@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 {958, title = {Autosomal recessive variants in alter the γ-tubulin ring complex leading to neurodevelopmental disease.}, journal = {iScience}, volume = {24}, year = {2021}, month = {2021 Jan 22}, pages = {101948}, abstract = {

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101948}, author = {G{\"u}ng{\"o}r, Serdal and Oktay, Yavuz and Hiz, Semra and Aranguren-Ib{\'a}{\~n}ez, {\'A}lvaro and Kalafatcilar, Ipek and Yaramis, Ahmet and Karaca, Ezgi and Yis, Uluc and Sonmezler, Ece and Ekinci, Burcu and Aslan, Mahmut and Yilmaz, Elmasnur and {\"O}zg{\"o}r, Bilge and Balaraju, Sunitha and Szabo, Nora and Laurie, Steven and Beltran, Sergi and MacArthur, Daniel G and Hathazi, Denisa and Topf, Ana and Roos, Andreas and Lochm{\"u}ller, Hanns and Vernos, Isabelle and Horvath, Rita} } @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 {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 {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 {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 {1023, title = {Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 Jun 07}, abstract = {

Advances in genome sequencing have resulted in the identification of the causes for numerous rare diseases. However, many cases remain unsolved with standard molecular analyses. We describe a family presenting with a phenotype resembling inherited thrombocytopenia 2 (THC2). THC2 is generally caused by single nucleotide variants that prevent silencing of ANKRD26 expression during hematopoietic differentiation. Short-read whole-exome and genome sequencing approaches were unable to identify a causal variant in this family. Using long-read whole-genome sequencing, a large complex structural variant involving a paired-duplication inversion was identified. Through functional studies, we show that this structural variant results in a pathogenic gain-of-function WAC-ANKRD26 fusion transcript. Our findings illustrate how complex structural variants that may be missed by conventional genome sequencing approaches can cause human disease.

}, issn = {1540-9538}, doi = {10.1084/jem.20210444}, author = {Wahlster, Lara and Verboon, Jeffrey M and Ludwig, Leif S and Black, Susan C and Luo, Wendy and Garg, Kopal and Voit, Richard A and Collins, Ryan L and Garimella, Kiran and Costello, Maura and Chao, Katherine R and Goodrich, Julia K and DiTroia, Stephanie P and O{\textquoteright}Donnell-Luria, Anne and Talkowski, Michael E and Michelson, Alan D and Cantor, Alan B and Sankaran, Vijay G} } @article {985, title = {Generation of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches.}, journal = {Kidney Int Rep}, volume = {6}, year = {2021}, month = {2021 Feb}, pages = {460-471}, abstract = {

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of chronic kidney disease during childhood. Identification of 63 monogenic human genes has delineated 12 distinct pathogenic pathways.

Methods: Here, we generated 2 independent sets of nephrotic syndrome (NS) candidate genes to augment the discovery of additional monogenic causes based on whole-exome sequencing (WES) data from 1382 families with NS.

Results: We first identified 63 known monogenic causes of NS in mice from public databases and scientific publications, and 12 of these genes overlapped with the 63 known human monogenic SRNS genes. Second, we used a set of 64 genes that are regulated by the transcription factor Wilms tumor 1 (WT1), which causes SRNS if mutated. Thirteen of these WT1-regulated genes overlapped with human or murine NS genes. Finally, we overlapped these lists of murine and WT1 candidate genes with our list of 120 candidate genes generated from WES in 1382 NS families, to identify novel candidate genes for monogenic human SRNS. Using this approach, we identified 7 overlapping genes, of which 3 genes were shared by all datasets, including . We show that loss-of-function of leads to decreased CDC42 activity and reduced podocyte migration rate, both of which are rescued by overexpression of wild-type complementary DNA (cDNA), but not by cDNA representing the patient mutation.

Conclusion: Thus, we identified 3 novel candidate genes for human SRNS using 3 independent, nonoverlapping hypotheses, and generated functional evidence for as a novel potential monogenic cause of NS.

}, issn = {2468-0249}, doi = {10.1016/j.ekir.2020.11.013}, author = {Kl{\"a}mbt, Verena and Mao, Youying and Schneider, Ronen and Buerger, Florian and Shamseldin, Hanan and Onuchic-Whitford, Ana C and Deutsch, Konstantin and Kitzler, Thomas M and Nakayama, Makiko and Majmundar, Amar J and Mann, Nina and Hugo, Hannah and Widmeier, Eugen and Tan, Weizhen and Rehm, Heidi L and Mane, Shrikant and Lifton, Richard P and Alkuraya, Fowzan S and Shril, Shirlee and Hildebrandt, Friedhelm} } @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 {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 {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 {991, title = {Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans.}, journal = {Nephrol Dial Transplant}, volume = {36}, year = {2021}, month = {2021 01 25}, pages = {237-246}, abstract = {

BACKGROUND: An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in \~{}20\% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis.

METHODS: In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD.

RESULTS: We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1~was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1~in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient{\textquoteright}s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.

CONCLUSION: Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

}, keywords = {Animals, Child, DNA-Binding Proteins, Epithelial-Mesenchymal Transition, Female, HEK293 Cells, Humans, Kidney Diseases, Mice, Mice, Knockout, Mutation, Rats, Repressor Proteins, Single-Cell Analysis, Transcription Factors, Whole Exome Sequencing}, issn = {1460-2385}, doi = {10.1093/ndt/gfaa215}, author = {Kl{\"a}mbt, Verena and Werth, Max and Onuchic-Whitford, Ana C and Getwan, Maike and Kitzler, Thomas M and Buerger, Florian and Mao, Youying and Deutsch, Konstantin and Mann, Nina and Majmundar, Amar J and Kaminski, Michael M and Shen, Tian and Schmidt-Ott, Kai M and Shalaby, Mohamed and El Desoky, Sherif and Kari, Jameela A and Shril, Shirlee and Lienkamp, Soeren S and Barasch, Jonathan and Hildebrandt, Friedhelm} } @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 {971, title = {Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy.}, journal = {Eur J Hum Genet}, volume = {29}, year = {2021}, month = {2021 Jan}, pages = {61-66}, abstract = {

X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1 variant NG_008199.1(NM_000252.2):c.1468-577A>G, which strengthened a cryptic 5{\textquoteright} splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1 transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1 in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.

}, issn = {1476-5438}, doi = {10.1038/s41431-020-00715-7}, author = {Bryen, Samantha J and Oates, Emily C and Evesson, Frances J and Lu, Jessica K and Waddell, Leigh B and Joshi, Himanshu and Ryan, Monique M and Cummings, Beryl B and McLean, Catriona A and MacArthur, Daniel G and Kornberg, Andrew J and Cooper, Sandra T} } @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 {969, title = {Rapid response to the alpha-1 adrenergic agent phenylephrine in the perioperative period is impacted by genomics and ancestry.}, journal = {Pharmacogenomics J}, volume = {21}, year = {2021}, month = {2021 Apr}, pages = {174-189}, abstract = {

The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups: European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3\% increase, p value < 6e-08 and 22.9\% increase, p value < 5e-05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1\% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.

}, issn = {1473-1150}, doi = {10.1038/s41397-020-00194-5}, author = {Wenric, Stephane and Jeff, Janina M and Joseph, Thomas and Yee, Muh-Ching and Belbin, Gillian M and Owusu Obeng, Aniwaa and Ellis, Stephen B and Bottinger, Erwin P and Gottesman, Omri and Levin, Matthew A and Kenny, Eimear E} } @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 {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 {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 {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 {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 {976, title = {Beyond the tubule: pathological variants of , encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.}, journal = {Am J Physiol Renal Physiol}, volume = {319}, year = {2020}, month = {2020 12 01}, pages = {F988-F999}, abstract = {

Pathogenic variants in the gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and -acetyl-β-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19\% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.

}, keywords = {Adolescent, Adult, Animals, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Kidney Glomerulus, Low Density Lipoprotein Receptor-Related Protein-2, Male, Mice, Mice, Knockout, Middle Aged, Renal Insufficiency, Chronic, Young Adult}, issn = {1522-1466}, doi = {10.1152/ajprenal.00295.2020}, author = {Charlton, Jennifer R and Tan, Weizhen and Daouk, Ghaleb and Teot, Lisa and Rosen, Seymour and Bennett, Kevin M and Cwiek, Aleksandra and Nam, Sejin and Emma, Francesco and Jouret, Fran{\c c}ois and Oliveira, Jo{\~a}o Paulo and Tranebj{\ae}rg, Lisbeth and Frykholm, Carina and Mane, Shrikant and Hildebrandt, Friedhelm and Srivastava, Tarak and Storm, Tina and Christensen, Erik Ils{\o} and Nielsen, Rikke} } @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 {842, title = {Cell type-specific genetic regulation of gene expression across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

}, keywords = {Cells, Gene Expression Regulation, Humans, Organ Specificity, Quantitative Trait Loci, RNA, Long Noncoding, Transcriptome}, issn = {1095-9203}, doi = {10.1126/science.aaz8528}, author = {Kim-Hellmuth, Sarah and Aguet, Francois and Oliva, Meritxell and Mu{\~n}oz-Aguirre, Manuel and Kasela, Silva and Wucher, Valentin and Castel, Stephane E and Hamel, Andrew R and Vi{\~n}uela, Ana and Roberts, Amy L and Mangul, Serghei and Wen, Xiaoquan and Wang, Gao and Barbeira, Alvaro N and Garrido-Mart{\'\i}n, Diego and Nadel, Brian B and Zou, Yuxin and Bonazzola, Rodrigo and Quan, Jie and Brown, Andrew and Martinez-Perez, Angel and Soria, Jos{\'e} Manuel and Getz, Gad and Dermitzakis, Emmanouil T and Small, Kerrin S and Stephens, Matthew and Xi, Hualin S and Im, Hae Kyung and Guig{\'o}, Roderic and Segr{\`e}, Ayellet V and Stranger, Barbara E and Ardlie, Kristin G and Lappalainen, Tuuli} } @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 {919, title = {DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 12 03}, pages = {1113-1128}, abstract = {

The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney sections. Further, the variants impair DAAM2-dependent actin remodeling processes: wild-type DAAM2 cDNA, but not cDNA representing missense variants found in individuals with NS, rescued reduced podocyte migration rate (PMR) and restored reduced filopodia formation in shRNA-induced DAAM2-knockdown podocytes. Filopodia restoration was also induced by the formin-activating molecule IMM-01. DAAM2 also co-localizes and co-immunoprecipitates with INF2, which is intriguing since variants in both formins cause NS. Using in~vitro bulk and TIRF microscopy assays, we find that DAAM2 variants alter actin assembly activities of the formin. In a Xenopus daam2-CRISPR knockout model, we demonstrate actin dysregulation in~vivo and glomerular maldevelopment that is rescued by WT-DAAM2 mRNA. We conclude that DAAM2 variants are a likely cause of monogenic human SRNS due to actin dysregulation in podocytes. Further, we provide evidence that DAAM2-associated SRNS may be amenable to treatment using actin regulating compounds.

}, keywords = {Actins, Alleles, Animals, Animals, Genetically Modified, Cell Movement, Cytoplasm, Formins, Genetic Variation, Humans, Kidney, Kidney Glomerulus, Microfilament Proteins, Mutation, Missense, Nephrotic Syndrome, Podocytes, Pseudopodia, rho GTP-Binding Proteins, RNA, Small Interfering, Whole Exome Sequencing, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.11.008}, author = {Schneider, Ronen and Deutsch, Konstantin and Hoeprich, Gregory J and Marquez, Jonathan and Hermle, Tobias and Braun, Daniela A and Seltzsam, Steve and Kitzler, Thomas M and Mao, Youying and Buerger, Florian and Majmundar, Amar J and Onuchic-Whitford, Ana C and Kolvenbach, Caroline M and Schierbaum, Luca and Schneider, Sophia and Halawi, Abdul A and Nakayama, Makiko and Mann, Nina and Connaughton, Dervla M and Kl{\"a}mbt, Verena and Wagner, Matias and Riedhammer, Korbinian M and Renders, Lutz and Katsura, Yoshichika and Thumkeo, Dean and Soliman, Neveen A and Mane, Shrikant and Lifton, Richard P and Shril, Shirlee and Khokha, Mustafa K and Hoefele, Julia and Goode, Bruce L and Hildebrandt, Friedhelm} } @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 {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 {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 {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 {791, title = {Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.}, journal = {Hum Mol Genet}, volume = {29}, year = {2020}, month = {2020 06 03}, pages = {1426-1439}, abstract = {

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddaa051}, author = {Woldegebriel, Rosa and Kvist, Jouni and Andersson, Noora and {\~O}unap, Katrin and Reinson, Karit and Wojcik, Monica H and Bijlsma, Emilia K and Hoffer, Mariette J V and Ryan, Monique M and Stark, Zornitza and Walsh, Maie and Cuppen, Inge and van den Boogaard, Marie-Jose H and Bharucha-Goebel, Diana and Donkervoort, Sandra and Winchester, Sara and Zori, Roberto and B{\"o}nnemann, Carsten G and Maroofian, Reza and O{\textquoteright}Connor, Emer and Houlden, Henry and Zhao, Fang and Carp{\'e}n, Olli and White, Matthew and Sreedharan, Jemeen and Stewart, Murray and Ylikallio, Emil and Tyynismaa, Henna} } @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 {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 {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 {855, title = {Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {40}, year = {2020}, month = {2020 11}, pages = {2738-2746}, abstract = {

OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPS) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPS in 28 556 middle-aged participants of the Malm{\"o} Diet and Cancer Study, of whom 4122 (14.4\%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16\% for those in the lowest GPS decile to 48\% in the highest. We evaluated the discriminative capacity of the GPS-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPS (+0.045, <0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPS and 10-year risk defined by the PCE (=0.03), and addition of GPS improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPS, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank.

CONCLUSIONS: GPS-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPS may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.

}, keywords = {Adult, Aged, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Disease Risk Factors, Heredity, Humans, Incidence, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Prognosis, Risk Assessment, Sweden, Time Factors, United Kingdom}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.120.314856}, author = {Hindy, George and Aragam, Krishna G and Ng, Kenney and Chaffin, Mark and Lotta, Luca A and Baras, Aris and Drake, Isabel and Orho-Melander, Marju and Melander, Olle and Kathiresan, Sekar and Khera, Amit V} } @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 {917, title = {Human CRY1 variants associate with attention deficit/hyperactivity disorder.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 07 01}, pages = {3885-3900}, abstract = {

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1\% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.

}, keywords = {Adult, ARNTL Transcription Factors, Attention Deficit Disorder with Hyperactivity, CLOCK Proteins, Cryptochromes, Female, Genetic Association Studies, HEK293 Cells, Humans, Male, Mutation, Sleep Disorders, Circadian Rhythm}, issn = {1558-8238}, doi = {10.1172/JCI135500}, author = {Onat, O Emre and Kars, M Ece and G{\"u}l, {\c S}eref and Bilguvar, Kaya and Wu, Yiming and {\"O}zhan, Ay{\c s}e and Ayd{\i}n, Cihan and Ba{\c s}ak, A Nazl{\i} and Trusso, M Allegra and Goracci, Arianna and Fallerini, Chiara and Renieri, Alessandra and Casanova, Jean-Laurent and Itan, Yuval and Atba{\c s}o{\u g}lu, Cem E and Saka, Meram C and Kavakl{\i}, {\.I} Halil and Ozcelik, Tayfun} } @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 {704, title = {Identification of genetic variants in CFAP221 as a cause of primary ciliary dyskinesia.}, journal = {J Hum Genet}, volume = {65}, year = {2020}, month = {2020 Jan}, pages = {175-180}, abstract = {

Primary ciliary dyskinesia (PCD) is a rare disorder that affects the biogenesis or function of motile cilia resulting in chronic airway disease. PCD is genetically and phenotypically heterogeneous, with causative mutations identified in over 40 genes; however, the genetic basis of many cases is unknown. Using whole-exome sequencing, we identified three affected siblings with clinical symptoms of PCD but normal ciliary structure, carrying compound heterozygous loss-of-function variants in CFAP221. Computational analysis suggests that these variants are the most damaging alleles shared by all three siblings. Nasal epithelial cells from one of the subjects demonstrated slightly reduced beat frequency (16.5 Hz vs 17.7 Hz, p = 0.16); however, waveform analysis revealed that the CFAP221 defective cilia beat in an aberrant circular pattern. These results show that genetic variants in CFAP221 cause PCD and that CFAP221 should be considered a candidate gene in cases where PCD is suspected but cilia structure and beat frequency appear normal.

}, keywords = {Alleles, Calmodulin-Binding Proteins, Cilia, Ciliary Motility Disorders, Epithelial Cells, Exons, Genetic Variation, Humans, Mutation, Proteins, Whole Exome Sequencing}, issn = {1435-232X}, doi = {10.1038/s10038-019-0686-1}, author = {Bustamante-Marin, Ximena M and Shapiro, Adam and Sears, Patrick R and Charng, Wu-Lin and Conrad, Donald F and Leigh, Margaret W and Knowles, Michael R and Ostrowski, Lawrence E and Zariwala, Maimoona A} } @article {773, title = {Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with NK dysfunction and EBV-driven malignancy treated with stem cell transplantation.}, journal = {J Allergy Clin Immunol Pract}, volume = {8}, year = {2020}, month = {2020 03}, pages = {1103-1106.e3}, keywords = {Herpesvirus 4, Human, Humans, Immunologic Deficiency Syndromes, Mutation, Neoplasms, Primary Immunodeficiency Diseases, Stem Cell Transplantation}, issn = {2213-2201}, doi = {10.1016/j.jaip.2019.08.040}, author = {Burk, Caitlin M and Coffey, Kara E and Mace, Emily M and Bostwick, Bret L and Chinn, Ivan K and Coban-Akdemir, Zeynep H and Jhangiani, Shalini N and Lupski, James R and Ortiz, Damara and Barnum, Jessie L and Allen, Steven W and Robertson, Leanna-Marie and Orange, Jordan S and Chong, Hey J} } @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 {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 {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 {887, title = {Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.}, journal = {Genetics}, volume = {215}, year = {2020}, month = {2020 07}, pages = {869-886}, abstract = {

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV on chromosome 12 in 867 African American children with asthma ( = 1.26 {\texttimes} 10, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with (KIT ligand, also known as ), and their minor alleles were associated with increased expression of the gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure ( = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV, possibly mediated through , in African American children with asthma. This is the first study that has identified a genetic association between lung function and , which has established a role in orchestrating allergic inflammation in asthma.

}, issn = {1943-2631}, doi = {10.1534/genetics.120.303231}, author = {Mak, Angel C Y and Sajuthi, Satria and Joo, Jaehyun and Xiao, Shujie and Sleiman, Patrick M and White, Marquitta J and Lee, Eunice Y and Saef, Benjamin and Hu, Donglei and Gui, Hongsheng and Keys, Kevin L and Lurmann, Fred and Jain, Deepti and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Winterkorn, Lara and Reeves, Catherine and Huntsman, Scott and Eng, Celeste and Salazar, Sandra and Oh, Sam S and Gilliland, Frank D and Chen, Zhanghua and Kumar, Rajesh and Mart{\'\i}nez, Fernando D and Wu, Ann Chen and Ziv, Elad and Hakonarson, Hakon and Himes, Blanca E and Williams, L Keoki and Seibold, Max A and Burchard, Esteban G} } @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 {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 {807, title = {Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia.}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 08}, pages = {e1008691}, abstract = {

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, reduced fertility, and randomization of the left/right body axis. It is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious axonemal defect for pathogenic variants using whole exome capture, next generation sequencing, and bioinformatic analysis assuming an autosomal recessive trait. We identified one subject with an apparently homozygous nonsense variant [(c.1762C>T), p.(Arg588*)] in the uncharacterized CFAP57 gene. Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Nasal cells from the PCD patient express a shorter, mutant version of CFAP57 and the protein is not incorporated into the axoneme. The missing 58 amino acids include portions of WD repeats that may be important for loading onto the intraflagellar transport (IFT) complexes for transport or docking onto the axoneme. A reduced beat frequency and an alteration in ciliary waveform was observed. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is highly conserved in organisms that assemble motile cilia. CFAP57 is allelic with the BOP2/IDA8/FAP57 gene identified previously in Chlamydomonas reinhardtii. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass tag (TMT) mass spectroscopy shows that FAP57 is missing, and the "g" inner dyneins (DHC7 and DHC3) and the "d" inner dynein (DHC2) are reduced, but the FAP57 paralog FBB7 is increased. Together, our data identify a homozygous variant in CFAP57 that causes PCD that is likely due to a defect in the inner dynein arm assembly process.

}, keywords = {3T3 Cells, Adult, Animals, Axoneme, Cells, Cultured, Chlamydomonas reinhardtii, Cilia, Ciliary Motility Disorders, Codon, Nonsense, Conserved Sequence, Dyneins, Humans, Male, Mice, Microtubule-Associated Proteins, Plant Proteins, Proteins, Respiratory Mucosa}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008691}, author = {Bustamante-Marin, Ximena M and Horani, Amjad and Stoyanova, Mihaela and Charng, Wu-Lin and Bottier, Mathieu and Sears, Patrick R and Yin, Wei-Ning and Daniels, Leigh Anne and Bowen, Hailey and Conrad, Donald F and Knowles, Michael R and Ostrowski, Lawrence E and Zariwala, Maimoona A and Dutcher, Susan K} } @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 {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 {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 {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 {965, title = {A novel homozygous variant in results in a neurodevelopmental disorder and disrupts TRAPP complex function.}, journal = {J Med Genet}, year = {2020}, month = {2020 Aug 25}, abstract = {

BACKGROUND: Next-generation sequencing has facilitated the diagnosis of neurodevelopmental disorders with variable and non-specific clinical findings. Recently, a homozygous missense p.(Asp37Tyr) variant in a core subunit of TRAPP complexes which function as tethering factors during membrane trafficking, was reported in two unrelated individuals with neurodevelopmental delay, post-infectious encephalopathy-associated developmental arrest, tetraplegia and accompanying rhabdomyolysis.

METHODS: We performed whole genome sequencing on members of an Ashkenazi Jewish pedigree to identify the underlying genetic aetiology of global developmental delay/intellectual disability in three affected siblings. To assess the effect of the identified variant, we performed biochemical and cell biological functional studies on the TRAPPC2L protein.

RESULTS: A rare homozygous predicted deleterious missense variant, p.(Ala2Gly), in was identified in the affected siblings and it segregated with the neurodevelopmental phenotype within the family. Using a yeast two-hybrid assay and binding, we demonstrate that the p.(Ala2Gly) variant, but not the p.(Asp37Tyr) variant, disrupted the interaction between TRAPPC2L and another core TRAPP protein, TRAPPC6a. Size exclusion chromatography suggested that this variant affects the assembly of TRAPP complexes. Employing two different membrane trafficking assays using fibroblasts from one of the affected siblings, we found a delay in traffic into and out of the Golgi. Similar to the p.(Asp37Tyr) variant, the p.(Ala2Gly) variant resulted in an increase in the levels of active RAB11.

CONCLUSION: Our data fill in a gap in the knowledge of TRAPP architecture with TRAPPC2L interacting with TRAPPC6a, positioning it as a putative adaptor for other TRAPP subunits. Collectively, our findings support the pathogenicity of the p.(Ala2Gly) variant.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2020-107016}, author = {Al-Deri, Noraldin and Okur, Volkan and Ahimaz, Priyanka and Milev, Miroslav and Valivullah, Zaheer and Hagen, Jacob and Sheng, Yufeng and Chung, Wendy and Sacher, Michael and Ganapathi, Mythily} } @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 {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 {977, title = {Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT).}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 10}, pages = {1673-1681}, abstract = {

PURPOSE: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood and adolescence. We aim to identify novel monogenic causes of CAKUT.

METHODS: Exome sequencing was performed in 550 CAKUT-affected families.

RESULTS: We discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in <5 alleles in the gnomAD database with ~141,456 controls. FOXC1 is a causal gene for Axenfeld-Rieger syndrome type 3 and anterior segment dysgenesis 3. Pathogenic variants in FOXC1 have not been detected in patients with CAKUT yet. Interestingly, mouse models for Foxc1 show severe CAKUT phenotypes with incomplete penetrance and variable expressivity. The FOXC1 variants are enriched in the CAKUT cohort compared with the control. Genotype-phenotype correlations showed that Axenfeld-Rieger syndrome or anterior segment dysgenesis can be caused by both truncating and missense pathogenic variants, and the missense variants are located at the forkhead domain. In contrast, for CAKUT, there is no truncating pathogenic variant, and all variants except one are located outside the forkhead domain.

CONCLUSION: We thereby expanded the phenotype of FOXC1 pathogenic variants toward involvement of CAKUT, which can potentially be explained by allelism.

}, keywords = {Child, Eye Abnormalities, Forkhead Transcription Factors, Heterozygote, Humans, Kidney, Phenotype, Urinary Tract}, issn = {1530-0366}, doi = {10.1038/s41436-020-0844-z}, author = {Wu, Chen-Han Wilfred and Mann, Nina and Nakayama, Makiko and Connaughton, Dervla M and Dai, Rufeng and Kolvenbach, Caroline M and Kause, Franziska and Ottlewski, Isabel and Wang, Chunyan and Kl{\"a}mbt, Verena and Seltzsam, Steve and Lai, Ethan W and Selvin, Aravind and Senguttuva, Prabha and Bodamer, Olaf and Stein, Deborah R and El Desoky, Sherif and Kari, Jameela A and Tasic, Velibor and Bauer, Stuart B and Shril, Shirlee and Hildebrandt, Friedhelm} } @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 {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 {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 {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 {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 {755, title = {Severe neurodevelopmental disease caused by a homozygous TLK2 variant.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 03}, pages = {383-387}, abstract = {

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

}, keywords = {Adult, Cerebellum, Child, Developmental Disabilities, Female, Heterozygote, Homozygote, Humans, Infant, Male, Mutation, Missense, Nervous System Malformations, Pedigree, Protein Kinases, Spasms, Infantile}, issn = {1476-5438}, doi = {10.1038/s41431-019-0519-x}, author = {Topf, Ana and Oktay, Yavuz and Balaraju, Sunitha and Yilmaz, Elmasnur and Sonmezler, Ece and Yis, Uluc and Laurie, Steven and Thompson, Rachel and Roos, Andreas and MacArthur, Daniel G and Yaramis, Ahmet and G{\"u}ng{\"o}r, Serdal and Lochm{\"u}ller, Hanns and Hiz, Semra and Horvath, Rita} } @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 {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 {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 {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 {567, title = {ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).}, journal = {Acta Neuropathol}, volume = {137}, year = {2019}, month = {2019 03}, pages = {501-519}, abstract = {

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.

}, issn = {1432-0533}, doi = {10.1007/s00401-019-01963-8}, author = {Lornage, Xavi{\`e}re and Romero, Norma B and Grosgogeat, Claire A and Malfatti, Edoardo and Donkervoort, Sandra and Marchetti, Michael M and Neuhaus, Sarah B and Foley, A Reghan and Labasse, Cl{\'e}mence and Schneider, Rapha{\"e}l and Carlier, Robert Y and Chao, Katherine R and Medne, Livija and Deleuze, Jean-Fran{\c c}ois and Orlikowski, David and B{\"o}nnemann, Carsten G and Gupta, Vandana A and Fardeau, Michel and B{\"o}hm, Johann and Laporte, Jocelyn} } @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 {574, title = {Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 12}, pages = {707}, abstract = {

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.

}, keywords = {Alleles, Anticodon, Child, Child, Preschool, Disease Progression, Epilepsy, Female, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Loss of Function Mutation, Male, Microcephaly, Models, Molecular, Mutation, Neurodevelopmental Disorders, Pedigree, Protein Biosynthesis, Protein Interaction Domains and Motifs, RNA, Transfer, Valine-tRNA Ligase, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-018-07067-3}, author = {Friedman, Jennifer and Smith, Desiree E and Issa, Mahmoud Y and Stanley, Valentina and Wang, Rengang and Mendes, Marisa I and Wright, Meredith S and Wigby, Kristen and Hildreth, Amber and Crawford, John R and Koehler, Alanna E and Chowdhury, Shimul and Nahas, Shareef and Zhai, Liting and Xu, Zhiwen and Lo, Wing-Sze and James, Kiely N and Musaev, Damir and Accogli, Andrea and Guerrero, Kether and Tran, Luan T and Omar, Tarek E I and Ben-Omran, Tawfeg and Dimmock, David and Kingsmore, Stephen F and Salomons, Gajja S and Zaki, Maha S and Bernard, Genevi{\`e}ve and Gleeson, Joseph G} } @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 {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 {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 {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 {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 {736, title = {Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank.}, journal = {Genome Med}, volume = {12}, year = {2019}, month = {2019 Dec 31}, pages = {2}, abstract = {

BACKGROUND: Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City.

METHODS: Exome sequence data from 30,223 adult BioMe participants were evaluated for pathogenic variants in BRCA1/2. Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals.

RESULTS: There were 218 (0.7\%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other~Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4\%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28\% of variant-positive individuals had a personal history, and 45\% had a personal or family history of BRCA1/2-associated cancers. Approximately 27\% of variant-positive individuals had prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (39\%) than those with other pathogenic variants (20\%).

CONCLUSIONS: These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.

}, issn = {1756-994X}, doi = {10.1186/s13073-019-0691-1}, author = {Abul-Husn, Noura S and Soper, Emily R and Odgis, Jacqueline A and Cullina, Sinead and Bobo, Dean and Moscati, Arden and Rodriguez, Jessica E and Loos, Ruth J F and Cho, Judy H and Belbin, Gillian M and Suckiel, Sabrina A and Kenny, Eimear E} } @article {732, title = {The Genetic Landscape of Diamond-Blackfan Anemia.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 Feb 07}, pages = {356}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.011}, author = {Ulirsch, Jacob C and Verboon, Jeffrey M and Kazerounian, Shideh and Guo, Michael H and Yuan, Daniel and Ludwig, Leif S and Handsaker, Robert E and Abdulhay, Nour J and Fiorini, Claudia and Genovese, Giulio and Lim, Elaine T and Cheng, Aaron and Cummings, Beryl B and Chao, Katherine R and Beggs, Alan H and Genetti, Casie A and Sieff, Colin A and Newburger, Peter E and Niewiadomska, Edyta and Matysiak, Michal and Vlachos, Adrianna and Lipton, Jeffrey M and Atsidaftos, Eva and Glader, Bertil and Narla, Anupama and Gleizes, Pierre-Emmanuel and O{\textquoteright}Donohue, Marie-Fran{\c c}oise and Montel-Lehry, Nathalie and Amor, David J and McCarroll, Steven A and O{\textquoteright}Donnell-Luria, Anne H and Gupta, Namrata and Gabriel, Stacey B and MacArthur, Daniel G and Lander, Eric S and Lek, Monkol and Da Costa, Lydie and Nathan, David G and Korostelev, Andrei A and Do, Ron and Sankaran, Vijay G and Gazda, Hanna T} } @article {671, title = {Genome Sequencing Identifies the Pathogenic Variant Missed by Prior Testing in an Infant with Marfan Syndrome.}, journal = {J Pediatr}, volume = {213}, year = {2019}, month = {2019 Oct}, pages = {235-240}, abstract = {

We describe an infant with a phenotype typical of early onset Marfan syndrome whose genetic evaluation, including Sanger sequencing and deletion/duplication testing of FBN1 and exome sequencing, was negative. Ultimately, genome sequencing revealed a deletion missed on prior testing, demonstrating the unique utility of genome sequencing for molecular genetic diagnosis.

}, issn = {1097-6833}, doi = {10.1016/j.jpeds.2019.05.029}, author = {Wojcik, Monica H and Thiele, Katri and Grant, Carly F and Chao, Katherine and Goodrich, Julia and O{\textquoteright}Donnell-Luria, Anne and Lacro, Ronald V and Tan, Wen-Hann and Agrawal, Pankaj B} } @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 {664, title = {Heterozygosity mapping for human dominant trait variants.}, journal = {Hum Mutat}, volume = {40}, year = {2019}, month = {2019 07}, pages = {996-1004}, abstract = {

Homozygosity mapping is a well-known technique to identify runs of homozygous variants that are likely to harbor genes responsible for autosomal recessive disease, but a comparable method for autosomal dominant traits has been lacking. We developed an approach to map dominant disease genes based on heterozygosity frequencies of sequence variants in the immediate vicinity of a dominant trait. We demonstrate through theoretical analysis that DNA variants surrounding an inherited dominant disease variant tend to have increased heterozygosity compared with variants elsewhere in the genome. We confirm existence of this phenomenon in sequence data with known dominant pathogenic variants obtained on family members and in unrelated population controls. A computer-based approach to estimating empirical significance levels associated with our test statistics shows genome-wide p-values smaller than 0.05 for many but not all of the individuals carrying a pathogenic variant.

}, issn = {1098-1004}, doi = {10.1002/humu.23765}, author = {Imai-Okazaki, Atsuko and Li, Yi and Horpaopan, Sukanya and Riazalhosseini, Yasser and Garshasbi, Masoud and Mosse, Yael P and Zhang, Di and Schrauwen, Isabelle and Sharma, Aarushi and Fann, Cathy S J and Leal, Suzanne M and Lathrop, Mark and Ott, Jurg} } @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 {727, title = {Homozygous noncanonical splice variant in in two siblings with multiple congenital anomalies and global developmental delay.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {5}, year = {2019}, month = {2019 Jun}, abstract = {

Two siblings, one male and one female, ages 6 and 13 yr old, have similar clinical features of global developmental delay, multiple congenital anomalies affecting the cardiac, genitourinary, and skeletal systems, and abnormal eye movements. Whole-genome sequencing revealed a homozygous splice variant (NM_014462.3:c.231+4A>C) in that segregated with the phenotype in the family. LSM1 has a role in pre-mRNA splicing and degradation. Expression studies revealed absence of expression of the canonical isoform in the affected individuals. The knockout mice have a partially overlapping phenotype that affects the brain, heart, and eye. To our knowledge, has not been associated with any human disorder; however, the tissue expression pattern, gene constraint, and the similarity of the phenotype in our patients and the knockout mice models suggest it has a role in the development of multiple organ systems in humans.

}, issn = {2373-2873}, doi = {10.1101/mcs.a004101}, author = {Okur, Volkan and LeDuc, Charles A and Guzman, Edwin and Valivullah, Zaheer M and Anyane-Yeboa, Kwame and Chung, Wendy K} } @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 {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 {583, title = {Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {229-245}, abstract = {

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p.Val296Glyfs13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_343+1207del; p.?) starting in exon 5. Both individuals had clinical features of PCD but normal ciliary axoneme structure. In this research, using human nasal cells, mouse models, and X.laevis embryos, we show that GAS2L2 is abundant at the apical surface of ciliated cells, where it localizes with basal bodies, basal feet, rootlets, and actin filaments. Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8~Hz versus control = 15.8~Hz) ciliary-beat pattern. These results were recapitulated in Gas2l2 mouse tracheal epithelial cell (mTEC) cultures and in X.~laevis embryos treated with Gas2l2 morpholinos. In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation. These results show that a pathogenic variant in GAS2L2 causes a genetic defect in ciliary orientation and impairs MCC and results in~PCD.

}, keywords = {Animals, Cilia, Ciliary Motility Disorders, Disease Models, Animal, Exons, Female, Gene Deletion, Genes, Lethal, Humans, Male, Mice, Mice, Knockout, Microfilament Proteins, Microtubule-Associated Proteins, Phenotype, Rotation, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.009}, author = {Bustamante-Marin, Ximena M and Yin, Wei-Ning and Sears, Patrick R and Werner, Michael E and Brotslaw, Eva J and Mitchell, Brian J and Jania, Corey M and Zeman, Kirby L and Rogers, Troy D and Herring, Laura E and Refab{\'e}rt, Luc and Thomas, Lucie and Amselem, Serge and Escudier, Estelle and Legendre, Marie and Grubb, Barbara R and Knowles, Michael R and Zariwala, Maimoona A and Ostrowski, Lawrence E} } @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 {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 {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 {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 {565, title = {A Patient with Berardinelli-Seip Syndrome, Novel Splicesite Mutation and Concomitant Development of Non-diabetic Polyneuropathy}, journal = {J Clin Res Pediatr Endocrinol}, volume = {11}, year = {2019}, month = {2019 09 03}, pages = {319-326}, abstract = {

Primary polyneuropathy in the context of Seip-Berardinelli type 1 seipinopathy, or congenital generalized lipodystrophy type 1 (CGL1) has not been previously reported. We report the case history of a 27 year old female CGL1 patient presenting with an unusual additional development of non-diabetic peripheral neuropathy and learning disabilities in early adolescence. Whole exome sequencing (WES) of the patient genome identified a novel variant, homozygous for a 52 bp intronic deletion in the locus, coding for 1-acylglycerol-3-phosphate O-acyltransferase 2, which is uniquely associated with CGL1 seipinopathies, with no molecular evidence for dual diagnosis. Functional studies using RNA isolated from patient peripheral blood leucocytes showed abnormal RNA splicing resulting in the loss of 25 amino acids from the patient AGPAT2 protein coding sequence. Stability and transcription levels for the misspliced mRNA in our patient nonetheless remained normal. Any AGPAT2 protein produced in our patient is therefore likely to be dysfunctional. However, formal linkage of this deletion to the neuropathy observed remains to be shown. The classical clinical presentation of a patient with -associated lipodystrophy shows normal cognition and no development of polyneuropathy. Cognitive disabilities and polyneuropathy are features associated exclusively with clinical CGL type 2 arising from seipin gene mutations. This case study suggests that in some genetic contexts, mutations can also produce phenotypes with primary polyneuropathy.

}, issn = {1308-5735}, doi = {10.4274/jcrpe.galenos.2018.2018.0227}, author = {Oswiecimska, Joanna and Dawidziuk, Mateusz and Gambin, Tomasz and Ziora, Katarzyna and Marek, Marta and Rzonca, Sylwia and Guilbride, D. Lys and Jhangiani, Shalini N. and Obuchowicz, Anna and Sikora, Alicja and Lupski, James R. and Wiszniewski, Wojciech and Gawlinski, Pawel} } @article {571, title = {Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 15}, pages = {797}, abstract = {

FXR1 is an alternatively spliced gene that encodes RNA binding proteins (FXR1P) involved in muscle development. In contrast to other tissues, cardiac and skeletal muscle express two FXR1P isoforms that incorporate an additional exon-15. We report that recessive mutations in this particular exon of FXR1 cause congenital multi-minicore myopathy in humans and mice. Additionally, we show that while Myf5-dependent depletion of all FXR1P isoforms is neonatal lethal, mice carrying mutations in exon-15 display non-lethal myopathies which vary in severity depending on the specific effect of each mutation on the protein.

}, keywords = {Animals, Cells, Cultured, Exons, Gene Expression, Genes, Recessive, Genetic Predisposition to Disease, HEK293 Cells, HeLa Cells, Humans, Mice, Transgenic, Muscle, Skeletal, Mutation, Myopathies, Structural, Congenital, Ophthalmoplegia, RNA-Binding Proteins, Ryanodine Receptor Calcium Release Channel}, issn = {2041-1723}, doi = {10.1038/s41467-019-08548-9}, author = {Esta{\~n}, Mar{\'\i}a Cristina and Fern{\'a}ndez-N{\'u}{\~n}ez, Elisa and Zaki, Maha S and Esteban, Mar{\'\i}a Isabel and Donkervoort, Sandra and Hawkins, Cynthia and Caparros-Martin, Jos{\'e} A and Saade, Dimah and Hu, Ying and Bolduc, Veronique and Chao, Katherine Ru-Yui and Nevado, Juli{\'a}n and Lamuedra, Ana and Largo, Raquel and Herrero-Beaumont, Gabriel and Regadera, Javier and Hernandez-Chico, Concepci{\'o}n and Tizzano, Eduardo F and Martinez-Glez, Victor and Carvajal, Jaime J and Zong, Ruiting and Nelson, David L and Otaify, Ghada A and Temtamy, Samia and Aglan, Mona and Issa, Mahmoud and B{\"o}nnemann, Carsten G and Lapunzina, Pablo and Yoon, Grace and Ruiz-Perez, Victor L} } @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 {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 {702, title = {Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene.}, journal = {Biol Psychiatry}, volume = {86}, year = {2019}, month = {2019 Oct 01}, pages = {523-535}, abstract = {

BACKGROUND: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder.

METHODS: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one.

RESULTS: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials.

CONCLUSIONS: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.

}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2019.04.031}, author = {Bodkin, J Alexander and Coleman, Michael J and Godfrey, Laura J and Carvalho, Claudia M B and Morgan, Charity J and Suckow, Raymond F and Anderson, Thea and {\"O}ng{\"u}r, Dost and Kaufman, Marc J and Lewandowski, Kathryn E and Siegel, Arthur J and Waldstreicher, Elliot and Grochowski, Christopher M and Javitt, Daniel C and Rujescu, Dan and Hebbring, Scott and Weinshilboum, Richard and Rodriguez, Stephanie Burgos and Kirchhoff, Colette and Visscher, Timothy and Vuckovic, Alexander and Fialkowski, Allison and McCarthy, Shane and Malhotra, Dheeraj and Sebat, Jonathan and Goff, Donald C and Hudson, James I and Lupski, James R and Coyle, Joseph T and Rudolph, Uwe and Levy, Deborah L} } @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 {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 {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 {444, title = {CLCN2 chloride channel mutations in familial hyperaldosteronism type II.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Mar}, pages = {349-354}, abstract = {

Primary aldosteronism, a common cause of severe hypertension , features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in the proband. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels show gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0048-5}, author = {Scholl, Ute I and St{\"o}lting, Gabriel and Schewe, Julia and Thiel, Anne and Tan, Hua and Nelson-Williams, Carol and Vichot, Alfred A and Jin, Sheng Chih and Loring, Erin and Untiet, Verena and Yoo, Taekyeong and Choi, Jungmin and Xu, Shengxin and Wu, Aihua and Kirchner, Marieluise and Mertins, Philipp and Rump, Lars C and Onder, Ali Mirza and Gamble, Cory and McKenney, Daniel and Lash, Robert W and Jones, Deborah P and Chune, Gary and Gagliardi, Priscila and Choi, Murim and Gordon, Richard and Stowasser, Michael and Fahlke, Christoph and Lifton, Richard P} } @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 {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 {483, title = {De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 08 02}, pages = {305-316}, abstract = {

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.07.003}, author = {Gregor, Anne and Sadleir, Lynette G and Asadollahi, Reza and Azzarello-Burri, Silvia and Battaglia, Agatino and Ousager, Lilian Bomme and Boonsawat, Paranchai and Bruel, Ange-Line and Buchert, Rebecca and Calpena, Eduardo and Cogn{\'e}, Benjamin and Dallapiccola, Bruno and Distelmaier, Felix and Elmslie, Frances and Faivre, Laurence and Haack, Tobias B and Harrison, Victoria and Henderson, Alex and Hunt, David and Isidor, Bertrand and Joset, Pascal and Kumada, Satoko and Lachmeijer, Augusta M A and Lees, Melissa and Lynch, Sally Ann and Martinez, Francisco and Matsumoto, Naomichi and McDougall, Carey and Mefford, Heather C and Miyake, Noriko and Myers, Candace T and Moutton, S{\'e}bastien and Nesbitt, Addie and Novelli, Antonio and Orellana, Carmen and Rauch, Anita and Rosello, Monica and Saida, Ken and Santani, Avni B and Sarkar, Ajoy and Scheffer, Ingrid E and Shinawi, Marwan and Steindl, Katharina and Symonds, Joseph D and Zackai, Elaine H and Reis, Andr{\'e} and Sticht, Heinrich and Zweier, Christiane} } @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 {438, title = {ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 02}, pages = {255-265}, abstract = {

Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5{\textquoteright} incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C~>~T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A~>~T; c.2579C~>~A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined.

}, keywords = {Actins, Aged, Cockayne Syndrome, DNA Repair, DNA-Binding Proteins, Fanconi Anemia, Female, Genetic Predisposition to Disease, Humans, Lamin Type A, Male, Middle Aged, Pedigree, Xeroderma Pigmentosum}, issn = {1098-1004}, doi = {10.1002/humu.23367}, author = {Mori, Takayasu and Yousefzadeh, Matthew J and Faridounnia, Maryam and Chong, Jessica X and Hisama, Fuki M and Hudgins, Louanne and Mercado, Gabriela and Wade, Erin A and Barghouthy, Amira S and Lee, Lin and Martin, George M and Nickerson, Deborah A and Bamshad, Michael J and Niedernhofer, Laura J and Oshima, Junko} } @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 {578, title = {The Genetic Landscape of Diamond-Blackfan Anemia.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 12 06}, pages = {930-947}, abstract = {

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole-exome sequencing (WES). We identified relevant rare and predicted damaging mutations for 78\% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and located in 1 of 19 previously reported ribosomal protein (RP)-encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in cell lines obtained from individuals with DBA. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in seven previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including nine individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain >5\% of DBA-affected case subjects. Overall, this report should inform not only clinical practice for DBA-affected individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.10.027}, author = {Ulirsch, Jacob C and Verboon, Jeffrey M and Kazerounian, Shideh and Guo, Michael H and Yuan, Daniel and Ludwig, Leif S and Handsaker, Robert E and Abdulhay, Nour J and Fiorini, Claudia and Genovese, Giulio and Lim, Elaine T and Cheng, Aaron and Cummings, Beryl B and Chao, Katherine R and Beggs, Alan H and Genetti, Casie A and Sieff, Colin A and Newburger, Peter E and Niewiadomska, Edyta and Matysiak, Michal and Vlachos, Adrianna and Lipton, Jeffrey M and Atsidaftos, Eva and Glader, Bertil and Narla, Anupama and Gleizes, Pierre-Emmanuel and O{\textquoteright}Donohue, Marie-Fran{\c c}oise and Montel-Lehry, Nathalie and Amor, David J and McCarroll, Steven A and O{\textquoteright}Donnell-Luria, Anne H and Gupta, Namrata and Gabriel, Stacey B and MacArthur, Daniel G and Lander, Eric S and Lek, Monkol and Da Costa, Lydie and Nathan, David G and Korostelev, Andrei A and Do, Ron and Sankaran, Vijay G and Gazda, Hanna T} } @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 {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 {558, title = {MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 12 06}, pages = {1009-1021}, abstract = {

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but~only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A~gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.10.019}, author = {Dobyns, William B and Aldinger, Kimberly A and Ishak, Gisele E and Mirzaa, Ghayda M and Timms, Andrew E and Grout, Megan E and Dremmen, Marjolein H G and Schot, Rachel and Vandervore, Laura and van Slegtenhorst, Marjon A and Wilke, Martina and Kasteleijn, Esmee and Lee, Arthur S and Barry, Brenda J and Chao, Katherine R and Szcza{\l}uba, Krzysztof and Kobori, Joyce and Hanson-Kahn, Andrea and Bernstein, Jonathan A and Carr, Lucinda and D{\textquoteright}Arco, Felice and Miyana, Kaori and Okazaki, Tetsuya and Saito, Yoshiaki and Sasaki, Masayuki and Das, Soma and Wheeler, Marsha M and Bamshad, Michael J and Nickerson, Deborah A and Engle, Elizabeth C and Verheijen, Frans W and Doherty, Dan and Mancini, Grazia M S} } @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 {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 {615, title = {Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.}, journal = {PLoS Genet}, volume = {14}, year = {2018}, month = {2018 08}, pages = {e1007504}, abstract = {

We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.

}, keywords = {Animals, Asian Continental Ancestry Group, Cell Line, Chloride Channels, Cytoplasm, Eye Proteins, HEK293 Cells, Homozygote, Humans, Mice, Mice, Knockout, Mutation, Missense, Pakistan, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1007504}, author = {Li, Lin and Jiao, Xiaodong and D{\textquoteright}Atri, Ilaria and Ono, Fumihito and Nelson, Ralph and Chan, Chi-Chao and Nakaya, Naoki and Ma, Zhiwei and Ma, Yan and Cai, Xiaoying and Zhang, Longhua and Lin, Siying and Hameed, Abdul and Chioza, Barry A and Hardy, Holly and Arno, Gavin and Hull, Sarah and Khan, Muhammad Imran and Fasham, James and Harlalka, Gaurav V and Michaelides, Michel and Moore, Anthony T and Coban Akdemir, Zeynep Hande and Jhangiani, Shalini and Lupski, James R and Cremers, Frans P M and Qamar, Raheel and Salman, Ahmed and Chilton, John and Self, Jay and Ayyagari, Radha and Kabir, Firoz and Naeem, Muhammad Asif and Ali, Muhammad and Akram, Javed and Sieving, Paul A and Riazuddin, Sheikh and Baple, Emma L and Riazuddin, S Amer and Crosby, Andrew H and Hejtmancik, J Fielding} } @article {622, title = {Mutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment.}, journal = {J Allergy Clin Immunol}, volume = {142}, year = {2018}, month = {2018 Aug}, pages = {605-617.e7}, abstract = {

BACKGROUND: Heterozygous gain-of-function mutations in PI3K110δ lead to lymphadenopathy, lymphoid hyperplasia, EBV and cytomegalovirus viremia, and sinopulmonary infections.

OBJECTIVE: The known role of natural killer (NK) cell function in the control of EBV and cytomegalovirus prompted us to investigate the functional and phenotypic effects of PI3K110δ mutations on NK cell subsets and cytotoxic function.

METHODS: Mutations in patients were identified by using whole-exome or targeted sequencing. We performed NK cell phenotyping and functional analysis of patients{\textquoteright} cells using flow cytometry, standard Cr cytotoxicity assays, and quantitative confocal microscopy.

RESULTS: PI3K110δ mutations led to an altered NK cell developmental phenotype and cytotoxic dysfunction. Impaired NK cell cytotoxicity was due to decreased conjugate formation with susceptible target cells and abrogated activation of cell machinery required for target cell killing. These defects were restored partially after initiation of treatment with rapamycin in 3 patients.

CONCLUSION: We describe novel NK cell functional deficiency caused by PI3K110δ mutation, which is a likely contributor to the severe viremia observed in these patients. Rapamycin treatment partially restores NK cell function, providing a further rationale for its use in patients with this disease.

}, issn = {1097-6825}, doi = {10.1016/j.jaci.2017.11.042}, author = {Ruiz-Garc{\'\i}a, Raquel and Vargas-Hernandez, Alexander and Chinn, Ivan K and Angelo, Laura S and Cao, Tram N and Coban-Akdemir, Zeynep and Jhangiani, Shalini N and Meng, Qingchang and Forbes, Lisa R and Muzny, Donna M and Allende, Luis M and Ehlayel, Mohammed S and Gibbs, Richard A and Lupski, James R and Uzel, Gulbu and Orange, Jordan S and Mace, Emily M} } @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 {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 {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 {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 {551, title = {Ximmer: a system for improving accuracy and consistency of CNV calling from exome data.}, journal = {Gigascience}, volume = {7}, year = {2018}, month = {2018 10 01}, abstract = {

Background: While exome and targeted next-generation DNA sequencing are primarily used for detecting single nucleotide changes and small indels, detection of copy number variants (CNVs) can provide highly valuable additional information from the data. Although there are dozens of exome CNV detection methods available, these are often difficult to use, and accuracy varies unpredictably between and within datasets.

Findings: We present Ximmer, a tool that supports an end-to-end process for evaluating, tuning, and running analysis methods for detection of CNVs in germline samples. Ximmer includes a simulation framework, implementations of several commonly used CNV detection methods, and a visualization and curation tool that together enable interactive exploration and quality control of CNV results. Using Ximmer, we comprehensively evaluate CNV detection on four datasets using five different detection methods. We show that application of Ximmer can improve accuracy and aid in quality control of CNV detection results. In addition, Ximmer can be used to run analyses and explore CNV results in exome data.

Conclusions: Ximmer offers a comprehensive tool and method for applying and improving accuracy of CNV detection methods for exome data.

}, keywords = {Algorithms, Computational Biology, Computer Simulation, DNA Copy Number Variations, Exome, High-Throughput Nucleotide Sequencing, Humans, Reproducibility of Results, ROC Curve, Sensitivity and Specificity, Software}, issn = {2047-217X}, doi = {10.1093/gigascience/giy112}, author = {Sadedin, Simon P and Ellis, Justine A and Masters, Seth L and Oshlack, Alicia} } @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 {394, title = {Clinical report: A patient with a late diagnosis of cerebrotendinous xanthomatosis and a response to treatment.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Aug}, pages = {2275-2279}, abstract = {

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn error of bile acid metabolism characterized by diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas developing in the second to third decades of life, and progressive neurologic dysfunction in adulthood. The condition is caused by mutations in the CYP27A1 gene that result in decreased production of chenodeoxycholic acid (CDCA) and elevated levels of cholestanol and bile alcohols. We present a 36-year-old male of Han ethnicity who developed xanthomas of his Achilles tendons and suffered neurocognitive declines and gait deterioration in his second decade. The diagnosis of CTX was confirmed by marked elevation of the serum cholestanol level. Sequencing of CYP27A1 showed a paternally inherited splice mutation, c.446 + 1G>T, and a maternally inherited nonsense mutation, c.808C>T, predicting p.(Arg270*). Despite the advanced disease in this patient, treatment with CDCA reduced the xanthoma size and improved his cognition and strength, and the patient made significant gains in his ambulation and coordination. We report this case to illustrate the potential benefits of therapy in patients with CTX who have advanced disease at the time of diagnosis.

}, keywords = {Achilles Tendon, Adult, Bile Acids and Salts, Chenodeoxycholic Acid, Cholestanetriol 26-Monooxygenase, Cholestanol, Codon, Nonsense, Humans, Male, Xanthomatosis, Cerebrotendinous}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38314}, author = {Alhariri, Ahmad and Hamilton, Katherine and Oza, Vikash and Cordoro, Kelly and Sobreira, Nara L and Malloy, Mary and Slavotinek, Anne} } @article {353, title = {Corner fracture type spondylometaphyseal dysplasia: Overlap with type II collagenopathies.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Mar}, pages = {733-739}, abstract = {

Spondylometaphyseal dysplasia (SMD) corner fracture type (also known as SMD "Sutcliffe" type, MIM 184255) is a rare skeletal dysplasia that presents with mild to moderate short stature, developmental coxa vara, mild platyspondyly, corner fracture-like lesions, and metaphyseal abnormalities with sparing of the epiphyses. The molecular basis for this disorder has yet to be clarified. We describe two patients with SMD corner fracture type and heterozygous pathogenic variants in COL2A1. These two cases together with a third case of SMD corner fracture type with a heterozygous COL2A1 pathogenic variant previously described suggest that this disorder overlaps with type II collagenopathies. The finding of one of the pathogenic variants in a previously reported case of spondyloepimetaphyseal dysplasia (SEMD) Strudwick type and the significant clinical similarity suggest an overlap between SMD corner fracture and SEMD Strudwick types. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Alleles, Amino Acid Substitution, Bone Diseases, Developmental, Child, Preschool, Collagen Type II, Diagnosis, Differential, Exome, Genetic Association Studies, Genotype, Growth Disorders, High-Throughput Nucleotide Sequencing, Hip Joint, Humans, Infant, Male, Mutation, Osteochondrodysplasias, Phenotype, Radiography, Tibial Fractures}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38059}, author = {Machol, Keren and Jain, Mahim and Almannai, Mohammed and Orand, Thibault and Lu, James T and Tran, Alyssa and Chen, Yuqing and Schlesinger, Alan and Gibbs, Richard and Bonafe, Luisa and Campos-Xavier, Ana Belinda and Unger, Sheila and Superti-Furga, Andrea and Lee, Brendan H and Campeau, Philippe M and Burrage, Lindsay C} } @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 {638, title = {A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 07 06}, pages = {16077}, abstract = {

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

}, keywords = {Adult, Amino Acid Sequence, Animals, Cell Fusion, Child, Disease Models, Animal, Embryo, Nonmammalian, Female, Gene Expression, Genes, Recessive, Genetic Complementation Test, Humans, Infant, Male, Membrane Proteins, Mobius Syndrome, Morphogenesis, Muscle Proteins, Muscle, Skeletal, Muscular Diseases, Mutation, Myoblasts, Pedigree, Pierre Robin Syndrome, Sequence Alignment, Sequence Homology, Amino Acid, Zebrafish, Zebrafish Proteins}, issn = {2041-1723}, doi = {10.1038/ncomms16077}, author = {Di Gioia, Silvio Alessandro and Connors, Samantha and Matsunami, Norisada and Cannavino, Jessica and Rose, Matthew F and Gilette, Nicole M and Artoni, Pietro and de Macena Sobreira, Nara Lygia and Chan, Wai-Man and Webb, Bryn D and Robson, Caroline D and Cheng, Long and Van Ryzin, Carol and Ramirez-Martinez, Andres and Mohassel, Payam and Leppert, Mark and Scholand, Mary Beth and Grunseich, Christopher and Ferreira, Carlos R and Hartman, Tyler and Hayes, Ian M and Morgan, Tim and Markie, David M and Fagiolini, Michela and Swift, Amy and Chines, Peter S and Speck-Martins, Carlos E and Collins, Francis S and Jabs, Ethylin Wang and B{\"o}nnemann, Carsten G and Olson, Eric N and Carey, John C and Robertson, Stephen P and Manoli, Irini and Engle, Elizabeth C} } @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 {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 {377, title = {Identification of ASAH1 as a susceptibility gene for familial keloids.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 10}, pages = {1155-1161}, abstract = {

Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N-acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing.

}, keywords = {Acid Ceramidase, Adult, Female, Humans, Keloid, Male, Mutation, Missense, Pedigree}, issn = {1476-5438}, doi = {10.1038/ejhg.2017.121}, author = {Santos-Cortez, Regie Lyn P and Hu, Ying and Sun, Fanyue and Benahmed-Miniuk, Fairouz and Tao, Jian and Kanaujiya, Jitendra K and Ademola, Samuel and Fadiora, Solomon and Odesina, Victoria and Nickerson, Deborah A and Bamshad, Michael J and Olaitan, Peter B and Oluwatosin, Odunayo M and Leal, Suzanne M and Reichenberger, Ernst J} } @article {364, title = {Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.}, journal = {Sci Transl Med}, volume = {9}, year = {2017}, month = {2017 04 19}, abstract = {

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50\%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35\%. We also report the discovery of a highly recurrent de novo intronic mutation in that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25\% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.

}, keywords = {Collagen Type VI, High-Throughput Nucleotide Sequencing, Humans, Muscular Diseases, Mutation, Transcriptome}, issn = {1946-6242}, doi = {10.1126/scitranslmed.aal5209}, author = {Cummings, Beryl B and Marshall, Jamie L and Tukiainen, Taru and Lek, Monkol and Donkervoort, Sandra and Foley, A Reghan and Bolduc, Veronique and Waddell, Leigh B and Sandaradura, Sarah A and O{\textquoteright}Grady, Gina L and Estrella, Elicia and Reddy, Hemakumar M and Zhao, Fengmei and Weisburd, Ben and Karczewski, Konrad J and O{\textquoteright}Donnell-Luria, Anne H and Birnbaum, Daniel and Sarkozy, Anna and Hu, Ying and Gonorazky, Hernan and Claeys, Kristl and Joshi, Himanshu and Bournazos, Adam and Oates, Emily C and Ghaoui, Roula and Davis, Mark R and Laing, Nigel G and Topf, Ana and Kang, Peter B and Beggs, Alan H and North, Kathryn N and Straub, Volker and Dowling, James J and Muntoni, Francesco and Clarke, Nigel F and Cooper, Sandra T and B{\"o}nnemann, Carsten G and MacArthur, Daniel G} } @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 {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 {393, title = {Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Jul 06}, pages = {123-129}, abstract = {

Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital disorder characterized by loss of smooth muscle contraction in the bladder and intestine. To date, three genes are known to be involved in MMIHS pathogenesis: ACTG2, MYH11, and LMOD1. However, for approximately 10\% of affected individuals, the genetic cause of the disease is unknown, suggesting that~other~loci are most likely involved. Here, we report on three MMIHS-affected subjects from two consanguineous families with~no~variants~in the known MMIHS-associated genes. By performing homozygosity mapping and whole-exome sequencing, we found~homozygous variants in myosin light chain kinase (MYLK) in both families. We identified a 7~bp duplication (c.3838_3844dupGAAAGCG~[p.Glu1282_Glyfs51]) in one family and a putative splice-site variant (c.3985+5C>A) in the other. Expression studies and splicing assays indicated that both variants affect normal MYLK expression. Because MYLK encodes an important kinase required for myosin activation and subsequent interaction with actin filaments, it is likely that in its absence, contraction of smooth muscle cells is impaired. The existence of a conditional-Mylk-knockout mouse model with severe gut dysmotility and abnormal function of the bladder supports the involvement of this gene in MMIHS pathogenesis. In aggregate, our findings implicate MYLK as a gene involved in the recessive form of MMIHS, confirming that this disease of the visceral organs is heterogeneous with a myopathic origin.

}, keywords = {Abnormalities, Multiple, Base Sequence, Colon, Female, Genes, Recessive, Homozygote, Humans, Intestinal Pseudo-Obstruction, Male, Mutation, Myosin-Light-Chain Kinase, Pedigree, Urinary Bladder}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.05.011}, author = {Halim, Danny and Brosens, Erwin and Muller, Fran{\c c}oise and Wangler, Michael F and Beaudet, Arthur L and Lupski, James R and Akdemir, Zeynep H Coban and Doukas, Michael and Stoop, Hans J and de Graaf, Bianca M and Brouwer, Rutger W W and van Ijcken, Wilfred F J and Oury, Jean-Fran{\c c}ois and Rosenblatt, Jonathan and Burns, Alan J and Tibboel, Dick and Hofstra, Robert M W and Alves, Maria M} } @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 {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 {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 {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 {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 {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 {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 {14, title = {Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Nov 03}, pages = {1181-1189}, abstract = {

Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.

}, keywords = {Alleles, Amino Acid Sequence, Basement Membrane, Brain, Carrier Proteins, Cerebellum, Cobblestone Lissencephaly, Developmental Disabilities, Dystroglycans, Eye Abnormalities, Female, Humans, Infant, Male, Membrane Proteins, Mutation, Nervous System Malformations, Neuroglia, Neurons, Pedigree, Phenotype}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.007}, author = {Jerber, Julie and Zaki, Maha S and Al-Aama, Jumana Y and Rosti, Rasim Ozgur and Ben-Omran, Tawfeg and Dikoglu, Esra and Silhavy, Jennifer L and Caglar, Caner and Musaev, Damir and Albrecht, Beate and Campbell, Kevin P and Willer, Tobias and Almuriekhi, Mariam and {\c C}a{\u g}layan, Ahmet Okay and Vajsar, Jiri and Bilguvar, Kaya and Ogur, Gonul and Abou Jamra, Rami and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {38, title = {Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy.}, journal = {J Am Acad Dermatol}, volume = {75}, year = {2016}, month = {2016 Aug}, pages = {420-7}, abstract = {

BACKGROUND: We recently demonstrated multilineage somatic mosaicism in cutaneous skeletal hypophosphatemia syndrome (CSHS), which features epidermal or melanocytic nevi, elevated fibroblast growth factor (FGF)-23, and hypophosphatemia, finding identical RAS mutations in affected skin and bone.

OBJECTIVE: We sought to: (1) provide an updated overview of CSHS; (2) review its pathobiology; (3)~present a new patient with CSHS; and (4) discuss treatment modalities.

METHODS: We searched PubMed for "nevus AND rickets," and "nevus AND hypophosphatemia," identifying cases of nevi with hypophosphatemic rickets or elevated serum FGF-23. For our additional patient with CSHS, we performed histopathologic and radiographic surveys of skin and skeletal lesions, respectively. Sequencing was performed for HRAS, KRAS, and NRAS to determine causative mutations.

RESULTS: Our new case harbored somatic activating HRAS p.G13~R mutation in affected tissue, consistent with previous findings. Although the mechanism of FGF-23 dysregulation is unknown in CSHS, interaction between FGF and MAPK pathways may provide insight into pathobiology. Anti-FGF-23 antibody KRN-23 may be useful in managing CSHS.

LIMITATIONS: Multilineage RAS mutation in CSHS was recently identified; further studies on mechanism are unavailable.

CONCLUSION: Patients with nevi in association with skeletal disease should be evaluated for serum phosphate and FGF-23. Further studies investigating the role of RAS in FGF-23 regulation are needed.

}, keywords = {Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Fibroblast Growth Factor-23, Fibroblast Growth Factors, Genes, ras, Humans, Mosaicism, Nevus, Pigmented, Osteomalacia, Rickets, Hypophosphatemic, Skin Neoplasms, Syndrome}, issn = {1097-6787}, doi = {10.1016/j.jaad.2015.11.012}, author = {Lim, Young H and Ovejero, Diana and Derrick, Kristina M and Collins, Michael T and Choate, Keith A} } @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 {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 {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 {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 {410, title = {Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.}, journal = {Cell}, volume = {167}, year = {2016}, month = {2016 Dec 01}, pages = {1481-1494.e18}, abstract = {

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.

}, keywords = {Amino Acids, Animals, Autism Spectrum Disorder, Blood-Brain Barrier, Brain, Female, Humans, Infant, Infant, Newborn, Large Neutral Amino Acid-Transporter 1, Male, Mice, Mice, Knockout, Mutation, Pedigree, Protein Biosynthesis, Receptor, TIE-2}, issn = {1097-4172}, doi = {10.1016/j.cell.2016.11.013}, author = {T{\u a}rlungeanu, Dora C and Deliu, Elena and Dotter, Christoph P and Kara, Majdi and Janiesch, Philipp Christoph and Scalise, Mariafrancesca and Galluccio, Michele and Tesulov, Mateja and Morelli, Emanuela and Sonmez, Fatma Mujgan and Bilguvar, Kaya and Ohgaki, Ryuichi and Kanai, Yoshikatsu and Johansen, Anide and Esharif, Seham and Ben-Omran, Tawfeg and Topcu, Meral and Schlessinger, Avner and Indiveri, Cesare and Duncan, Kent E and {\c C}a{\u g}layan, Ahmet Okay and G{\"u}nel, Murat and Gleeson, Joseph G and Novarino, Gaia} } @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 {74, title = {Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Mar 03}, pages = {579-587}, abstract = {

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.

}, keywords = {Adolescent, Cell Line, Tumor, Central Nervous System Neoplasms, Child, Preschool, Exome, Eye, Eye Diseases, Female, Humans, Infant, Lipomatosis, Male, Mutation, Mutation, Missense, Neurocutaneous Syndromes, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, Fibroblast Growth Factor, Type 1, Seizures, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.02.006}, author = {Bennett, James T and Tan, Tiong Yang and Alcantara, Diana and T{\'e}trault, Martine and Timms, Andrew E and Jensen, Dana and Collins, Sarah and Nowaczyk, Malgorzata J M and Lindhurst, Marjorie J and Christensen, Katherine M and Braddock, Stephen R and Brandling-Bennett, Heather and Hennekam, Raoul C M and Chung, Brian and Lehman, Anna and Su, John and Ng, SuYuen and Amor, David J and Majewski, Jacek and Biesecker, Les G and Boycott, Kym M and Dobyns, William B and O{\textquoteright}Driscoll, Mark and Moog, Ute and McDonell, Laura M} } @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 {56, title = {Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 06 02}, pages = {1082-1091}, abstract = {

Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In~vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.

}, keywords = {Cell Differentiation, Cells, Cultured, Ductus Arteriosus, Patent, Epigenesis, Genetic, Female, Fluorescent Antibody Technique, Histones, Humans, Immunoblotting, Male, Muscle Proteins, Muscle, Smooth, Vascular, Mutation, Pedigree, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.022}, author = {Li, Na and Subrahmanyan, Lakshman and Smith, Emily and Yu, Xiaoqing and Zaidi, Samir and Choi, Murim and Mane, Shrikant and Nelson-Williams, Carol and Behjati, Mohaddeseh and Kazemi, Mohammad and Hashemi, Mohammad and Fathzadeh, Mohsen and Narayanan, Anand and Tian, Likun and Montazeri, Farhad and Mani, Mitra and Begleiter, Michael L and Coon, Brian G and Lynch, Henry T and Olson, Eric N and Zhao, Hongyu and Ruland, J{\"u}rgen and Lifton, Richard P and Mani, Arya} } @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 {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 {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 {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 {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 {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 {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 {179, title = {Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {528-34}, abstract = {

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

}, keywords = {Animals, Atrophy, Autophagy, Cerebellar Diseases, Cerebellum, Child, Preschool, Female, Gene Frequency, Humans, Infant, Lod Score, Lysosomal Storage Diseases, Lysosomes, Male, Mutation, Phagosomes, Sorting Nexins, Spinocerebellar Ataxias, Syndrome, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3256}, author = {Akizu, Naiara and Cantagrel, Vincent and Zaki, Maha S and Al-Gazali, Lihadh and Wang, Xin and Rosti, Rasim Ozgur and Dikoglu, Esra and Gelot, Antoinette Bernabe and Rosti, Basak and Vaux, Keith K and Scott, Eric M and Silhavy, Jennifer L and Schroth, Jana and Copeland, Brett and Schaffer, Ashleigh E and Gordts, Philip L S M and Esko, Jeffrey D and Buschman, Matthew D and Field, Seth J and Napolitano, Gennaro and Abdel-Salam, Ghada M and Ozgul, R Koksal and Sag{\i}roglu, Mahmut Samil and Azam, Matloob and Ismail, Samira and Aglan, Mona and Selim, Laila and Mahmoud, Iman G and Abdel-Hadi, Sawsan and Badawy, Amera El and Sadek, Abdelrahim A and Mojahedi, Faezeh and Kayserili, H{\"u}lya and Masri, Amira and Bastaki, Laila and Temtamy, Samia and M{\"u}ller, Ulrich and Desguerre, Isabelle and Casanova, Jean-Laurent and Dursun, Ali and G{\"u}nel, Murat and Gabriel, Stacey B and de Lonlay, Pascale and Gleeson, Joseph G} } @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 {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 {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 {182, title = {Genetic linkage analysis in the age of whole-genome sequencing.}, journal = {Nat Rev Genet}, volume = {16}, year = {2015}, month = {2015 May}, pages = {275-84}, abstract = {

For many years, linkage analysis was the primary tool used for the genetic mapping of Mendelian and complex traits with familial aggregation. Linkage analysis was largely supplanted by the wide adoption of genome-wide association studies (GWASs). However, with the recent increased use of whole-genome sequencing (WGS), linkage analysis is again emerging as an important and powerful analysis method for the identification of genes involved in disease aetiology, often in conjunction with WGS filtering approaches. Here, we review the principles of linkage analysis and provide practical guidelines for carrying out linkage studies using WGS data.

}, keywords = {Algorithms, Female, Genetic Linkage, Genome, Human, Genome-Wide Association Study, Genotyping Techniques, Humans, Lod Score, Male, Pedigree, Penetrance, Phenotype, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Software}, issn = {1471-0064}, doi = {10.1038/nrg3908}, author = {Ott, Jurg and Wang, Jing and Leal, Suzanne M} } @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 {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 {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 {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 {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 {125, title = {Somatic p.T771R KDR (VEGFR2) Mutation Arising in a Sporadic Angioma During Ramucirumab Therapy.}, journal = {JAMA Dermatol}, volume = {151}, year = {2015}, month = {2015 Nov}, pages = {1240-3}, abstract = {

IMPORTANCE: Inhibition of angiogenesis is an effective anticancer strategy because neoplasms require a rich blood supply. Ramucirumab, approved by the US Food and Drug Administration in 2014 to treat gastric adenocarcinomas and non-small cell lung carcinomas, targets vascular endothelial growth factor 2 (VEGFR2). We identified a patient prescribed a regimen of irinotecan hydrochloride, cetuximab, and ramucirumab for metastatic rectal cancer (diagnosed in November 2013 and treated through early January 2015) who developed a new-onset, expanding vascular lesion on his right leg. Via exome sequencing, we found that the lesion contained a single somatic mutation in KDR (encodes VEGFR2), possibly in response to ramucirumab. Vascular tumors are not a known complication of antiangiogenic therapeutics.

OBSERVATIONS: Exome sequencing of the well-demarcated, blanching vascular lesion on the lateral right shin revealed a somatic p.T771R mutation in KDR, without evidence of other somatic mutations or loss of heterozygosity. Histological features included lobules of small vessels within the dermis, resembling a tufted angioma.

CONCLUSIONS AND RELEVANCE: A potential adverse effect of ramucirumab in combination therapy is the development of sporadic angiomas. The p.T771R mutation was previously implicated in autophosphorylation of VEGFR2 and reported in angiosarcomas alongside other driver mutations. Our observations suggest that this mutation confers a proliferative advantage in the setting of ramucirumab therapy. Patients receiving ramucirumab should be monitored for the development of new vascular lesions.

}, keywords = {Adult, Angiogenesis Inhibitors, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Cetuximab, Hemangioma, Humans, Irinotecan, Male, Mutation, Rectal Neoplasms, Skin Neoplasms, Vascular Endothelial Growth Factor Receptor-2}, issn = {2168-6084}, doi = {10.1001/jamadermatol.2015.1925}, author = {Lim, Young H and Odell, Ian D and Ko, Christine J and Choate, Keith A} } @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 {230, title = {Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy.}, journal = {J Clin Immunol}, volume = {34}, year = {2014}, month = {2014 Oct}, pages = {871-90}, abstract = {

PURPOSE: Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A (OMIM 605000) that results in T-cell lymphopenia and is classified as T(-)B(+)NK(+)severe combined immunodeficiency (SCID). Only two other CORO1A-kindred are known to date, thus the defining characteristics are not well delineated. We identified a unique CORO1A-kindred.

METHODS: We captured a 10-year analysis of the immune-clinical phenotypes in two affected siblings from disease debut of age 7 years. Target-specific genetic studies were pursued but unrevealing. Telomere lengths were also assessed. Whole exome sequencing (WES) uncovered the molecular diagnosis and Western blot validated findings.

RESULTS: We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44) (NM_007074.3) in two affected non-consanguineous siblings that manifested as absent CD4CD45RA(+) (na{\"\i}ve) T and memory B cells, low NK cells and abnormally increased double-negative (DN) ϒδ T-cells. Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers; the older female sibling also had a disfiguring granulomatous tuberculoid leprosy. Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years. The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations.

CONCLUSION: We reveal the third CORO1A-mutated kindred, with the immune phenotype of abnormal na{\"\i}ve CD4 and DN T-cells and newfound characteristics of a late/hypomorphic-like SCID of an EV-HPV mucocutaneous syndrome with also B and NK defects and shortened telomeres. Our findings contribute to the elucidation of the CORO1A-SCID-CID spectrum.

}, keywords = {Adolescent, B-Lymphocytes, CD4-Positive T-Lymphocytes, Child, DNA Mutational Analysis, Epidermodysplasia Verruciformis, Female, Genetic Predisposition to Disease, Granuloma, Heterozygote, Humans, Immunologic Memory, Killer Cells, Natural, Leprosy, Tuberculoid, Male, Microfilament Proteins, Molluscum Contagiosum, Mucous Membrane, Mutation, Papillomavirus Infections, Polymorphism, Genetic, Severe Combined Immunodeficiency, Siblings, Skin, Telomere Shortening}, issn = {1573-2592}, doi = {10.1007/s10875-014-0074-8}, author = {Stray-Pedersen, Asbjorg and Jouanguy, Emmanuelle and Crequer, Amandine and Bertuch, Alison A and Brown, Betty S and Jhangiani, Shalini N and Muzny, Donna M and Gambin, Tomasz and Sorte, Hanne and Sasa, Ghadir and Metry, Denise and Campbell, Judith and Sockrider, Marianna M and Dishop, Megan K and Scollard, David M and Gibbs, Richard A and Mace, Emily M and Orange, Jordan S and Lupski, James R and Casanova, Jean-Laurent and Noroski, Lenora M} } @article {244, title = {Cytogenomic delineation and clinical follow-up of two siblings with an 8.5 Mb 6q24.2-q25.2 deletion inherited from a paternal insertion.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2378-84}, abstract = {

The chromosomal segment 6q24-q25 comprises a contiguous gene microdeletion syndrome characterized by intrauterine growth retardation, growth delay, intellectual disability, cardiac anomalies, and a dysmorphic facial phenotype. We describe here a 10-year follow-up with detailed clinical, neuropsychological, and cytomolecular data of two siblings, male and female, who presented with developmental delay, microcephaly, short stature, characteristic facial dysmorphisms, multiple organ anomalies, and intellectual disability. Microarray analysis showed an 8.5 Mb 6q24.2-q25.2 interstitial deletion. Fluorescence in situ hybridization analyses confirmed the deletions and identified an insertion of 6q into 8q13 in their father, resulting in a high recurrence risk. This is the first report in sibs with distinct neuropsychological involvement, one of them with stenosis of the descending branch of the aorta.

}, keywords = {Adolescent, Base Pairing, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 6, Cytogenetic Analysis, Fathers, Female, Follow-Up Studies, Humans, Infant, Newborn, Inheritance Patterns, Male, Mutagenesis, Insertional, Siblings}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36631}, author = {Meloni, Vera Ayres and Guilherme, Roberta Santos and Oliveira, Mariana Moyses and Migliavacca, Michele and Takeno, Sylvia Satomi and Sobreira, Nara Lygia Macena and de Fatima Faria Soares, Maria and de Mello, Claudia Berlim and Melaragno, Maria Isabel} } @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 {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 {266, title = {A general framework for estimating the relative pathogenicity of human genetic variants.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Mar}, pages = {310-5}, abstract = {

Current methods for annotating and interpreting human genetic variation tend to exploit a single information type (for example, conservation) and/or are restricted in scope (for example, to missense changes). Here we describe Combined Annotation-Dependent Depletion (CADD), a method for objectively integrating many diverse annotations into a single measure (C score) for each variant. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human-derived alleles from 14.7 million simulated variants. We precompute C scores for all 8.6 billion possible human single-nucleotide variants and enable scoring of short insertions-deletions. C scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects and complex trait associations, and they highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current single-annotation method.

}, keywords = {Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, INDEL Mutation, Models, Genetic, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Selection, Genetic, Support Vector Machine}, issn = {1546-1718}, doi = {10.1038/ng.2892}, author = {Kircher, Martin and Witten, Daniela M and Jain, Preti and O{\textquoteright}Roak, Brian J and Cooper, Gregory M and Shendure, Jay} } @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 {262, title = {Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy.}, journal = {Chest}, volume = {146}, year = {2014}, month = {2014 Nov}, pages = {1176-1186}, abstract = {

BACKGROUND: Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied.

METHODS: In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD.

RESULTS: Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9\%), 125 (41.0\%), and 37 (12.1\%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6\% and 2.3\% with SA plus complex or simple cardiac defects, respectively; 4.6\% with SA but no cardiac defect; and 2.6\% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P < .001; year-round nasal congestion, P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P < .001).

CONCLUSIONS: At least 12.1\% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects.

TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov.

}, keywords = {Adolescent, Adult, Biopsy, Child, Child, Preschool, Cilia, DNA, DNA Mutational Analysis, Female, Humans, Infant, Infant, Newborn, Kartagener Syndrome, Male, Microscopy, Electron, Transmission, Middle Aged, Mutation, Prevalence, Prospective Studies, Tomography, X-Ray Computed, United States, Young Adult}, issn = {1931-3543}, doi = {10.1378/chest.13-1704}, author = {Shapiro, Adam J and Davis, Stephanie D and Ferkol, Thomas and Dell, Sharon D and Rosenfeld, Margaret and Olivier, Kenneth N and Sagel, Scott D and Milla, Carlos and Zariwala, Maimoona A and Wolf, Whitney and Carson, Johnny L and Hazucha, Milan J and Burns, Kimberlie and Robinson, Blair and Knowles, Michael R and Leigh, Margaret W} } @article {289, title = {Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jan 15}, pages = {397-407}, abstract = {

Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

}, keywords = {Adolescent, Child, Exome, Female, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, GTP Phosphohydrolases, Humans, Hypophosphatemia, Male, Membrane Proteins, Mutation, Nevus, Nevus, Pigmented, Osteomalacia, Proto-Oncogene Proteins p21(ras), Sequence Analysis, DNA, Skin, Skin Neoplasms}, issn = {1460-2083}, doi = {10.1093/hmg/ddt429}, author = {Lim, Young H and Ovejero, Diana and Sugarman, Jeffrey S and Deklotz, Cynthia M C and Maruri, Ann and Eichenfield, Lawrence F and Kelley, Patrick K and J{\"u}ppner, Harald and Gottschalk, Michael and Tifft, Cynthia J and Gafni, Rachel I and Boyce, Alison M and Cowen, Edward W and Bhattacharyya, Nisan and Guthrie, Lori C and Gahl, William A and Golas, Gretchen and Loring, Erin C and Overton, John D and Mane, Shrikant M and Lifton, Richard P and Levy, Moise L and Collins, Michael T and Choate, Keith A} } @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 {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 {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 {222, title = {Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Oct 02}, pages = {345-59}, abstract = {

Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.

}, keywords = {Adult, Aged, Aged, 80 and over, Chromosome Aberrations, DNA Copy Number Variations, Fathers, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Inheritance Patterns, Male, Middle Aged, Models, Theoretical, Mosaicism, Mothers, Pregnancy, Recurrence, Risk Factors, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.08.010}, author = {Campbell, Ian M and Stewart, Jonathan R and James, Regis A and Lupski, James R and Stankiewicz, Pawe{\l} and Olofsson, Peter and Shaw, Chad A} } @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 {279, title = {Rare-variant extensions of the transmission disequilibrium test: application to autism exome sequence data.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {33-46}, abstract = {

Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.

}, keywords = {Alleles, Autistic Disorder, Computer Simulation, Exome, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Linkage Disequilibrium, Models, Genetic, Phenotype, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.021}, author = {He, Zongxiao and O{\textquoteright}Roak, Brian J and Smith, Joshua D and Wang, Gao and Hooker, Stanley and Santos-Cortez, Regie Lyn P and Li, Biao and Kan, Mengyuan and Krumm, Nik and Nickerson, Deborah A and Shendure, Jay and Eichler, Evan E and Leal, Suzanne 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 {286, title = {Somatic HRAS p.G12S mutation causes woolly hair and epidermal nevi.}, journal = {J Invest Dermatol}, volume = {134}, year = {2014}, month = {2014 Apr}, pages = {1149-1152}, keywords = {Adherens Junctions, Child, Exome, Female, Genes, ras, Hair, Hair Diseases, Hair Follicle, Humans, Intermediate Filaments, Mosaicism, Mutation, Nevus, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction}, issn = {1523-1747}, doi = {10.1038/jid.2013.430}, author = {Levinsohn, Jonathan L and Teng, Joyce and Craiglow, Brittany G and Loring, Erin C and Burrow, T Andrew and Mane, Shrikant S and Overton, John D and Lifton, Richard P and McNiff, Jennifer M and Lucky, Anne W and Choate, Keith 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 {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 {309, title = {Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Mar 07}, pages = {468-74}, abstract = {

Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.

}, keywords = {Basement Membrane, Brain, Cerebellum, Cerebral Cortex, Encephalocele, Female, Genetic Predisposition to Disease, Homozygote, Humans, Laminin, Male, Muscular Dystrophies, Nervous System Malformations, Neuroglia, Neurons, Sequence Deletion, Walker-Warburg Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.02.005}, author = {Radmanesh, Farid and {\c C}a{\u g}layan, Ahmet Okay and Silhavy, Jennifer L and Yilmaz, Cahide and Cantagrel, Vincent and Omar, Tarek and Rosti, Basak and Kaymak{\c c}alan, Hande and Gabriel, Stacey and Li, Mingfeng and {\v S}estan, Nenad and Bilguvar, Kaya and Dobyns, William B and Zaki, Maha S and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {311, title = {Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {2013 Feb 26}, pages = {3489-94}, abstract = {

Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.

}, keywords = {Adult, Age of Onset, Amino Acid Sequence, Base Sequence, Child, Preschool, Exome, Female, Genes, Recessive, Homozygote, Humans, Hydrolysis, Male, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Nerve Degeneration, Neurons, Pedigree, Protein Binding, Sequence Analysis, DNA, Substrate Specificity, Syndrome, Thermodynamics, Ubiquitin, Ubiquitin Thiolesterase}, issn = {1091-6490}, doi = {10.1073/pnas.1222732110}, author = {Bilguvar, Kaya and Tyagi, Navneet K and Ozkara, Cigdem and Tuysuz, Beyhan and Bakircioglu, Mehmet and Choi, Murim and Delil, Sakir and {\c C}a{\u g}layan, Ahmet O and Baranoski, Jacob F and Erturk, Ozdem and Yalcinkaya, Cengiz and Karacorlu, Murat and Dincer, Alp and Johnson, Michele H and Mane, Shrikant and Chandra, Sreeganga S and Louvi, Angeliki and Boggon, Titus J and Lifton, Richard P and Horwich, Arthur L and G{\"u}nel, Murat} } @article {306, title = {Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 May}, pages = {531-6}, abstract = {

Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.

}, keywords = {Acute Kidney Injury, Atypical Hemolytic Uremic Syndrome, Child, Child, Preschool, Diacylglycerol Kinase, Exome, Female, Genes, Recessive, Hemolytic-Uremic Syndrome, Humans, Immunoenzyme Techniques, Infant, Male, Molecular Sequence Data, Mutation, Renal Insufficiency, Chronic, Thrombocytopenia, Thrombotic Microangiopathies}, issn = {1546-1718}, doi = {10.1038/ng.2590}, author = {Lemaire, Mathieu and Fremeaux-Bacchi, Veronique and Schaefer, Franz and Choi, Murim and Tang, Wai Ho and Le Quintrec, Moglie and Fakhouri, Fadi and Taque, Sophie and Nobili, Fran{\c c}ois and Martinez, Frank and Ji, Weizhen and Overton, John D and Mane, Shrikant M and N{\"u}rnberg, Gudrun and Altm{\"u}ller, Janine and Thiele, Holger and Morin, Denis and Deschenes, Georges and Baudouin, V{\'e}ronique and Llanas, Brigitte and Collard, Laure and Majid, Mohammed A and Simkova, Eva and N{\"u}rnberg, Peter and Rioux-Leclerc, Nathalie and Moeckel, Gilbert W and Gubler, Marie Claire and Hwa, John and Loirat, Chantal and Lifton, Richard P} } @article {300, title = {A recurrent PDGFRB mutation causes familial infantile myofibromatosis.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jun 06}, pages = {996-1000}, abstract = {

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.

}, keywords = {Amino Acid Sequence, Female, Genes, Dominant, Genetic Association Studies, Germ-Line Mutation, Heterozygote, Humans, Male, Models, Molecular, Mutation, Missense, Myofibromatosis, Pedigree, Protein Structure, Tertiary, Receptor, Notch3, Receptor, Platelet-Derived Growth Factor beta, Receptors, Notch, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.04.026}, author = {Cheung, Yee Him and Gayden, Tenzin and Campeau, Philippe M and LeDuc, Charles A and Russo, Donna and Nguyen, Van-Hung and Guo, Jiancheng and Qi, Ming and Guan, Yanfang and Albrecht, Steffen and Moroz, Brenda and Eldin, Karen W and Lu, James T and Schwartzentruber, Jeremy and Malkin, David and Berghuis, Albert M and Emil, Sherif and Gibbs, Richard A and Burk, David L and Vanstone, Megan and Lee, Brendan H and Orchard, David and Boycott, Kym M and Chung, Wendy K and Jabado, Nada} } @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 {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 {324, title = {Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Jul 08}, pages = {922-7}, abstract = {

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Disease Models, Animal, Female, Fibrillin-1, Fibrillins, Haploinsufficiency, Humans, Loeys-Dietz Syndrome, Male, Marfan Syndrome, Mice, Mice, Knockout, Mice, Mutant Strains, Microfilament Proteins, Mutation, Pedigree, Phenotype, Signal Transduction, Syndrome, Transforming Growth Factor beta2}, issn = {1546-1718}, doi = {10.1038/ng.2349}, author = {Lindsay, Mark E and Schepers, Dorien and Bolar, Nikhita Ajit and Doyle, Jefferson J and Gallo, Elena and Fert-Bober, Justyna and Kempers, Marlies J E and Fishman, Elliot K and Chen, Yichun and Myers, Loretha and Bjeda, Djahita and Oswald, Gretchen and Elias, Abdallah F and Levy, Howard P and Anderlid, Britt-Marie and Yang, Margaret H and Bongers, Ernie M H F and Timmermans, Janneke and Braverman, Alan C and Canham, Natalie and Mortier, Geert R and Brunner, Han G and Byers, Peter H and Van Eyk, Jennifer and Van Laer, Lut and Dietz, Harry C and Loeys, Bart L} }