {

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States.

METHODS: We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families.

RESULTS: RNF213 p.R4810K was identified in 56\% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6\% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29\% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant.

CONCLUSIONS: These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD.

}, keywords = {Adenosine Triphosphatases, Adolescent, Adult, Child, Cohort Studies, Ethnic Groups, Female, Genetic Variation, Humans, Male, Moyamoya Disease, Population Surveillance, Ubiquitin-Protein Ligases, Young Adult}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.006244}, author = {Cecchi, Alana C and Guo, Dongchuan and Ren, Zhao and Flynn, Kelly and Santos-Cortez, Regie Lyn P and Leal, Suzanne M and Wang, Gao T and Regalado, Ellen S and Steinberg, Gary K and Shendure, Jay and Bamshad, Michael J and Grotta, James C and Nickerson, Deborah A and Pannu, Hariyadarshi and Milewicz, Dianna M} } @article {269, title = {Sclerocornea in a patient with van den Ende-Gupta syndrome homozygous for a SCARF2 microdeletion.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 May}, pages = {1170-4}, abstract = {

Van den Ende-Gupta Syndrome (VDEGS) is an autosomal recessive disorder characterized by blepharophimosis, distinctive nose, hypoplastic maxilla, and skeletal abnormalities. Using homozygosity mapping in four VDEGS patients from three consanguineous families, Anastacio et al. [Anastacio et al. (2010); Am J Hum Genet 87:553-559] identified homozygous mutations in SCARF2, located at 22q11.2. Bedeschi et al. [2010] described a VDEGS patient with sclerocornea and cataracts with compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 mutation. Because sclerocornea had been described in DiGeorge-velo-cardio-facial syndrome but not in VDEGS, they suggested that the ocular abnormalities were caused by the 22q11.2 microdeletion. We report on a 23-year-old male who presented with bilateral sclerocornea and the VDGEGS phenotype who was subsequently found to be homozygous for a 17 bp deletion in exon 4 of SCARF2. The occurrence of bilateral sclerocornea in our patient together with that of Bedeschi et al., suggests that the full VDEGS phenotype may include sclerocornea resulting from homozygosity or compound heterozygosity for loss of function variants in SCARF2.

}, keywords = {Abnormalities, Multiple, Adult, Arachnodactyly, Blepharophimosis, Bone and Bones, Chromosomes, Human, Pair 22, Contracture, Cornea, Corneal Diseases, Exons, Facies, Hand Deformities, Congenital, Homozygote, Humans, Male, Phenotype, Radiography, Scavenger Receptors, Class F, Sequence Analysis, DNA, Sequence Deletion, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36425}, author = {Migliavacca, Michele P and Sobreira, Nara L M and Antonialli, Graziela P M and Oliveira, Mariana M and Melaragno, Maria Isabel S A and Casteels, Ingele and de Ravel, Thomy and Brunoni, Decio and Valle, David and Perez, Ana Beatriz A} } @article {226, title = {Somatic mutations in cerebral cortical malformations.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Aug 21}, pages = {733-43}, abstract = {

BACKGROUND: Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.

METHODS: Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, >=200{\texttimes}) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.

RESULTS: Validated, causal mutations were found in 27 persons (17\%; range, 10 to 30\% for each phenotype). Mutations were somatic in 8 of the 27 (30\%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63\%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.

CONCLUSIONS: Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).

}, keywords = {Cerebral Cortex, Classical Lissencephalies and Subcortical Band Heterotopias, DNA Mutational Analysis, Humans, Lissencephaly, Magnetic Resonance Imaging, Malformations of Cortical Development, Mutation, Periventricular Nodular Heterotopia}, issn = {1533-4406}, doi = {10.1056/NEJMoa1314432}, author = {Jamuar, Saumya S and Lam, Anh-Thu N and Kircher, Martin and D{\textquoteright}Gama, Alissa M and Wang, Jian and Barry, Brenda J and Zhang, Xiaochang and Hill, Robert Sean and Partlow, Jennifer N and Rozzo, Aldo and Servattalab, Sarah and Mehta, Bhaven K and Topcu, Meral and Amrom, Dina and Andermann, Eva and Dan, Bernard and Parrini, Elena and Guerrini, Renzo and Scheffer, Ingrid E and Berkovic, Samuel F and Leventer, Richard J and Shen, Yiping and Wu, Bai Lin and Barkovich, A James and Sahin, Mustafa and Chang, Bernard S and Bamshad, Michael and Nickerson, Deborah A and Shendure, Jay and Poduri, Annapurna and Yu, Timothy W and Walsh, Christopher A} } @article {232, title = {Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray.}, journal = {Clin Exp Immunol}, volume = {178}, year = {2014}, month = {2014 Dec}, pages = {459-69}, abstract = {

In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30\%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10\%) demonstrated in pretransplant blood DNA. This may be responsible for the patient{\textquoteright}s unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.

}, keywords = {CD4-Positive T-Lymphocytes, Chickenpox, DNA Copy Number Variations, Exome, Female, Humans, Infant, Lymphopenia, Mutation, Oligonucleotide Array Sequence Analysis, Receptors, Interleukin-7, Rubella, Severe Combined Immunodeficiency, Vaccination}, issn = {1365-2249}, doi = {10.1111/cei.12421}, author = {Bayer, D K and Martinez, C A and Sorte, H S and Forbes, L R and Demmler-Harrison, G J and Hanson, I C and Pearson, N M and Noroski, L M and Zaki, S R and Bellini, W J and Leduc, M S and Yang, Y and Eng, C M and Patel, A and Rodningen, O K and Muzny, D M and Gibbs, R A and Campbell, I M and Shaw, C A and Baker, M W and Zhang, V and Lupski, J R and Orange, J S and Seeborg, F O and Stray-Pedersen, A} } @article {249, title = {Variant association tools for quality control and analysis of large-scale sequence and genotyping array data.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {770-83}, abstract = {

Currently there is great interest in detecting associations between complex traits and rare variants. In this report, we describe Variant Association Tools (VAT) and the VAT pipeline, which implements best practices for rare-variant association studies. Highlights of VAT include variant-site and call-level quality control (QC), summary statistics, phenotype- and genotype-based sample selection, variant annotation, selection of variants for association analysis, and a collection of rare-variant association methods for analyzing qualitative and quantitative traits. The association testing framework for VAT is regression based, which readily allows for flexible construction of association models with multiple covariates and weighting themes based on allele frequencies or predicted functionality. Additionally, pathway analyses, conditional analyses, and analyses of gene-gene and gene-environment interactions can be performed. VAT is capable of rapidly scanning through data by using multi-process computation, adaptive permutation, and simultaneously conducting association analysis via multiple methods. Results are available in text or graphic file formats and additionally can be output to relational databases for further annotation and filtering. An interface to R language also facilitates user implementation of novel association methods. The VAT{\textquoteright}s data QC and association-analysis pipeline can be applied to sequence, imputed, and genotyping array, e.g., "exome chip," data, providing a reliable and reproducible computational environment in which to analyze small- to large-scale studies with data from the latest genotyping and sequencing technologies. Application of the VAT pipeline is demonstrated through analysis of data from the 1000 Genomes project.

}, keywords = {Genetic Association Studies, Genetic Variation, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Multifactorial Inheritance, Quality Control, Software}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.04.004}, author = {Wang, Gao T and Peng, Bo and Leal, Suzanne M} } @article {276, title = {Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia.}, journal = {J Med Genet}, volume = {51}, year = {2014}, month = {2014 Mar}, pages = {197-202}, abstract = {

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a common birth defect affecting 1 in 3000 births. It is characterised by herniation of abdominal viscera through an incompletely formed diaphragm. Although chromosomal anomalies and mutations in several genes have been implicated, the cause for most patients is unknown.

METHODS: We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both.

RESULTS: In the first family, we identified a de novo missense mutation (c.1366C>T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G>T, p.G238*) was identified in two siblings with CDH and a large ventricular septal defect. The G238* mutation was inherited from their mother, who was clinically affected with congenital absence of the pericardium, patent ductus arteriosus and intestinal malrotation. Deep sequencing of blood and saliva-derived DNA from the mother suggested somatic mosaicism as an explanation for her milder phenotype, with only approximately 15\% mutant alleles. To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation (c.1071delG, p.V358Cfs34*).

CONCLUSIONS: Mutations in GATA6 have been previously associated with pancreatic agenesis and congenital heart disease. We conclude that, in addition to the heart and the pancreas, GATA6 is involved in development of two additional organs, the diaphragm and the pericardium. In addition, we have shown that de novo mutations can contribute to the development of CDH, a common birth defect.

}, keywords = {Amino Acid Sequence, DNA Mutational Analysis, Exome, Female, GATA6 Transcription Factor, Hernia, Diaphragmatic, Hernias, Diaphragmatic, Congenital, Humans, Male, Molecular Sequence Data, Mutation, Sequence Alignment, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2013-101989}, author = {Yu, Lan and Bennett, James T and Wynn, Julia and Carvill, Gemma L and Cheung, Yee Him and Shen, Yufeng and Mychaliska, George B and Azarow, Kenneth S and Crombleholme, Timothy M and Chung, Dai H and Potoka, Douglas and Warner, Brad W and Bucher, Brian and Lim, Foong-Yen and Pietsch, John and Stolar, Charles and Aspelund, Gudrun and Arkovitz, Marc S and Mefford, Heather and Chung, Wendy K} } @article {233, title = {Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2328-34}, abstract = {

GAPO syndrome (OMIM$\#$230740) is the acronym for growth retardation, alopecia, pseudoanodontia, and optic atrophy. About 35 cases have been reported, making it among one of the rarest recessive conditions. Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype. While this genomic study was in progress mutations in ANTXR1 were reported to cause GAPO syndrome. In our study we performed whole exome sequencing (WES) for five affected individuals from three Turkish kindreds segregating the GAPO trait. Exome sequencing analysis identified three novel homozygous mutations including; one frame-shift (c.1220_1221insT; p.Ala408Cysfs*2), one splice site (c.411A>G; p.Gln137Gln), and one non-synonymous (c.1150G>A; p.Gly384Ser) mutation in the ANTXR1 gene. Our studies expand the allelic spectrum in this rare condition and potentially provide insight into the role of ANTXR1 in the regulation of the extracellular matrix.

}, keywords = {Adolescent, Adult, Alopecia, Anodontia, Base Sequence, Child, Chromosome Segregation, DNA Mutational Analysis, Exome, Facies, Family, Female, Growth Disorders, Humans, Male, Molecular Sequence Data, Mutation, Neoplasm Proteins, Optic Atrophies, Hereditary, Pedigree, Protein Structure, Tertiary, Receptors, Cell Surface}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36678}, author = {Bayram, Yavuz and Pehlivan, Davut and Karaca, Ender and Gambin, Tomasz and Jhangiani, Shalini N and Erdin, Serkan and Gonzaga-Jauregui, Claudia and Wiszniewski, Wojciech and Muzny, Donna and Elcioglu, Nursel H and Yildirim, M Selman and Bozkurt, Banu and Zamani, Ayse Gul and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R} } @article {272, title = {Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia.}, journal = {Eur J Hum Genet}, volume = {22}, year = {2014}, month = {2014 Sep}, pages = {1145-8}, abstract = {

Whole-exome sequencing (WES) is a type of disruptive technology that has tremendous influence on human and clinical genetics research. An efficient and cost-effective method, WES is now widely used as a diagnostic tool for identifying the molecular basis of genetic syndromes that are often challenging to diagnose. Here we report a patient with a clinical diagnosis of cerebro-facio-thoracic dysplasia (CFTD; MIM$\#$213980) in whom we identified a homozygous splice-site mutation in the transmembrane and coiled-coil domains 1 (TMCO1) gene using WES. TMCO1 mutations cause craniofacial dysmorphism, skeletal anomalies characterized by multiple malformations of the vertebrae and ribs, and intellectual disability (MIM$\#$614132). A retrospective review revealed that clinical manifestations of both syndromes are very similar and overlap remarkably. We propose that mutations of TMCO1 are not only responsible for craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome but also for CFTD.

}, keywords = {Abnormalities, Multiple, Exome, Humans, Infant, Intellectual Disability, Male, Membrane Proteins, Mutation, Protein Isoforms}, issn = {1476-5438}, doi = {10.1038/ejhg.2013.291}, author = {Pehlivan, Davut and Karaca, Ender and Aydin, Hatip and Beck, Christine R and Gambin, Tomasz and Muzny, Donna M and Bilge Geckinli, B and Karaman, Ali and Jhangiani, Shalini N and Gibbs, Richard A and Lupski, James R} } @article {259, title = {Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {59}, year = {2014}, month = {2014 Jul}, pages = {17-21}, abstract = {

Severe congenital hypertriglyceridemia (HTG) is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week-old Hispanic girl with severe HTG (12,031 mg/dL, normal limit 150 mg/dL) who presented with the unusual combination of lower gastrointestinal bleeding and milky plasma. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. After negative sequencing of the LPL gene, whole-exome sequencing revealed novel compound heterozygous mutations in GPIHBP1. Our study broadens the phenotype of GPIHBP1-associated HTG, reinforces the effectiveness of whole-exome sequencing in Mendelian diagnoses, and implicates triglycerides in gastrointestinal mucosal injury.

}, keywords = {Colitis, DNA Mutational Analysis, Exome, Female, Humans, Hypertriglyceridemia, Infant, Receptors, Lipoprotein}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000000363}, author = {Gonzaga-Jauregui, Claudia and Mir, Sabina and Penney, Samantha and Jhangiani, Shalini and Midgen, Craig and Finegold, Milton and Muzny, Donna M and Wang, Min and Bacino, Carlos A and Gibbs, Richard A and Lupski, James R and Kellermayer, Richard and Hanchard, Neil A} } @article {282, title = {ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption.}, journal = {J Clin Invest}, volume = {123}, year = {2013}, month = {2013 Dec}, pages = {5179-89}, abstract = {

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

}, keywords = {Adolescent, Adrenal Cortex Hormones, Amino Acid Sequence, Animals, Cells, Cultured, Child, Consanguinity, Conserved Sequence, Disease Models, Animal, DNA Mutational Analysis, Drosophila Proteins, Drug Resistance, Exome, Fibroblasts, Gene Knockdown Techniques, Humans, Mitochondria, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Podocytes, Protein Kinases, Rats, Sequence Alignment, Sequence Homology, Amino Acid, Ubiquinone, Young Adult, Zebrafish, Zebrafish Proteins}, issn = {1558-8238}, doi = {10.1172/JCI69000}, author = {Ashraf, Shazia and Gee, Heon Yung and Woerner, Stephanie and Xie, Letian X and Vega-Warner, Virginia and Lovric, Svjetlana and Fang, Humphrey and Song, Xuewen and Cattran, Daniel C and Avila-Casado, Carmen and Paterson, Andrew D and Nitschk{\'e}, Patrick and Bole-Feysot, Christine and Cochat, Pierre and Esteve-Rudd, Julian and Haberberger, Birgit and Allen, Susan J and Zhou, Weibin and Airik, Rannar and Otto, Edgar A and Barua, Moumita and Al-Hamed, Mohamed H and Kari, Jameela A and Evans, Jonathan and Bierzynska, Agnieszka and Saleem, Moin A and Bockenhauer, Detlef and Kleta, Robert and El Desoky, Sherif and Hacihamdioglu, Duygu O and Gok, Faysal and Washburn, Joseph and Wiggins, Roger C and Choi, Murim and Lifton, Richard P and Levy, Shawn and Han, Zhe and Salviati, Leonardo and Prokisch, Holger and Williams, David S and Pollak, Martin and Clarke, Catherine F and Pei, York and Antignac, Corinne and Hildebrandt, Friedhelm} } @article {296, title = {ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Aug 08}, pages = {357-67}, abstract = {

The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which are preassembled in the cytoplasm prior to transport to the ciliary axonemal compartment. In humans, defects in structural components, docking complexes, or cytoplasmic assembly factors can cause primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease and defects in laterality. By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating. Transient suppression in zebrafish and analysis of an ENU mouse mutant confirmed in both model organisms that ARMC4 is critical for left-right patterning. We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs.

}, keywords = {Amino Acid Sequence, Animals, Armadillo Domain Proteins, Axoneme, Body Patterning, Cilia, DNA Copy Number Variations, DNA Mutational Analysis, Dyneins, Gene Expression Regulation, Humans, Kartagener Syndrome, Mice, Microtubule-Associated Proteins, Molecular Sequence Data, Mutation, Respiratory System, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.06.009}, author = {Hjeij, Rim and Lindstrand, Anna and Francis, Richard and Zariwala, Maimoona A and Liu, Xiaoqin and Li, You and Damerla, Rama and Dougherty, Gerard W and Abouhamed, Marouan and Olbrich, Heike and Loges, Niki T and Pennekamp, Petra and Davis, Erica E and Carvalho, Claudia M B and Pehlivan, Davut and Werner, Claudius and Raidt, Johanna and K{\"o}hler, Gabriele and H{\"a}ffner, Karsten and Reyes-Mugica, Miguel and Lupski, James R and Leigh, Margaret W and Rosenfeld, Margaret and Morgan, Lucy C and Knowles, Michael R and Lo, Cecilia W and Katsanis, Nicholas and Omran, Heymut} } @article {302, title = {De novo mutations in histone-modifying genes in congenital heart disease.}, journal = {Nature}, volume = {498}, year = {2013}, month = {2013 Jun 13}, pages = {220-3}, abstract = {

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8\% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes {\textquoteright}poised{\textquoteright} promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10\% of severe CHD.

}, keywords = {Adult, Case-Control Studies, Child, Chromatin, DNA Mutational Analysis, Enhancer Elements, Genetic, Exome, Female, Genes, Developmental, Heart Diseases, Histones, Humans, Lysine, Male, Methylation, Mutation, Odds Ratio, Promoter Regions, Genetic}, issn = {1476-4687}, doi = {10.1038/nature12141}, author = {Zaidi, Samir and Choi, Murim and Wakimoto, Hiroko and Ma, Lijiang and Jiang, Jianming and Overton, John D and Romano-Adesman, Angela and Bjornson, Robert D and Breitbart, Roger E and Brown, Kerry K and Carriero, Nicholas J and Cheung, Yee Him and Deanfield, John and DePalma, Steve and Fakhro, Khalid A and Glessner, Joseph and Hakonarson, Hakon and Italia, Michael J and Kaltman, Jonathan R and Kaski, Juan and Kim, Richard and Kline, Jennie K and Lee, Teresa and Leipzig, Jeremy and Lopez, Alexander and Mane, Shrikant M and Mitchell, Laura E and Newburger, Jane W and Parfenov, Michael and Pe{\textquoteright}er, Itsik and Porter, George and Roberts, Amy E and Sachidanandam, Ravi and Sanders, Stephan J and Seiden, Howard S and State, Mathew W and Subramanian, Sailakshmi and Tikhonova, Irina R and Wang, Wei and Warburton, Dorothy and White, Peter S and Williams, Ismee A and Zhao, Hongyu and Seidman, Jonathan G and Brueckner, Martina and Chung, Wendy K and Gelb, Bruce D and Goldmuntz, Elizabeth and Seidman, Christine E and Lifton, Richard P} } @article {301, title = {Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles.}, journal = {Genome Res}, volume = {23}, year = {2013}, month = {2013 Sep}, pages = {1383-94}, abstract = {

Over 1200 recessive disease genes have been described in humans. The prevalence, allelic architecture, and per-genome load of pathogenic alleles in these genes remain to be fully elucidated, as does the contribution of DNA copy-number variants (CNVs) to carrier status and recessive disease. We mined CNV data from 21,470 individuals obtained by array-comparative genomic hybridization in a clinical diagnostic setting to identify deletions encompassing or disrupting recessive disease genes. We identified 3212 heterozygous potential carrier deletions affecting 419 unique recessive disease genes. Deletion frequency of these genes ranged from one occurrence to 1.5\%. When compared with recessive disease genes never deleted in our cohort, the 419 recessive disease genes affected by at least one carrier deletion were longer and located farther from known dominant disease genes, suggesting that the formation and/or prevalence of carrier CNVs may be affected by both local and adjacent genomic features and by selection. Some subjects had multiple carrier CNVs (307 subjects) and/or carrier deletions encompassing more than one recessive disease gene (206 deletions). Heterozygous deletions spanning multiple recessive disease genes may confer carrier status for multiple single-gene disorders, for complex syndromes resulting from the combination of two or more recessive conditions, or may potentially cause clinical phenotypes due to a multiply heterozygous state. In addition to carrier mutations, we identified homozygous and hemizygous deletions potentially causative for recessive disease. We provide further evidence that CNVs contribute to the allelic architecture of both carrier and recessive disease-causing mutations. Thus, a complete recessive carrier screening method or diagnostic test should detect CNV alleles.

}, keywords = {Alleles, Comparative Genomic Hybridization, Databases, Genetic, DNA Copy Number Variations, Gene Deletion, Gene Frequency, Genes, Dominant, Genes, Recessive, Genetic Diseases, Inborn, Homozygote, Humans}, issn = {1549-5469}, doi = {10.1101/gr.156075.113}, author = {Boone, Philip M and Campbell, Ian M and Baggett, Brett C and Soens, Zachry T and Rao, Mitchell M and Hixson, Patricia M and Patel, Ankita and Bi, Weimin and Cheung, Sau Wai and Lalani, Seema R and Beaudet, Arthur L and Stankiewicz, Pawel and Shaw, Chad A and Lupski, James R} } @article {290, title = {Evidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome.}, journal = {Am J Med Genet A}, volume = {161A}, year = {2013}, month = {2013 Dec}, pages = {3182-6}, abstract = {

Haploinsufficiency of CHD7 (OMIM$\#$ 608892) is known to cause CHARGE syndrome (OMIM$\#$ 214800). Molecular testing supports a definitive diagnosis in approximately 65-70\% of cases. Most CHD7 mutations arise de novo, and no mutations affecting exon-7 have been reported to date. We report on an 8-year-old girl diagnosed with CHARGE syndrome that was referred to our laboratory for comprehensive CHD7 gene screening. Genomic DNA from the subject with a suspected diagnosis of CHARGE was isolated from peripheral blood lymphocytes and comprehensive Sanger sequencing, along with deletion/duplication analysis of the CHD7 gene using multiplex ligation-dependent probe amplification (MLPA), was performed. MLPA analysis identified a reduced single probe signal for exon-7 of the CHD7 gene consistent with potential heterozygous deletion. Long-range PCR breakpoint analysis identified a complex genomic rearrangement (CGR) leading to the deletion of exon-7 and breakpoints consistent with a replicative mechanism such as fork stalling and template switching (FoSTeS) or microhomology-mediated break-induced replication (MMBIR). Taken together this represents the first evidence for a CHD7 intragenic CGR in a patient with CHARGE syndrome leading to what appears to be also the first report of a mutation specifically disrupting exon-7. Although likely rare, CGR may represent an overlooked mechanism in subjects with CHARGE syndrome that can be missed by current sequencing and dosage assays.

}, keywords = {Abnormalities, Multiple, CHARGE Syndrome, Child, DNA Helicases, DNA Replication, DNA-Binding Proteins, Exons, Female, Gene Deletion, Haploinsufficiency, Humans, Mutation}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36178}, author = {Vatta, Matteo and Niu, Zhiyv and Lupski, James R and Putnam, Philip and Spoonamore, Katherine G and Fang, Ping and Eng, Christine M and Willis, Alecia S} } @article {323, title = {Incidental copy-number variants identified by routine genome testing in a clinical population.}, journal = {Genet Med}, volume = {15}, year = {2013}, month = {2013 Jan}, pages = {45-54}, abstract = {

PURPOSE: Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained.

METHODS: Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed.

RESULTS: In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients{\textquoteright} referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition.

CONCLUSION: Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient.

}, keywords = {Age of Onset, Base Sequence, Chromosome Mapping, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Gene Order, Genetic Predisposition to Disease, Humans, Inheritance Patterns, Male, Reproducibility of Results}, issn = {1530-0366}, doi = {10.1038/gim.2012.95}, author = {Boone, Philip M and Soens, Zachry T and Campbell, Ian M and Stankiewicz, Pawel and Cheung, Sau Wai and Patel, Ankita and Beaudet, Arthur L and Plon, Sharon E and Shaw, Chad A and McGuire, Amy L and Lupski, James R} } @article {315, title = {Macular telangiectasia type 2.}, journal = {Prog Retin Eye Res}, volume = {34}, year = {2013}, month = {2013 May}, pages = {49-77}, abstract = {

Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1\% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment-outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the non-neovascular disease stages. Recent progress in structure-function correlation may help to develop surrogate outcome measures for future clinical trials. In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.

}, keywords = {Diagnosis, Differential, Humans, Macula Lutea, Retinal Diseases, Telangiectasis, Visual Acuity}, issn = {1873-1635}, doi = {10.1016/j.preteyeres.2012.11.002}, author = {Charbel Issa, Peter and Gillies, Mark C and Chew, Emily Y and Bird, Alan C and Heeren, Tjebo F C and Peto, Tunde and Holz, Frank G and Scholl, Hendrik P N} } @article {305, title = {Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {632-6}, abstract = {

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.

}, keywords = {Biological Transport, Case-Control Studies, Child, Child, Preschool, Congenital Disorders of Glycosylation, Exome, Female, Glycosylation, Humans, Male, Monosaccharide Transport Proteins, Mosaicism, Mutation, Spectrometry, Mass, Electrospray Ionization, Transferrin, Uridine Diphosphate Galactose}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.012}, author = {Ng, Bobby G and Buckingham, Kati J and Raymond, Kimiyo and Kircher, Martin and Turner, Emily H and He, Miao and Smith, Joshua D and Eroshkin, Alexey and Szybowska, Marta and Losfeld, Marie E and Chong, Jessica X and Kozenko, Mariya and Li, Chumei and Patterson, Marc C and Gilbert, Rodney D and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Freeze, Hudson H} } @article {295, title = {Mutations in DSTYK and dominant urinary tract malformations.}, journal = {N Engl J Med}, volume = {369}, year = {2013}, month = {2013 Aug 15}, pages = {621-9}, abstract = {

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.

METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.

RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.

CONCLUSIONS: We detected independent DSTYK mutations in 2.3\% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

}, keywords = {Adult, Animals, Base Sequence, Child, Exome, Female, Gene Knockdown Techniques, Genetic Linkage, Genome-Wide Association Study, Heterozygote, Humans, Infant, Kidney, Male, Mice, Molecular Sequence Data, Mutation, Pedigree, Receptor-Interacting Protein Serine-Threonine Kinases, RNA, Small Interfering, Urinary Tract, Urogenital Abnormalities, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa1214479}, author = {Sanna-Cherchi, Simone and Sampogna, Rosemary V and Papeta, Natalia and Burgess, Katelyn E and Nees, Shannon N and Perry, Brittany J and Choi, Murim and Bodria, Monica and Liu, Yan and Weng, Patricia L and Lozanovski, Vladimir J and Verbitsky, Miguel and Lugani, Francesca and Sterken, Roel and Paragas, Neal and Caridi, Gianluca and Carrea, Alba and Dagnino, Monica and Materna-Kiryluk, Anna and Santamaria, Giuseppe and Murtas, Corrado and Ristoska-Bojkovska, Nadica and Izzi, Claudia and Kacak, Nilgun and Bianco, Beatrice and Giberti, Stefania and Gigante, Maddalena and Piaggio, Giorgio and Gesualdo, Loreto and Vukic, Durdica Kosuljandic and Vukojevic, Katarina and Saraga-Babic, Mirna and Saraga, Marijan and Gucev, Zoran and Allegri, Landino and Latos-Bielenska, Anna and Casu, Domenica and State, Matthew and Scolari, Francesco and Ravazzolo, Roberto and Kiryluk, Krzysztof and Al-Awqati, Qais and D{\textquoteright}Agati, Vivette D and Drummond, Iain A and Tasic, Velibor and Lifton, Richard P and Ghiggeri, Gian Marco and Gharavi, Ali G} } @article {314, title = {Mutations in ECEL1 cause distal arthrogryposis type 5D.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jan 10}, pages = {150-6}, abstract = {

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ~50\% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ~70\% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.

}, keywords = {Arthrogryposis, Consanguinity, Female, Genetic Linkage, Humans, Male, Metalloendopeptidases, Mutation, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.11.014}, author = {McMillin, Margaret J and Below, Jennifer E and Shively, Kathryn M and Beck, Anita E and Gildersleeve, Heidi I and Pinner, Jason and Gogola, Gloria R and Hecht, Jacqueline T and Grange, Dorothy K and Harris, David J and Earl, Dawn L and Jagadeesh, Sujatha and Mehta, Sarju G and Robertson, Stephen P and Swanson, James M and Faustman, Elaine M and Mefford, Heather C and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {299, title = {Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Jul 11}, pages = {132-40}, abstract = {

Previously, DFNB89, a locus associated with autosomal-recessive nonsyndromic hearing impairment (ARNSHI), was mapped to chromosomal region 16q21-q23.2 in three unrelated, consanguineous Pakistani families. Through whole-exome sequencing of a hearing-impaired individual from each family, missense mutations were identified at highly conserved residues of lysyl-tRNA synthetase (KARS): the c.1129G>A (p.Asp377Asn) variant was found in one family, and the c.517T>C (p.Tyr173His) variant was found in the other two families. Both variants were predicted to be damaging by multiple bioinformatics tools. The two variants both segregated with the nonsyndromic-hearing-impairment phenotype within the three families, and neither mutation was identified in ethnically matched controls or within variant databases. Individuals homozygous for KARS mutations had symmetric, severe hearing impairment across all frequencies but did not show evidence of auditory or limb neuropathy. It has been demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice. Moreover, KARS has strong localization to the spiral ligament region of the cochlea, as well as to Deiters{\textquoteright} cells, the sulcus epithelium, the basilar membrane, and the surface of the spiral limbus. It is hypothesized that KARS variants affect aminoacylation in inner-ear cells by interfering with binding activity to tRNA or p38 and with tetramer formation. The identification of rare KARS variants in ARNSHI-affected families defines a gene that is associated with ARNSHI.

}, keywords = {Animals, Case-Control Studies, Chickens, Cochlea, Computational Biology, Consanguinity, Female, Genetic Linkage, Hair Cells, Auditory, Inner, Haplotypes, Hearing Loss, Homozygote, Humans, Lysine-tRNA Ligase, Male, Mice, Mutation, Missense, Pedigree, Transfer RNA Aminoacylation, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.05.018}, author = {Santos-Cortez, Regie Lyn P and Lee, Kwanghyuk and Azeem, Zahid and Antonellis, Patrick J and Pollock, Lana M and Khan, Saadullah and Andrade-Elizondo, Paula B and Chiu, Ilene and Adams, Mark D and Basit, Sulman and Smith, Joshua D and Nickerson, Deborah A and McDermott, Brian M and Ahmad, Wasim and Leal, Suzanne M} } @article {307, title = {Mutations in KCTD1 cause scalp-ear-nipple syndrome.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {621-6}, abstract = {

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Branchio-Oto-Renal Syndrome, Ear, External, Ectodermal Dysplasia, Exome, Female, Humans, Hypospadias, Male, Molecular Sequence Data, Muscle Hypotonia, Mutation, Missense, Nipples, Pedigree, Phenotype, Protein Structure, Tertiary, Repressor Proteins, Scalp, Sequence Homology, Amino Acid}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.002}, author = {Marneros, Alexander G and Beck, Anita E and Turner, Emily H and McMillin, Margaret J and Edwards, Matthew J and Field, Michael and de Macena Sobreira, Nara Lygia and Perez, Ana Beatriz A and Fortes, Jose A R and Lampe, Anne K and Giovannucci Uzielli, Maria Luisa and Gordon, Christopher T and Plessis, Ghislaine and Le Merrer, Martine and Amiel, Jeanne and Reichenberger, Ernst and Shively, Kathryn M and Cerrato, Felecia and Labow, Brian I and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {287, title = {Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly.}, journal = {JAMA Neurol}, volume = {70}, year = {2013}, month = {2013 Dec}, pages = {1491-8}, abstract = {

IMPORTANCE: Patients with rare diseases and complex clinical presentations represent a challenge for clinical diagnostics. Genomic approaches are allowing the identification of novel variants in genes for very rare disorders, enabling a molecular diagnosis. Genomics is also revealing a phenotypic expansion whereby the full spectrum of clinical expression conveyed by mutant alleles at a locus can be better appreciated.

OBJECTIVE: To elucidate the molecular cause of a complex neuropathy phenotype in 3 patients by applying genomic sequencing strategies.

DESIGN, SETTING, AND PARTICIPANTS: Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly. They were recruited into the Centers for Mendelian Genomics research program to identify the molecular cause of their phenotype. Whole-genome, targeted whole-exome sequencing, and high-resolution single-nucleotide polymorphism arrays were performed in genetics clinics of tertiary care pediatric hospitals and biomedical research institutions.

MAIN OUTCOMES AND MEASURES: Whole-genome and whole-exome sequencing identified the variants responsible for the patients{\textquoteright} clinical phenotype.

RESULTS: We identified compound heterozygous alleles in 2 affected siblings from 1 family and a homozygous nonsense variant in the third unrelated patient in the vaccinia-related kinase 1 gene (VRK1). In the latter subject, we found a common haplotype on which the nonsense mutation occurred and that segregates in the Ashkenazi Jewish population.

CONCLUSIONS AND RELEVANCE: We report the identification of disease-causing alleles in 3 children from 2 unrelated families with a previously uncharacterized complex axonal motor and sensory neuropathy accompanied by severe nonprogressive microcephaly and cerebral dysgenesis. Our data raise the question of whether VRK1 mutations disturb cell cycle progression and may result in apoptosis of cells in the nervous system. The application of unbiased genomic approaches allows the identification of potentially pathogenic mutations in unsuspected genes in highly genetically heterogeneous and uncharacterized neurological diseases.

}, keywords = {Child, Child, Preschool, DNA Mutational Analysis, Female, Genotype, Hereditary Sensory and Motor Neuropathy, Humans, Infant, Intracellular Signaling Peptides and Proteins, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Neural Conduction, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2013.4598}, author = {Gonzaga-Jauregui, Claudia and Lotze, Timothy and Jamal, Leila and Penney, Samantha and Campbell, Ian M and Pehlivan, Davut and Hunter, Jill V and Woodbury, Suzanne L and Raymond, Gerald and Adesina, Adekunle M and Jhangiani, Shalini N and Reid, Jeffrey G and Muzny, Donna M and Boerwinkle, Eric and Lupski, James R and Gibbs, Richard A and Wiszniewski, Wojciech} } @article {288, title = {Replicative mechanisms for CNV formation are error prone.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Nov}, pages = {1319-26}, abstract = {

We investigated 67 breakpoint junctions of gene copy number gains in 31 unrelated subjects. We observed a strikingly high frequency of small deletions and insertions (29\%) apparently originating from polymerase slippage events, in addition to frameshifts and point mutations in homonucleotide runs (13\%), at or flanking the breakpoint junctions of complex copy number variants. These single-nucleotide variants were generated concomitantly with the de novo complex genomic rearrangement (CGR) event. Our findings implicate low-fidelity, error-prone DNA polymerase activity in synthesis associated with DNA repair mechanisms as the cause of local increase in point mutation burden associated with human CGR.

}, keywords = {Base Sequence, DNA Breaks, DNA Copy Number Variations, DNA Repair, DNA Replication, Frameshift Mutation, Gene Rearrangement, Genetic Variation, Genotype, Humans, Sequence Analysis, DNA, Sequence Deletion}, issn = {1546-1718}, doi = {10.1038/ng.2768}, author = {Carvalho, Claudia M B and Pehlivan, Davut and Ramocki, Melissa B and Fang, Ping and Alleva, Benjamin and Franco, Luis M and Belmont, John W and Hastings, P J and Lupski, James R} } @article {293, title = {Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Sep}, pages = {1050-4}, abstract = {

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause \~{}40\% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.

}, keywords = {Adrenal Cortex Neoplasms, Adrenocortical Adenoma, Aldosterone, Amino Acid Sequence, Calcium Channels, L-Type, Cell Line, Child, Child, Preschool, Female, Germ-Line Mutation, Humans, Hyperaldosteronism, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Sequence Alignment}, issn = {1546-1718}, doi = {10.1038/ng.2695}, author = {Scholl, Ute I and Goh, Gerald and St{\"o}lting, Gabriel and de Oliveira, Regina Campos and Choi, Murim and Overton, John D and Fonseca, Annabelle L and Korah, Reju and Starker, Lee F and Kunstman, John W and Prasad, Manju L and Hartung, Erum A and Mauras, Nelly and Benson, Matthew R and Brady, Tammy and Shapiro, Jay R and Loring, Erin and Nelson-Williams, Carol and Libutti, Steven K and Mane, Shrikant and Hellman, Per and Westin, Gunnar and Akerstr{\"o}m, G{\"o}ran and Bj{\"o}rklund, Peyman and Carling, Tobias and Fahlke, Christoph and Hidalgo, Patricia and Lifton, Richard P} } @article {297, title = {TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Aug 08}, pages = {197-210}, abstract = {

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70\% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1\%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

}, keywords = {Age of Onset, Aging, Premature, Asian Continental Ancestry Group, Base Sequence, Brain, Child, Child, Preschool, Chromosomes, Human, Pair 2, Exons, Female, Genetic Predisposition to Disease, Humans, Language Development Disorders, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Pedigree, Sequence Analysis, DNA, Sequence Deletion, Tetraspanins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.05.027}, author = {Wiszniewski, Wojciech and Hunter, Jill V and Hanchard, Neil A and Willer, Jason R and Shaw, Chad and Tian, Qi and Illner, Anna and Wang, Xueqing and Cheung, Sau W and Patel, Ankita and Campbell, Ian M and Gelowani, Violet and Hixson, Patricia and Ester, Audrey R and Azamian, Mahshid S and Potocki, Lorraine and Zapata, Gladys and Hernandez, Patricia P and Ramocki, Melissa B and Santos-Cortez, Regie L P and Wang, Gao and York, Michele K and Justice, Monica J and Chu, Zili D and Bader, Patricia I and Omo-Griffith, Lisa and Madduri, Nirupama S and Scharer, Gunter and Crawford, Heather P and Yanatatsaneejit, Pattamawadee and Eifert, Anna and Kerr, Jeffery and Bacino, Carlos A and Franklin, Adiaha I A and Goin-Kochel, Robin P and Simpson, Gayle and Immken, LaDonna and Haque, Muhammad E and Stosic, Marija and Williams, Misti D and Morgan, Thomas M and Pruthi, Sumit and Omary, Reed and Boyadjiev, Simeon A and Win, Kay K and Thida, Aye and Hurles, Matthew and Hibberd, Martin Lloyd and Khor, Chiea Chuen and Van Vinh Chau, Nguyen and Gallagher, Thomas E and Mutirangura, Apiwat and Stankiewicz, Pawel and Beaudet, Arthur L and Maletic-Savatic, Mirjana and Rosenfeld, Jill A and Shaffer, Lisa G and Davis, Erica E and Belmont, John W and Dunstan, Sarah and Simmons, Cameron P and Bonnen, Penelope E and Leal, Suzanne M and Katsanis, Nicholas and Lupski, James R and Lalani, Seema R} } @article {312, title = {Whole-exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum.}, journal = {Clin Genet}, volume = {84}, year = {2013}, month = {2013 Oct}, pages = {394-5}, keywords = {Abnormalities, Multiple, Base Sequence, Child, Consanguinity, Exome, Humans, Male, Membrane Proteins, Pedigree, Phenotype, Sequence Analysis, DNA, Syndrome}, issn = {1399-0004}, doi = {10.1111/cge.12088}, author = {Caglayan, A O and Per, H and Akgumus, G and Gumus, H and Baranoski, J and Canpolat, M and Calik, M and Yikilmaz, A and Bilguvar, K and Kumandas, S and Gunel, M} } @article {318, title = {Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.}, journal = {J Invest Dermatol}, volume = {133}, year = {2013}, month = {2013 Mar}, pages = {827-830}, keywords = {Adolescent, Adult, Amino Acid Sequence, Biopsy, Child, Child, Preschool, Cohort Studies, Epidermis, Exome, Humans, Infant, Middle Aged, Molecular Sequence Data, Mutation, Nevus, Sebaceous of Jadassohn, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Sequence Analysis, DNA, Young Adult}, issn = {1523-1747}, doi = {10.1038/jid.2012.379}, author = {Levinsohn, Jonathan L and Tian, Li C and Boyden, Lynn M and McNiff, Jennifer M and Narayan, Deepak and Loring, Erin S and Yun, Duri and Sugarman, Jeffrey L and Overton, John D and Mane, Shrikant M and Lifton, Richard P and Paller, Amy S and Wagner, Annette M and Antaya, Richard J and Choate, Keith A} } @article {317, title = {Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Dec}, pages = {1370-4}, abstract = {

Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.

}, keywords = {Adult, Aged, Chromosomal Proteins, Non-Histone, Chromosomes, Human, Pair 18, CpG Islands, DNA Methylation, Epigenesis, Genetic, Female, Haplotypes, Heredity, Homeodomain Proteins, Humans, Male, Middle Aged, Muscular Dystrophy, Facioscapulohumeral, Mutation}, issn = {1546-1718}, doi = {10.1038/ng.2454}, author = {Lemmers, Richard J L F and Tawil, Rabi and Petek, Lisa M and Balog, Judit and Block, Gregory J and Santen, Gijs W E and Amell, Amanda M and van der Vliet, Patrick J and Almomani, Rowida and Straasheijm, Kirsten R and Krom, Yvonne D and Klooster, Rinse and Sun, Yu and den Dunnen, Johan T and Helmer, Quinta and Donlin-Smith, Colleen M and Padberg, George W and van Engelen, Baziel G M and de Greef, Jessica C and Aartsma-Rus, Annemieke M and Frants, Rune R and de Visser, Marianne and Desnuelle, Claude and Sacconi, Sabrina and Filippova, Galina N and Bakker, Bert and Bamshad, Michael J and Tapscott, Stephen J and Miller, Daniel G and van der Maarel, Silv{\`e}re M} } @article {327, title = {Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.}, journal = {Am J Hum Genet}, volume = {90}, year = {2012}, month = {2012 May 04}, pages = {925-33}, abstract = {

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57\%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

}, keywords = {Adult, Child, Child, Preschool, Cohort Studies, Exome, Female, Haploinsufficiency, Humans, Limb Deformities, Congenital, Male, Mandibulofacial Dysostosis, Mutation, Reproducibility of Results, RNA Precursors, RNA Splicing Factors, RNA-Binding Proteins, Spliceosomes, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.04.004}, author = {Bernier, Francois P and Caluseriu, Oana and Ng, Sarah and Schwartzentruber, Jeremy and Buckingham, Kati J and Innes, A Micheil and Jabs, Ethylin Wang and Innis, Jeffrey W and Schuette, Jane L and Gorski, Jerome L and Byers, Peter H and Andelfinger, Gregor and Siu, Victoria and Lauzon, Julie and Fernandez, Bridget A and McMillin, Margaret and Scott, Richard H and Racher, Hilary and Majewski, Jacek and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Parboosingh, Jillian S} } @article {330, title = {Next generation analytic tools for large scale genetic epidemiology studies of complex diseases.}, journal = {Genet Epidemiol}, volume = {36}, year = {2012}, month = {2012 Jan}, pages = {22-35}, abstract = {

Over the past several years, genome-wide association studies (GWAS) have succeeded in identifying hundreds of genetic markers associated with common diseases. However, most of these markers confer relatively small increments of risk and explain only a small proportion of familial clustering. To identify obstacles to future progress in genetic epidemiology research and provide recommendations to NIH for overcoming these barriers, the National Cancer Institute sponsored a workshop entitled "Next Generation Analytic Tools for Large-Scale Genetic Epidemiology Studies of Complex Diseases" on September 15-16, 2010. The goal of the workshop was to facilitate discussions on (1) statistical strategies and methods to efficiently identify genetic and environmental factors contributing to the risk of complex disease; and (2) how to develop, apply, and evaluate these strategies for the design, analysis, and interpretation of large-scale complex disease association studies in order to guide NIH in setting the future agenda in this area of research. The workshop was organized as a series of short presentations covering scientific (gene-gene and gene-environment interaction, complex phenotypes, and rare variants and next generation sequencing) and methodological (simulation modeling and computational resources and data management) topic areas. Specific needs to advance the field were identified during each session and are summarized.

}, keywords = {Data Mining, Gene-Environment Interaction, Genetic Variation, Genome-Wide Association Study, Humans, Molecular Epidemiology, National Institutes of Health (U.S.), Neoplasms, Phenotype, United States}, issn = {1098-2272}, doi = {10.1002/gepi.20652}, author = {Mechanic, Leah E and Chen, Huann-Sheng and Amos, Christopher I and Chatterjee, Nilanjan and Cox, Nancy J and Divi, Rao L and Fan, Ruzong and Harris, Emily L and Jacobs, Kevin and Kraft, Peter and Leal, Suzanne M and McAllister, Kimberly and Moore, Jason H and Paltoo, Dina N and Province, Michael A and Ramos, Erin M and Ritchie, Marylyn D and Roeder, Kathryn and Schaid, Daniel J and Stephens, Matthew and Thomas, Duncan C and Weinberg, Clarice R and Witte, John S and Zhang, Shunpu and Z{\"o}llner, Sebastian and Feuer, Eric J and Gillanders, Elizabeth M} } @article {328, title = {Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis.}, journal = {Blood}, volume = {119}, year = {2012}, month = {2012 May 17}, pages = {4731-40}, abstract = {

Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole-exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.

}, keywords = {Adult, beta-Glucosidase, Child, Child, Preschool, Female, Gaucher Disease, Genome, Human, Hematologic Neoplasms, Humans, Individuality, Male, Pedigree, Phenotype, Sequence Analysis, DNA, Siblings}, issn = {1528-0020}, doi = {10.1182/blood-2011-10-386862}, author = {Lo, Sarah M and Choi, Murim and Liu, Jun and Jain, Dhanpat and Boot, Rolf G and Kallemeijn, Wouter W and Aerts, Johannes M F G and Pashankar, Farzana and Kupfer, Gary M and Mane, Shrikant and Lifton, Richard P and Mistry, Pramod K} }