@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 {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 {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 {941, title = {MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia.}, journal = {Ann Neurol}, volume = {89}, year = {2021}, month = {2021 04}, pages = {828-833}, abstract = {

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

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Cataract, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Dystonia, Epilepsy, Genetic Variation, Humans, Infant, Mediator Complex, Nervous System Malformations, Phenotype, Whole Exome Sequencing}, issn = {1531-8249}, doi = {10.1002/ana.26019}, author = {Meng, Linyan and Isohanni, Pirjo and Shao, Yunru and GrAHm, Brett H and Hickey, Scott E and Brooks, Stephanie and Suomalainen, Anu and Joset, Pascal and Steindl, Katharina and Rauch, Anita and Hackenberg, Annette and High, Frances A and Armstrong-Javors, Amy and Mencacci, Niccol{\`o} E and Gonz{\`a}lez-Latapi, Paulina and Kamel, Walaa A and Al-Hashel, Jasem Y and Bustos, Bernab{\'e} I and Hernandez, Alejandro V and Krainc, Dimitri and Lubbe, Steven J and Van Esch, Hilde and De Luca, Chiara and Ballon, Katleen and Ravelli, Claudia and Burglen, Lydie and Qebibo, Leila and Calame, Daniel G and Mitani, Tadahiro and Marafi, Dana and Pehlivan, Davut and Saadi, Nebal W and Sahin, Yavuz and Maroofian, Reza and Efthymiou, Stephanie and Houlden, Henry and Maqbool, Shazia and Rahman, Fatima and Gu, Shen and Posey, Jennifer E and Lupski, James R and Hunter, Jill V and Wangler, Michael F and Carroll, Christopher J and Yang, Yaping} } @article {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 {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 {992, title = {SARS-CoV-2-related MIS-C: A key to the viral and genetic causes of Kawasaki disease?}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 06 07}, abstract = {

Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.

}, keywords = {Biomarkers, Child, COVID-19, Cytokines, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammation, Inflammation Mediators, Lymphohistiocytosis, Hemophagocytic, Models, Biological, Mucocutaneous Lymph Node Syndrome, Pandemics, SARS-CoV-2, Systemic Inflammatory Response Syndrome}, issn = {1540-9538}, doi = {10.1084/jem.20210446}, author = {Sancho-Shimizu, Vanessa and Brodin, Petter and Cobat, Aurelie and Biggs, Catherine M and Toubiana, Julie and Lucas, Carrie L and Henrickson, Sarah E and Belot, Alexandre and Tangye, Stuart G and Milner, Joshua D and Levin, Michael and Abel, Laurent and Bogunovic, Dusan and Casanova, Jean-Laurent and Zhang, Shen-Ying} } @article {1008, title = {SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 03 04}, pages = {502-516}, abstract = {

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

}, keywords = {Adolescent, Autism Spectrum Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Haploinsufficiency, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.01.015}, author = {Radio, Francesca Clementina and Pang, Kaifang and Ciolfi, Andrea and Levy, Michael A and Hernandez-Garcia, Andres and Pedace, Lucia and Pantaleoni, Francesca and Liu, Zhandong and de Boer, Elke and Jackson, Adam and Bruselles, Alessandro and McConkey, Haley and Stellacci, Emilia and Lo Cicero, Stefania and Motta, Marialetizia and Carrozzo, Rosalba and Dentici, Maria Lisa and McWalter, Kirsty and Desai, Megha and Monaghan, Kristin G and Telegrafi, Aida and Philippe, Christophe and Vitobello, Antonio and Au, Margaret and Grand, Katheryn and Sanchez-Lara, Pedro A and Baez, Joanne and Lindstrom, Kristin and Kulch, Peggy and Sebastian, Jessica and Madan-Khetarpal, Suneeta and Roadhouse, Chelsea and MacKenzie, Jennifer J and Monteleone, Berrin and Saunders, Carol J and Jean Cuevas, July K and Cross, Laura and Zhou, Dihong and Hartley, Taila and Sawyer, Sarah L and Monteiro, Fabiola Paoli and Secches, Tania Vertemati and Kok, Fernando and Schultz-Rogers, Laura E and Macke, Erica L and Morava, Eva and Klee, Eric W and Kemppainen, Jennifer and Iascone, Maria and Selicorni, Angelo and Tenconi, Romano and Amor, David J and Pais, Lynn and Gallacher, Lyndon and Turnpenny, Peter D and Stals, Karen and Ellard, Sian and Cabet, Sara and Lesca, Gaetan and Pascal, Joset and Steindl, Katharina and Ravid, Sarit and Weiss, Karin and Castle, Alison M R and Carter, Melissa T and Kalsner, Louisa and de Vries, Bert B A and van Bon, Bregje W and Wevers, Marijke R and Pfundt, Rolph and Stegmann, Alexander P A and Kerr, Bronwyn and Kingston, Helen M and Chandler, Kate E and Sheehan, Willow and Elias, Abdallah F and Shinde, Deepali N and Towne, Meghan C and Robin, Nathaniel H and Goodloe, Dana and Vanderver, Adeline and Sherbini, Omar and Bluske, Krista and Hagelstrom, R Tanner and Zanus, Caterina and Faletra, Flavio and Musante, Luciana and Kurtz-Nelson, Evangeline C and Earl, Rachel K and Anderlid, Britt-Marie and Morin, Gilles and van Slegtenhorst, Marjon and Diderich, Karin E M and Brooks, Alice S and Gribnau, Joost and Boers, Ruben G and Finestra, Teresa Robert and Carter, Lauren B and Rauch, Anita and Gasparini, Paolo and Boycott, Kym M and Barakat, Tahsin Stefan and GrAHm, John M and Faivre, Laurence and Banka, Siddharth and Wang, Tianyun and Eichler, Evan E and Priolo, Manuela and Dallapiccola, Bruno and Vissers, Lisenka E L M and Sadikovic, Bekim and Scott, Daryl A and Holder, Jimmy Lloyd and Tartaglia, Marco} } @article {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 {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 {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 {758, title = {Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.}, journal = {Ann Clin Transl Neurol}, volume = {7}, year = {2020}, month = {2020 05}, pages = {610-627}, abstract = {

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

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

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

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

}, keywords = {Adolescent, Alleles, Atrophy, Child, Child, Preschool, Cohort Studies, Consanguinity, Epilepsy, Female, Humans, Infant, Male, Microcephaly, Neurodevelopmental Disorders, Pedigree, Phenotype, Receptors, Metabotropic Glutamate, Whole Exome Sequencing}, issn = {2328-9503}, doi = {10.1002/acn3.51003}, author = {Marafi, Dana and Mitani, Tadahiro and Isikay, Sedat and Hertecant, Jozef and Almannai, Mohammed and Manickam, Kandamurugu and Abou Jamra, Rami and El-Hattab, Ayman W and Rajah, Jaishen and Fatih, Jawid M and Du, Haowei and Karaca, Ender and Bayram, Yavuz and Punetha, Jaya and Rosenfeld, Jill A and Jhangiani, Shalini N and Boerwinkle, Eric and Akdemir, Zeynep C and Erdin, Serkan and Hunter, Jill V and Gibbs, Richard A and Pehlivan, Davut and Posey, Jennifer E and Lupski, James R} } @article {806, title = {Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 10}, pages = {2272-2283}, abstract = {

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.

}, keywords = {Adolescent, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Male, Muscle Hypotonia, Muscle Weakness, Mutation, Missense, Myasthenic Syndromes, Congenital, Pedigree, Phenotype, Synaptic Transmission, Synaptotagmin II}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61765}, author = {Donkervoort, Sandra and Mohassel, Payam and Laugwitz, Lucia and Zaki, MAH S and Kamsteeg, Erik-Jan and Maroofian, Reza and Chao, Katherine R and Verschuuren-Bemelmans, Corien C and Horber, Veronka and Fock, Annemarie J M and McCarty, Riley M and Jain, Minal S and Biancavilla, Victoria and McMacken, Grace and Nalls, Matthew and Voermans, Nicol C and Elbendary, Hasnaa M and Snyder, Molly and Cai, Chunyu and Lehky, Tanya J and Stanley, Valentina and Iannaccone, Susan T and Foley, A Reghan and Lochm{\"u}ller, Hanns and Gleeson, Joseph and Houlden, Henry and Haack, Tobias B and Horvath, Rita and B{\"o}nnemann, Carsten G} } @article {962, title = {Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 06 04}, pages = {779-792}, abstract = {

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

}, keywords = {Alleles, Base Sequence, Child, Child, Preschool, Cilia, Developmental Disabilities, Female, Hedgehog Proteins, Humans, Infant, Male, Models, Molecular, Neoplasms, Nerve Tissue Proteins, Nuclear Proteins, Pedigree, Signal Transduction, Smoothened Receptor, Zinc Finger Protein Gli2, Zinc Finger Protein Gli3}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.04.010}, author = {Le, Thuy-Linh and Sribudiani, Yunia and Dong, Xiaomin and Huber, Celine and Kois, Chelsea and Baujat, Genevi{\`e}ve and Gordon, Christopher T and Mayne, Valerie and Galmiche, Louise and Serre, Val{\'e}rie and Goudin, Nicolas and Zarhrate, Mohammed and Bole-Feysot, Christine and Masson, Cecile and Nitschk{\'e}, Patrick and Verheijen, Frans W and Pais, Lynn and Pelet, Anna and Sadedin, Simon and Pugh, John A and Shur, Natasha and White, Susan M and El Chehadeh, Salima and Christodoulou, John and Cormier-Daire, Val{\'e}rie and Hofstra, R M W and Lyonnet, Stanislas and Tan, Tiong Yang and Atti{\'e}-Bitach, Tania and Kerstjens-Frederikse, Wilhelmina S and Amiel, Jeanne and Thomas, Sophie} } @article {782, title = {CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 10}, pages = {1633-1641}, abstract = {

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

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

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

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

}, keywords = {Child, DNA Copy Number Variations, Exons, Humans, INDEL Mutation, Retrospective Studies, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-0864-8}, author = {Yuan, Bo and Wang, Lei and Liu, Pengfei and Shaw, Chad and Dai, Hongzheng and Cooper, Lance and Zhu, Wenmiao and Anderson, Stephanie A and Meng, Linyan and Wang, Xia and Wang, Yue and Xia, Fan and Xiao, Rui and Braxton, Alicia and Peacock, Sandra and Schmitt, Eric and Ward, Patricia A and Vetrini, Francesco and He, Weimin and Chiang, Theodore and Muzny, Donna and Gibbs, Richard A and Beaudet, Arthur L and Breman, Amy M and Smith, Janice and Cheung, Sau Wai and Bacino, Carlos A and Eng, Christine M and Yang, Yaping and Lupski, James R and Bi, Weimin} } @article {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 {780, title = {De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 04 02}, pages = {570-583}, abstract = {

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

}, keywords = {Adolescent, Ataxia, Child, Child, Preschool, Developmental Disabilities, eIF-2 Kinase, Female, Genetic Variation, Hereditary Central Nervous System Demyelinating Diseases, Humans, Infant, Leukoencephalopathies, Male, Nervous System Malformations, White Matter}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.02.016}, author = {Mao, Dongxue and Reuter, Chloe M and Ruzhnikov, Maura R Z and Beck, Anita E and Farrow, Emily G and Emrick, Lisa T and Rosenfeld, Jill A and Mackenzie, Katherine M and Robak, Laurie and Wheeler, Matthew T and Burrage, Lindsay C and Jain, Mahim and Liu, Pengfei and Calame, Daniel and K{\"u}ry, S{\'e}bastien and Sillesen, Martin and Schmitz-Abe, Klaus and Tonduti, Davide and Spaccini, Luigina and Iascone, Maria and Genetti, Casie A and Koenig, Mary K and Graf, Madeline and Tran, Alyssa and Alejandro, Mercedes and Lee, Brendan H and Thiffault, Isabelle and Agrawal, Pankaj B and Bernstein, Jonathan A and Bellen, Hugo J and Chao, Hsiao-Tuan} } @article {738, title = {Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 01 01}, pages = {112-130}, abstract = {

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

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

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

}, keywords = {Adult, Amino Acid Sequence, Autistic Disorder, Child, Child, Preschool, Developmental Disabilities, Dioxygenases, DNA Demethylation, Embryonic Development, Female, Gene Expression Regulation, Developmental, Growth Disorders, Humans, Infant, Male, Middle Aged, Movement Disorders, Pedigree, Protein Conformation, Sequence Homology, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.12.007}, author = {Beck, David B and Petracovici, Ana and He, Chongsheng and Moore, Hannah W and Louie, Raymond J and Ansar, Muhammad and Douzgou, Sofia and Sithambaram, Sivagamy and Cottrell, Trudie and Santos-Cortez, Regie Lyn P and Prijoles, Eloise J and Bend, Renee and Keren, Boris and Mignot, Cyril and Nougues, Marie-Christine and {\~O}unap, Katrin and Reimand, Tiia and Pajusalu, Sander and Zahid, Muhammad and Saqib, Muhammad Arif Nadeem and Buratti, Julien and Seaby, Eleanor G and McWalter, Kirsty and Telegrafi, Aida and Baldridge, Dustin and Shinawi, Marwan and Leal, Suzanne M and Schaefer, G Bradley and Stevenson, Roger E and Banka, Siddharth and Bonasio, Roberto and Fahrner, Jill A} } @article {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 {766, title = {Expanding the phenotypic spectrum in RDH12-associated retinal disease.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {6}, year = {2020}, month = {2020 02}, abstract = {

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

}, keywords = {Adolescent, Adult, Alcohol Oxidoreductases, Alleles, Amino Acid Substitution, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Humans, Male, Mutation, Optical Imaging, Pedigree, Phenotype, Retinal Diseases, Tomography, Optical Coherence, Whole Exome Sequencing, Young Adult}, issn = {2373-2873}, doi = {10.1101/mcs.a004754}, author = {Scott, Hilary A and Place, Emily M and Ferenchak, Kevin and Zampaglione, Erin and Wagner, Naomi E and Chao, Katherine R and DiTroia, Stephanie P and Navarro-Gomez, Daniel and Mukai, Shizuo and Huckfeldt, Rachel M and Pierce, Eric A and Bujakowska, Kinga M} } @article {973, title = {Four Individuals with a Homozygous Mutation in Exon 1f of the Gene and Associated Myasthenic Features.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 06 27}, abstract = {

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

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

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

}, keywords = {Abnormalities, Multiple, Adolescent, Animals, Bone Development, Child, Child, Preschool, Consanguinity, Extracellular Matrix, Female, Fibrillar Collagens, Founder Effect, Gene Frequency, Hip Dislocation, Homozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Scoliosis, Syndrome}, issn = {1476-5438}, doi = {10.1038/s41431-020-0632-x}, author = {Gonzaga-Jauregui, Claudia and Yesil, G{\"o}zde and Nistala, Harikiran and Gezdirici, Alper and Bayram, Yavuz and Nannuru, Kalyan C and Pehlivan, Davut and Yuan, Bo and Jimenez, Johanna and Sahin, Yavuz and Paine, Ingrid S and Akdemir, Zeynep Coban and Rajamani, Saathyaki and Staples, Jeffrey and Dronzek, John and Howell, Kristen and Fatih, Jawid M and Smaldone, Silvia and Schlesinger, Alan E and Ram{\'\i}rez, Norman and Cornier, Alberto S and Kelly, Melissa A and Haber, Robert and Chim, Shek Man and Nieman, Kristy and Wu, Nan and Walls, Johnathon and Poueymirou, William and Siao, Chia-Jen and Sutton, V Reid and Williams, Marc S and Posey, Jennifer E and Gibbs, Richard A and Carlo, Simon and Tegay, David H and Economides, Aris N and Lupski, James R} } @article {708, title = {Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 01}, pages = {e1023}, abstract = {

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

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

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

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

}, keywords = {Adolescent, Adult, Child, Female, Fibrillin-1, HEK293 Cells, Humans, Lipodystrophy, Marfan Syndrome, Mutation, Phenotype, Progeria, Protein Domains, Smad2 Protein}, issn = {2324-9269}, doi = {10.1002/mgg3.1023}, author = {Lin, Mao and Liu, Zhenlei and Liu, Gang and Zhao, Sen and Li, Chao and Chen, Weisheng and Coban Akdemir, Zeynep and Lin, Jiachen and Song, Xiaofei and Wang, Shengru and Xu, Qiming and Zhao, Yanxue and Wang, Lianlei and Zhang, Yuanqiang and Yan, Zihui and Liu, Sen and Liu, Jiaqi and Chen, Yixin and Zuo, Yuzhi and Yang, Xu and Sun, Tianshu and Yang, Xin-Zhuang and Niu, Yuchen and Li, Xiaoxin and You, Wesley and Qiu, Bintao and Ding, Chen and Liu, Pengfei and Zhang, Shuyang and Carvalho, Claudia M B and Posey, Jennifer E and Qiu, Guixing and Lupski, James R and Wu, Zhihong and Zhang, Jianguo and Wu, Nan} } @article {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 {757, title = {Gomez-L{\'o}pez-Hern{\'a}ndez syndrome: A case report with clinical and molecular evaluation and literature review.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 07}, pages = {1761-1766}, abstract = {

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

}, keywords = {Abnormalities, Multiple, Alopecia, Cerebellum, Child, Child, Preschool, Craniofacial Abnormalities, Female, Growth Disorders, Humans, Magnetic Resonance Imaging, Misoprostol, Neurocutaneous Syndromes, Phenotype, Rhombencephalon, Trigeminal Nerve}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61594}, author = {Perrone, Eduardo and D{\textquoteright}Almeida, V{\^a}nia and de Macena Sobreira, Nara Lygia and de Mello, Claudia Berlim and de Oliveira, Allan Chiaratti and Burlin, St{\^e}nio and Soares, Maria de F{\'a}tima de Faria and Cernach, Mirlene Cec{\'\i}lia Soares Pinho and Alvarez Perez, Ana Beatriz} } @article {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 {647, title = {Inherited glomerular diseases in the gilded age of genomic advancements.}, journal = {Pediatr Nephrol}, volume = {35}, year = {2020}, month = {2020 06}, pages = {959-968}, abstract = {

The synchronized advent of high-throughput next-generation sequencing technology and knowledge of the human genome has rendered exponential contributions to our understanding of the pathophysiology of glomerular kidney diseases. A genetic diagnosis can now be made or confirmed in about two-thirds of the suspected inherited glomerular diseases. Next-generation sequencing is adept at identifying single nucleotide variations and small insertions or deletions that constitute majority of the disease-causing mutations. Description of the complete mutation spectrum in syndromic glomerulopathies may require the use of both sequencing and cytogenetic methods to detect large structural DNA variation in addition to single nucleotide changes. The enthusiastic application of genetic and genomic knowledge to inherited glomerular diseases has uncovered anticipated and unforeseen challenges mainly related to the biological interpretation of variants of uncertain significance and the limited benefit on clinical management for the individual patient when a diagnosis is obtained. To attain the ultimate goal of transforming clinical decision-making based on accurate genetic diagnosis using genomic information, these challenges need to be addressed. Till then, the glory of genomic medicine stands the test of time in this gilded age of genomic advancements.

}, keywords = {Adolescent, Age Factors, Branchio-Oto-Renal Syndrome, Child, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Kidney Failure, Chronic, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, Whole Exome Sequencing}, issn = {1432-198X}, doi = {10.1007/s00467-019-04266-y}, author = {Gulati, Ashima and Dahl, Neera and Tufro, Alda} } @article {778, title = {KIAA1217: A novel candidate gene associated with isolated and syndromic vertebral malformations.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 07}, pages = {1664-1672}, abstract = {

Vertebral malformations (VMs) are caused by alterations in somitogenesis and may occur in association with other congenital anomalies. The genetic etiology of most VMs remains unknown and their identification may facilitate the development of novel therapeutic and prevention strategies. Exome sequencing was performed on both the discovery cohort of nine unrelated probands from the USA with VMs and the replication cohort from China (Deciphering Disorders Involving Scoliosis \& COmorbidities study). The discovery cohort was analyzed using the PhenoDB analysis tool. Heterozygous and homozygous, rare and functional variants were selected and evaluated for their ClinVar, HGMD, OMIM, GWAS, mouse model phenotypes, and other annotations to identify the best candidates. Genes with candidate variants in three or more probands were selected. The replication cohort was analyzed by another in-house developed pipeline. We identified rare heterozygous variants in KIAA1217 in four out of nine probands in the discovery cohort and in five out of 35 probands in the replication cohort. Collectively, we identified 11 KIAA1217 rare variants in 10 probands, three of which have not been described in gnomAD and one of which is a nonsense variant. We propose that genetic variations of KIAA1217 may contribute to the etiology of VMs.

}, keywords = {Adolescent, Cervical Vertebrae, Child, Codon, Nonsense, Databases, Genetic, Female, Heterozygote, Homozygote, Humans, Male, Proteins, Spinal Diseases, Thoracic Vertebrae}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61607}, author = {Al Dhaheri, Noura and Wu, Nan and Zhao, Sen and Wu, Zhihong and Blank, Robert D and Zhang, Jianguo and Raggio, Cathy and Halanski, Matthew and Shen, Jianxiong and Noonan, Ken and Qiu, Guixing and Nemeth, Blaise and Sund, Sarah and Dunwoodie, Sally L and Chapman, Gavin and Glurich, Ingrid and Steiner, Robert D and Wohler, Elizabeth and Martin, Renan and Sobreira, Nara Lygia and Giampietro, Philip F} } @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 {811, title = {Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 12}, pages = {2020-2028}, abstract = {

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

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

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

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

}, keywords = {Child, Hernias, Diaphragmatic, Congenital, Humans, Infant, Newborn, Retrospective Studies}, issn = {1530-0366}, doi = {10.1038/s41436-020-0908-0}, author = {Qiao, Lu and Wynn, Julia and Yu, Lan and Hernan, Rebecca and Zhou, Xueya and Duron, Vincent and Aspelund, Gudrun and Farkouh-Karoleski, Christiana and Zygumunt, Annette and Krishnan, Usha S and Nees, Shannon and Khlevner, Julie and Lim, Foong Yen and Crombleholme, Timothy and Cusick, Robert and Azarow, Kenneth and Danko, Melissa Ellen and Chung, Dai and Warner, Brad W and Mychaliska, George B and Potoka, Douglas and Wagner, Amy J and Soffer, Samuel and Schindel, David and McCulley, David J and Shen, Yufeng and Chung, Wendy K} } @article {804, title = {Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 12}, pages = {4038}, abstract = {

Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.

}, keywords = {Adolescent, Adult, Aspartate-tRNA Ligase, Base Sequence, Cell Differentiation, Cell Proliferation, Cell Size, Cell Survival, Cerebral Cortex, Child, Family, Female, Fibroblasts, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Ki-67 Antigen, Male, Microcephaly, Mutation, Neural Stem Cells, Neuroglia, Organoids, Pedigree, RNA, Transfer, Amino Acyl, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-020-17454-4}, author = {Wang, Lu and Li, Zhen and Sievert, David and Smith, Desir{\'e}e E C and Mendes, Marisa I and Chen, Dillon Y and Stanley, Valentina and Ghosh, Shereen and Wang, Yulu and Kara, Majdi and Aslanger, Ayca Dilruba and Rosti, Rasim O and Houlden, Henry and Salomons, Gajja S and Gleeson, Joseph 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 {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 {814, title = {Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 08 06}, pages = {293-310}, abstract = {

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

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

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

}, keywords = {Amphibian Proteins, Animals, Case-Control Studies, Child, Child, Preschool, DNA-Binding Proteins, Epigenesis, Genetic, Family, Female, Forkhead Transcription Factors, Heterozygote, Humans, Infant, Larva, Male, Mice, Mice, Knockout, Morpholinos, Mutation, Pedigree, Protein Binding, Repressor Proteins, Transcription Factors, Urinary Tract, Urogenital Abnormalities, Whole Exome Sequencing, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.08.013}, author = {Connaughton, Dervla M and Dai, Rufeng and Owen, Danielle J and Marquez, Jonathan and Mann, Nina and GrAHm-Paquin, Adda L and Nakayama, Makiko and Coyaud, Etienne and Laurent, Estelle M N and St-Germain, Jonathan R and Blok, Lot Snijders and Vino, Arianna and Kl{\"a}mbt, Verena and Deutsch, Konstantin and Wu, Chen-Han Wilfred and Kolvenbach, Caroline M and Kause, Franziska and Ottlewski, Isabel and Schneider, Ronen and Kitzler, Thomas M and Majmundar, Amar J and Buerger, Florian and Onuchic-Whitford, Ana C and Youying, Mao and Kolb, Amy and Salmanullah, Daanya and Chen, Evan and van der Ven, Amelie T and Rao, Jia and Ityel, Hadas and Seltzsam, Steve and Rieke, Johanna M and Chen, Jing and Vivante, Asaf and Hwang, Daw-Yang and Kohl, Stefan and Dworschak, Gabriel C and Hermle, Tobias and Alders, Marielle and Bartolomaeus, Tobias and Bauer, Stuart B and Baum, Michelle A and Brilstra, Eva H and Challman, Thomas D and Zyskind, Jacob and Costin, Carrie E and Dipple, Katrina M and Duijkers, Floor A and Ferguson, Marcia and FitzPatrick, David R and Fick, Roger and Glass, Ian A and Hulick, Peter J and Kline, Antonie D and Krey, Ilona and Kumar, Selvin and Lu, Weining and Marco, Elysa J and Wentzensen, Ingrid M and Mefford, Heather C and Platzer, Konrad and Povolotskaya, Inna S and Savatt, Juliann M and Shcherbakova, Natalia V and Senguttuvan, Prabha and Squire, Audrey E and Stein, Deborah R and Thiffault, Isabelle and Voinova, Victoria Y and Somers, Michael J G and Ferguson, Michael A and Traum, Avram Z and Daouk, Ghaleb H and Daga, Ankana and Rodig, Nancy M and Terhal, Paulien A and van Binsbergen, Ellen and Eid, Loai A and Tasic, Velibor and Rasouly, Hila Milo and Lim, Tze Y and Ahram, Dina F and Gharavi, Ali G and Reutter, Heiko M and Rehm, Heidi L and MacArthur, Daniel G and Lek, Monkol and Laricchia, Kristen M and Lifton, Richard P and Xu, Hong and Mane, Shrikant M and Sanna-Cherchi, Simone and Sharrocks, Andrew D and Raught, Brian and Fisher, Simon E and Bouchard, Maxime and Khokha, Mustafa K and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {938, title = {Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 05}, pages = {1093-1103}, abstract = {

Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant in 8.5\% of cases. OD is characterized by multiple enchondromas, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas bilaterally distributed in most of the cases. Both disorders feature multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain, loss of function, and pathological fractures. About 50\% of patients with OD or MS develop a malignancy, such as chondrosarcoma, glioma, and ovarian juvenile granulosa cell tumor. To better understand the natural history of OD and MS, we reviewed 287 papers describing patients with OD and MS. We also created a survey that was distributed directly to 162 patients through Facebook. Here, we compare the review of the cases described in the literature to the survey{\textquoteright}s responses. The review of the literature showed that: the patients with OD are diagnosed at a younger age; the prevalence of chondrosarcomas among patients with OD or MS was ~30\%; in four patients, vascular anomalies were identified in internal organs only; and, the prevalence of cancer among patients with OD or MS was ~50\%. With these data, health care providers will better understand the natural history, severity, and prognosis of these diseases and the prevalence of malignancies in these patients. Here, we recommend new guidelines for the care of patients with OD and MS.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chondrosarcoma, Enchondromatosis, Female, Granulosa Cell Tumor, Humans, Infant, Infant, Newborn, Male, Middle Aged, Ovarian Neoplasms, Prognosis, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61530}, author = {El Abiad, Jad M and Robbins, Sarah M and Cohen, Bernard and Levin, Adam S and Valle, David L and Morris, Carol D and de Macena Sobreira, Nara L} } @article {852, title = {Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 07 25}, abstract = {

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

}, keywords = {Autism Spectrum Disorder, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Gene Expression Regulation, Genetic Markers, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Mutation}, issn = {2073-4425}, doi = {10.3390/genes11080853}, author = {Yin, Jiani and Chun, Chun-An and Zavadenko, Nikolay N and Pechatnikova, Natalia L and Naumova, Oxana Yu and Doddapaneni, Harsha V and Hu, Jianhong and Muzny, Donna M and Schaaf, Christian P and Grigorenko, Elena L} } @article {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 {939, title = {A novel homozygous KY variant causing a complex neurological disorder.}, journal = {Eur J Med Genet}, volume = {63}, year = {2020}, month = {2020 Nov}, pages = {104031}, abstract = {

Mutations in the gene kyphoscoliosis peptidase (KY) are known to cause myofibrillar myopathy-7 and hereditary spastic paraplegia. We investigated the genetic cause of a complex neurological phenotype in a consanguineous Pakistani family with four affected members, manifesting lower limb spasticity and weakness, toe walking, pes equinovarus, and a speech disorder. Genome-wide linkage analysis with microsatellite markers delineated chromosome 3q22.2-q24 harboring the disease gene. Whole exome sequencing was performed for two subjects, identifying a homozygous 14-bp frameshift deletion NM_178554.6:c.842_855del; p(Val281GlyfsTer18) in KY. The variant segregated with the phenotype and was absent from public databases and 100 ethnically matched controls. We confirm a novel homozygous KY variant causing a complex neurological phenotype in this family. A review of previously reported KY variants suggests that variants in this gene can cause a spectrum of neurological phenotypes.

}, keywords = {Child, Female, Frameshift Mutation, Gait, Homozygote, Humans, Male, Myopathies, Structural, Congenital, Pedigree, Peptide Hydrolases, Phenotype, Spastic Paraplegia, Hereditary, Speech}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2020.104031}, author = {Arif, Beenish and Rasheed, Arisha and Kumar, Kishore R and Fatima, Amara and Abbas, Ghazanfar and Wohler, Elizabeth and Sobriera, Nara and Lohmann, Katja and Naz, Sadaf} } @article {910, title = {Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.}, journal = {Neuron}, volume = {106}, year = {2020}, month = {2020 04 22}, pages = {237-245.e8}, abstract = {

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

}, keywords = {Adolescent, Adult, Age of Onset, Animals, Centrosome, Child, Child, Preschool, Chromosome Aberrations, Classical Lissencephalies and Subcortical Band Heterotopias, Cytoskeletal Proteins, Female, Gene Knockdown Techniques, Genetic Variation, Heterozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Mice, Mutation, Oncogene Proteins, Fusion, Pedigree, Seizures, Young Adult}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.01.027}, author = {Tsai, Meng-Han and Muir, Alison M and Wang, Won-Jing and Kang, Yi-Ning and Yang, Kun-Chuan and Chao, Nian-Hsin and Wu, Mei-Feng and Chang, Ying-Chao and Porter, Brenda E and Jansen, Laura A and Sebire, Guillaume and Deconinck, Nicolas and Fan, Wen-Lang and Su, Shih-Chi and Chung, Wen-Hung and Almanza Fuerte, Edith P and Mehaffey, Michele G and Ng, Ching-Ching and Chan, Chung-Kin and Lim, Kheng-Seang and Leventer, Richard J and Lockhart, Paul J and Riney, Kate and Damiano, John A and Hildebrand, Michael S and Mirzaa, Ghayda M and Dobyns, William B and Berkovic, Samuel F and Scheffer, Ingrid E and Tsai, Jin-Wu and Mefford, Heather C} } @article {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 {707, title = {Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome).}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 01}, pages = {38-52}, abstract = {

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

}, keywords = {Adolescent, Adult, Autistic Disorder, Child, Child, Preschool, Exome, Female, Heterozygote, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Microcephaly, Middle Aged, Mutation, Phenotype, Transposases, Whole Exome Sequencing, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61380}, author = {Assia Batzir, Nurit and Posey, Jennifer E and Song, Xiaofei and Akdemir, Zeynep Coban and Rosenfeld, Jill A and Brown, Chester W and Chen, Emily and Holtrop, Shannon G and Mizerik, Elizabeth and Nieto Moreno, Margarita and Payne, Katelyn and Raas-Rothschild, Annick and Scott, Richard and Vernon, Hilary J and Zadeh, Neda and Lupski, James R and Sutton, V Reid} } @article {684, title = {The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 02}, pages = {427-431}, abstract = {

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

METHODS: Exome sequencing from 39 trios were analyzed.

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

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

}, keywords = {Adult, Cell Cycle Proteins, Cerebrovascular Disorders, Child, Child, Preschool, Developmental Disabilities, DNA Helicases, Exome, Female, Genetic Predisposition to Disease, Humans, Intellectual Disability, Male, Methyltransferases, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Middle Aged, Moyamoya Disease, Mutation, Nuclear Proteins, Transcription Factors, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-019-0639-2}, author = {Pinard, Amelie and Guey, St{\'e}phanie and Guo, Dongchuan and Cecchi, Alana C and Kharas, Natasha and Wallace, Stephanie and Regalado, Ellen S and Hostetler, Ellen M and Sharrief, Anjail Z and Bergametti, Fran{\c c}oise and Kossorotoff, Manoelle and Herv{\'e}, Dominique and Kraemer, Markus and Bamshad, Michael J and Nickerson, Deborah A and Smith, Edward R and Tournier-Lasserve, Elisabeth and Milewicz, Dianna M} } @article {940, title = {Polymicrogyria is Associated With Pathogenic Variants in PTEN.}, journal = {Ann Neurol}, volume = {88}, year = {2020}, month = {2020 12}, pages = {1153-1164}, abstract = {

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

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

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

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

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

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

}, keywords = {Cell Movement, Centrioles, Child, Child, Preschool, Cyclin-Dependent Kinase 5, Cytoskeletal Proteins, Female, Humans, Lissencephaly, Male, Microtubules, Neocortex, Nerve Tissue Proteins, Neurons, Oncogene Proteins, Fusion, Young Adult}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.01.030}, author = {Kodani, Andrew and Kenny, Connor and Lai, Abbe and Gonzalez, Dilenny M and Stronge, Edward and Sejourne, Gabrielle M and Isacco, Laura and Partlow, Jennifer N and O{\textquoteright}Donnell, Anne and McWalter, Kirsty and Byrne, Alicia B and Barkovich, A James and Yang, Edward and Hill, R Sean and Gawlinski, Pawel and Wiszniewski, Wojciech and Cohen, Julie S and Fatemi, S Ali and Baranano, Kristin W and Sahin, Mustafa and Vossler, David G and Yuskaitis, Christopher J and Walsh, Christopher A} } @article {956, title = {Recurrent homozygous damaging mutation in , encoding a protein disulfide isomerase, in four families with microlissencephaly.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {274-282}, abstract = {

BACKGROUND: Protein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.

METHODS: Eight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.

RESULTS: An identical homozygous variant in (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While is an activator of cellular repeat expansion toxicity, patients showed no evidence of repeat expansions.

CONCLUSION: The c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of expansions. is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

}, keywords = {Amino Acid Sequence, Child, Child, Preschool, Consanguinity, Endoplasmic Reticulum, Exons, Female, Genetic Predisposition to Disease, Homozygote, Humans, Male, Membrane Proteins, Microcephaly, Mutation, Protein Disulfide-Isomerases, Protein Folding, Thioredoxins, Whole Exome Sequencing}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106409}, author = {Ghosh, Shereen Georges and Wang, Lu and Breuss, Martin W and Green, Joshua D and Stanley, Valentina and Yang, Xiaoxu and Ross, Danica and Traynor, Bryan J and Alhashem, Amal M and Azam, Matloob and Selim, Laila and Bastaki, Laila and Elbastawisy, Hanan I and Temtamy, Samia and Zaki, MAH and Gleeson, Joseph G} } @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 {816, title = {Spectrum of genetic variants in moderate to severe sporadic hearing loss in Pakistan.}, journal = {Sci Rep}, volume = {10}, year = {2020}, month = {2020 07 17}, pages = {11902}, abstract = {

Hearing loss affects 380 million people worldwide due to environmental or genetic causes. Determining the cause of deafness in individuals without previous family history of hearing loss is challenging and has been relatively unexplored in Pakistan. We investigated the spectrum of genetic variants in hearing loss in a cohort of singleton affected individuals born to consanguineous parents. Twenty-one individuals with moderate to severe hearing loss were recruited. We performed whole-exome sequencing on DNA samples from the participants, which identified seventeen variants in ten known deafness genes and one novel candidate gene. All identified variants were homozygous except for two. Eleven of the variants were novel, including one multi-exonic homozygous deletion in OTOA. A missense variant in ESRRB was implicated for recessively inherited moderate to severe hearing loss. Two individuals were heterozygous for variants in MYO7A and CHD7, respectively, consistent with de novo variants or dominant inheritance with incomplete penetrance as the reason for their hearing loss. Our results indicate that similar to familial cases of deafness, variants in a large number of genes are responsible for moderate to severe hearing loss in sporadic individuals born to consanguineous couples.

}, keywords = {Adolescent, Amino Acid Sequence, Audiometry, Pure-Tone, Child, Child, Preschool, Deafness, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Hearing Loss, Heterozygote, Homozygote, Humans, Mutation, Missense, Pakistan, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {2045-2322}, doi = {10.1038/s41598-020-68779-5}, author = {Ramzan, Memoona and Bashir, Rasheeda and Salman, Midhat and Mujtaba, Ghulam and Sobreira, Nara and Witmer, P Dane and Naz, Sadaf} } @article {856, title = {Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 05}, pages = {945-953}, abstract = {

PURPOSE: Spinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics and Genomics.

METHODS: We developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2.

RESULTS: We characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses, and calculated a pan-ethnic carrier frequency of 2\%, consistent with previous studies. Additionally, 99.8\% of our SMN1 and 99.7\% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100\% for SMA and 97.8\% for carriers, and a precision of 100\% for both SMA and carriers.

CONCLUSION: This SMN copy-number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects.

}, keywords = {Base Sequence, Child, Child, Preschool, Humans, Muscular Atrophy, Spinal, Survival of Motor Neuron 1 Protein}, issn = {1530-0366}, doi = {10.1038/s41436-020-0754-0}, author = {Chen, Xiao and Sanchis-Juan, Alba and French, Courtney E and Connell, Andrew J and Delon, Isabelle and Kingsbury, Zoya and Chawla, Aditi and Halpern, Aaron L and Taft, Ryan J and Bentley, David R and Butchbach, Matthew E R and Raymond, F Lucy and Eberle, Michael A} } @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 {761, title = {Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 06}, pages = {1387-1399}, abstract = {

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

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

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

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

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

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

}, keywords = {Child, Child, Preschool, Chromosome Breakpoints, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, X, Comparative Genomic Hybridization, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Nervous System Diseases, Pedigree, Phenotype, Quantitative Trait, Heritable, Repetitive Sequences, Nucleic Acid, Sex Factors, Syndrome, X Chromosome Inactivation}, issn = {1098-1004}, doi = {10.1002/humu.23902}, author = {Hijazi, Hadia and Coelho, Fernanda S and Gonzaga-Jauregui, Claudia and Bernardini, Laura and Mar, Soe S and Manning, Melanie A and Hanson-Kahn, Andrea and Naidu, Sakkubai and Srivastava, Siddharth and Lee, Jennifer A and Jones, Julie R and Friez, Michael J and Alberico, Thomas and Torres, Barbara and Fang, Ping and Cheung, Sau Wai and Song, Xiaofei and Davis-Williams, Angelique and Jornlin, Carly and Wight, Patricia A and Patyal, Pankaj and Taube, Jennifer and Poretti, Andrea and Inoue, Ken and Zhang, Feng and Pehlivan, Davut and Carvalho, Claudia M B and Hobson, Grace M and Lupski, James R} } @article {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 {515, title = {Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 03}, pages = {663-675}, abstract = {

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

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

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

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

}, keywords = {Adolescent, Alleles, Antigens, Nuclear, Biological Variation, Population, Carrier Proteins, Cell Cycle Proteins, Child, Child, Preschool, Chromosomal Proteins, Non-Histone, Cohort Studies, De Lange Syndrome, Exome, Female, Gene Frequency, Genetic Heterogeneity, Humans, INDEL Mutation, Male, Mutation, Nuclear Proteins, Phenotype, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Retrospective Studies, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0085-6}, author = {Yuan, Bo and Neira, Juanita and Pehlivan, Davut and Santiago-Sim, Teresa and Song, Xiaofei and Rosenfeld, Jill and Posey, Jennifer E and Patel, Vipulkumar and Jin, Weihong and Adam, Margaret P and Baple, Emma L and Dean, John and Fong, Chin-To and Hickey, Scott E and Hudgins, Louanne and Leon, Eyby and Madan-Khetarpal, Suneeta and Rawlins, Lettie and Rustad, Cecilie F and Stray-Pedersen, Asbj{\o}rg and Tveten, Kristian and Wenger, Olivia and Diaz, Jullianne and Jenkins, Laura and Martin, Laura and McGuire, Marianne and Pietryga, Marguerite and Ramsdell, Linda and Slattery, Leah and Abid, Farida and Bertuch, Alison A and Grange, Dorothy and Immken, LaDonna and Schaaf, Christian P and Van Esch, Hilde and Bi, Weimin and Cheung, Sau Wai and Breman, Amy M and Smith, Janice L and Shaw, Chad and Crosby, Andrew H and Eng, Christine and Yang, Yaping and Lupski, James R and Xiao, Rui and Liu, Pengfei} } @article {580, title = {De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.}, journal = {Genome Med}, volume = {11}, year = {2019}, month = {2019 02 28}, pages = {12}, abstract = {

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

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

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

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

}, keywords = {Adolescent, Child, Child, Preschool, Craniofacial Abnormalities, Developmental Disabilities, Female, Humans, INDEL Mutation, Infant, Intellectual Disability, Male, Muscle Hypotonia, Smith-Magenis Syndrome, Transcription Factors, Young Adult}, issn = {1756-994X}, doi = {10.1186/s13073-019-0623-0}, author = {Vetrini, Francesco and McKee, Shane and Rosenfeld, Jill A and Suri, Mohnish and Lewis, Andrea M and Nugent, Kimberly Margaret and Roeder, Elizabeth and Littlejohn, Rebecca O and Holder, Sue and Zhu, Wenmiao and Alaimo, Joseph T and Graham, Brett and Harris, Jill M and Gibson, James B and Pastore, Matthew and McBride, Kim L and Komara, Makanko and Al-Gazali, Lihadh and Al Shamsi, Aisha and Fanning, Elizabeth A and Wierenga, Klaas J and Scott, Daryl A and Ben-Neriah, Ziva and Meiner, Vardiella and Cassuto, Hanoch and Elpeleg, Orly and Holder, J Lloyd and Burrage, Lindsay C and Seaver, Laurie H and Van Maldergem, Lionel and Mahida, Sonal and Soul, Janet S and Marlatt, Margaret and Matyakhina, Ludmila and Vogt, Julie and Gold, June-Anne and Park, Soo-Mi and Varghese, Vinod and Lampe, Anne K and Kumar, Ajith and Lees, Melissa and Holder-Espinasse, Muriel and McConnell, Vivienne and Bernhard, Birgitta and Blair, Ed and Harrison, Victoria and Muzny, Donna M and Gibbs, Richard A and Elsea, Sarah H and Posey, Jennifer E and Bi, Weimin and Lalani, Seema and Xia, Fan and Yang, Yaping and Eng, Christine M and Lupski, James R and Liu, Pengfei} } @article {575, title = {De Novo SOX4 Variants Cause a Neurodevelopmental Disease Associated with Mild Dysmorphism.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {246-259}, abstract = {

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

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Child, Child, Preschool, Coffin-Lowry Syndrome, Cohort Studies, Conserved Sequence, DNA, Female, Heterozygote, HMG-Box Domains, Humans, Male, Mutation, Missense, Neurodevelopmental Disorders, SOXC Transcription Factors, Transcriptional Activation, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.014}, author = {Zawerton, Ash and Yao, Baojin and Yeager, J Paige and Pippucci, Tommaso and Haseeb, Abdul and Smith, Joshua D and Wischmann, Lisa and K{\"u}hl, Susanne J and Dean, John C S and Pilz, Daniela T and Holder, Susan E and McNeill, Alisdair and Graziano, Claudio and Lefebvre, V{\'e}ronique} } @article {735, title = {Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.}, journal = {Br J Ophthalmol}, volume = {103}, year = {2019}, month = {2019 03}, pages = {390-397}, abstract = {

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

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

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

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

}, keywords = {Adolescent, Adult, Age of Onset, Aged, ATP-Binding Cassette Transporters, Child, Child, Preschool, Cohort Studies, Databases, Factual, DNA Mutational Analysis, Female, Gene Frequency, Genotyping Techniques, Geography, Humans, Internationality, Macular Degeneration, Male, Middle Aged, Mutation, Polymerase Chain Reaction}, issn = {1468-2079}, doi = {10.1136/bjophthalmol-2018-312064}, author = {Fujinami, Kaoru and Strauss, Rupert W and Chiang, John Pei-Wen and Audo, Isabelle S and Bernstein, Paul S and Birch, David G and Bomotti, Samantha M and Cideciyan, Artur V and Ervin, Ann-Margret and Marino, Meghan J and Sahel, Jos{\'e}-Alain and Mohand-Said, Saddek and Sunness, Janet S and Traboulsi, Elias I and West, Sheila and Wojciechowski, Robert and Zrenner, Eberhart and Michaelides, Michel and Scholl, Hendrik P N} } @article {656, title = {Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Mar}, pages = {257-269}, abstract = {

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

}, keywords = {Child, Child, Preschool, Comparative Genomic Hybridization, CREB-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Genetic, Facies, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Male, Mutation, Phenotype, Rubinstein-Taybi Syndrome, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-01985-y}, author = {Negri, Gloria and Magini, Pamela and Milani, Donatella and Crippa, Milena and Biamino, Elisa and Piccione, Maria and Sotgiu, Stefano and Perr{\`\i}a, Chiara and Vitiello, Giuseppina and Frontali, Marina and Boni, Antonella and Di Fede, Elisabetta and Gandini, Maria Chiara and Colombo, Elisa Adele and Bamshad, Michael J and Nickerson, Deborah A and Smith, Joshua D and Loddo, Italia and Finelli, Palma and Seri, Marco and Pippucci, Tommaso and Larizza, Lidia and Gervasini, Cristina} } @article {662, title = {Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families.}, journal = {Congenit Anom (Kyoto)}, volume = {59}, year = {2019}, month = {2019 May}, pages = {93-98}, abstract = {

Non-bullous congenital ichthyosiform erythroderma (NCIE) is characterized by skin scaling with erythema. In this study, two Pakistani families with NCIE are genetically characterized through Whole Exome and Sanger sequencing to identify molecular basis of the disease. We identified a nonsense homozygous c.2026C>T mutation of ALOXE3, causing premature termination of the eLOX3 protein (p.Q676X). In silico studies predicted impaired enzymatic activity of the premature truncated eLOX3, leading to abnormal synthesis of specific hepoxilin derivatives, essential for epidermal barrier formation. It is the first ever study reporting homozygotes of p.Q676X mutation in ethnically distinct two Pakistani families; otherwise, heterozygotes of the said mutation have been reported in South Asian population only. Hence, mutation seems to be region-specific and may be useful for molecular diagnosis of NCIE. Moreover, our findings should help in genetic counseling and career screening.

}, keywords = {8,11,14-Eicosatrienoic Acid, Adolescent, Adult, Base Sequence, Case-Control Studies, Child, Child, Preschool, Codon, Nonsense, Ethnic Groups, Female, Flavanones, Gene Expression, Homozygote, Humans, Ichthyosis, Lamellar, Lipoxygenase, Male, Middle Aged, Molecular Docking Simulation, Pakistan, Pedigree, Protein Binding, Protein Structure, Secondary, Skin, Whole Exome Sequencing}, issn = {1741-4520}, doi = {10.1111/cga.12303}, author = {Rahman, Simeen Ber and Mir, Asif and Ahmad, Nafees and Haider, Syed Husnain and Malik, Salman Akbar and Nasir, Muhammad} } @article {561, title = {Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations.}, journal = {Muscle Nerve}, volume = {59}, year = {2019}, month = {2019 03}, pages = {357-362}, abstract = {

INTRODUCTION: Centronuclear myopathies (CNMs) are a subtype of congenital myopathies (CMs) characterized by muscle weakness, predominant type 1 fibers, and increased central nuclei. SPEG (striated preferentially expressed protein kinase) mutations have recently been identified in 7 CM patients (6 with CNMs). We report 2 additional patients with SPEG mutations expanding the phenotype and evaluate genotype-phenotype correlations associated with SPEG mutations.

METHODS: Using whole exome/genome sequencing in CM families, we identified novel recessive SPEG mutations in 2 patients.

RESULTS: Patient 1, with severe muscle weakness requiring respiratory support, dilated cardiomyopathy, ophthalmoplegia, and findings of nonspecific CM on muscle biopsy carried a homozygous SPEG mutation (p.Val3062del). Patient 2, with milder muscle weakness, ophthalmoplegia, and CNM carried compound heterozygous mutations (p.Leu728Argfs*82) and (p.Val2997Glyfs*52).

CONCLUSIONS: The 2 patients add insight into genotype-phenotype correlations of SPEG-associated CMs. Clinicians should consider evaluating a CM patient for SPEG mutations even in the absence of CNM features. Muscle Nerve 59:357-362, 2019.

}, keywords = {Biopsy, Child, Child, Preschool, Consanguinity, Exome, Female, Genetic Association Studies, Humans, Infant, Male, Muscle Proteins, Muscle Weakness, Muscle, Skeletal, Mutation, Myopathies, Structural, Congenital, Protein-Serine-Threonine Kinases, Sequence Analysis}, issn = {1097-4598}, doi = {10.1002/mus.26378}, author = {Qualls, Anita E and Donkervoort, Sandra and Herkert, Johanna C and D{\textquoteright}Gama, Alissa M and Bharucha-Goebel, Diana and Collins, James and Chao, Katherine R and Foley, A Reghan and Schoots, Mirthe H and Jongbloed, Jan D H and B{\"o}nnemann, Carsten G and Agrawal, Pankaj B} } @article {608, title = {Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype.}, journal = {Am J Respir Crit Care Med}, volume = {199}, year = {2019}, month = {2019 01 15}, pages = {190-198}, abstract = {

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

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

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

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

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

}, keywords = {Child, Cilia, Cohort Studies, Female, Genotype, Humans, Kartagener Syndrome, Longitudinal Studies, Lung, Male, Mutation, Phenotype, Prospective Studies, Respiratory Function Tests}, issn = {1535-4970}, doi = {10.1164/rccm.201803-0548OC}, author = {Davis, Stephanie D and Rosenfeld, Margaret and Lee, Hye-Seung and Ferkol, Thomas W and Sagel, Scott D and Dell, Sharon D and Milla, Carlos and Pittman, Jessica E and Shapiro, Adam J and Sullivan, Kelli M and Nykamp, Keith R and Krischer, Jeffrey P and Zariwala, Maimoona A and Knowles, Michael R and Leigh, Margaret W} } @article {570, title = {TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.}, journal = {Hum Mol Genet}, volume = {28}, year = {2019}, month = {2019 02 15}, pages = {539-547}, abstract = {

Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. <50\%) as a potential mechanism of TBX6-associated CVMs. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found that 10 (9.3\%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in the newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM-associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6.

}, keywords = {Adolescent, Alleles, Animals, Child, Child, Preschool, Congenital Abnormalities, CRISPR-Cas Systems, Disease Models, Animal, Female, Haploinsufficiency, Humans, Infant, Male, Mice, Mutation, Phenotype, Scoliosis, Spine, T-Box Domain Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/ddy358}, author = {Yang, Nan and Wu, Nan and Zhang, Ling and Zhao, Yanxue and Liu, Jiaqi and Liang, Xiangyu and Ren, Xiaojun and Li, Weiyu and Chen, Weisheng and Dong, Shuangshuang and Zhao, Sen and Lin, Jiachen and Xiang, Hang and Xue, Huadan and Chen, Lu and Sun, Hao and Zhang, Jianguo and Shi, Jiangang and Zhang, Shuyang and Lu, Daru and Wu, Xiaohui and Jin, Li and Ding, Jiandong and Qiu, Guixing and Wu, Zhihong and Lupski, James R and Zhang, Feng} } @article {596, title = {Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients.}, journal = {J Am Soc Nephrol}, volume = {30}, year = {2019}, month = {2019 02}, pages = {201-215}, abstract = {

BACKGROUND: Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20\% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients.

METHODS: To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children{\textquoteright}s Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD.

RESULTS: By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7\%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroid-resistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WES-related molecular genetic diagnosis had implications for clinical care for five patients.

CONCLUSIONS: Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

}, keywords = {Adolescent, Boston, Child, Child, Preschool, Cohort Studies, Female, Genetic Predisposition to Disease, Genetic Testing, Graft Rejection, Graft Survival, Hospitals, Pediatric, Humans, Kidney Transplantation, Male, Precision Medicine, Prognosis, Renal Insufficiency, Chronic, Retrospective Studies, Risk Assessment, Severity of Illness Index, Survival Analysis, Transplant Recipients, Treatment Outcome, Whole Exome Sequencing}, issn = {1533-3450}, doi = {10.1681/ASN.2018060575}, author = {Mann, Nina and Braun, Daniela A and Amann, Kassaundra and Tan, Weizhen and Shril, Shirlee and Connaughton, Dervla M and Nakayama, Makiko and Schneider, Ronen and Kitzler, Thomas M and van der Ven, Amelie T and Chen, Jing and Ityel, Hadas and Vivante, Asaf and Majmundar, Amar J and Daga, Ankana and Warejko, Jillian K and Lovric, Svjetlana and Ashraf, Shazia and Jobst-Schwan, Tilman and Widmeier, Eugen and Hugo, Hannah and Mane, Shrikant M and Spaneas, Leslie and Somers, Michael J G and Ferguson, Michael A and Traum, Avram Z and Stein, Deborah R and Baum, Michelle A and Daouk, Ghaleb H and Lifton, Richard P and Manzi, Shannon and Vakili, Khashayar and Kim, Heung Bae and Rodig, Nancy M and Hildebrandt, Friedhelm} } @article {577, title = {ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {319-330}, abstract = {

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

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

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

}, keywords = {Adolescent, Alternative Splicing, Child, Female, Fetal Growth Retardation, Genetic Predisposition to Disease, Humans, Infant, Lamin Type A, Male, Mutation, Phenotype, Progeria, Pyrroline Carboxylate Reductases, RNA Polymerase III}, issn = {1432-1203}, doi = {10.1007/s00439-018-1957-1}, author = {Lessel, Davor and Ozel, Ayse Bilge and Campbell, Susan E and Saadi, Abdelkrim and Arlt, Martin F and McSweeney, Keisha Melodi and Plaiasu, Vasilica and Szakszon, Katalin and Sz{\H o}ll{\H o}s, Anna and Rusu, Cristina and Rojas, Armando J and Lopez-Valdez, Jaime and Thiele, Holger and N{\"u}rnberg, Peter and Nickerson, Deborah A and Bamshad, Michael J and Li, Jun Z and Kubisch, Christian and Glover, Thomas W and Gordon, Leslie B} } @article {466, title = {A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 04}, pages = {1015-1022}, abstract = {

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

}, keywords = {Alleles, Amino Acid Substitution, Animals, Anodontia, Child, Consanguinity, Facies, Genetic Association Studies, Genotype, Humans, Male, Mice, Mutation, Neoplasm Proteins, Pedigree, Phenotype, Radiography, Receptors, Cell Surface, Whole Exome Sequencing}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38625}, author = {Dinckan, Nuriye and Du, Renqian and Akdemir, Zeynep C and Bayram, Yavuz and Jhangiani, Shalini N and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Boerwinkle, Eric and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Uyguner, Zehra O and Letra, Ariadne} } @article {452, title = {Biallelic variants in KIF14 cause intellectual disability with microcephaly.}, journal = {Eur J Hum Genet}, volume = {26}, year = {2018}, month = {2018 03}, pages = {330-339}, abstract = {

Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly.

}, keywords = {Child, Child, Preschool, Female, Humans, Intellectual Disability, Kinesin, Loss of Function Mutation, Microcephaly, Mutation, Missense, Oncogene Proteins, Pedigree, Phenotype, Protein Domains, Syndrome}, issn = {1476-5438}, doi = {10.1038/s41431-017-0088-9}, author = {Makrythanasis, Periklis and Maroofian, Reza and Stray-Pedersen, Asbj{\o}rg and Musaev, Damir and Zaki, Maha S and Mahmoud, Iman G and Selim, Laila and Elbadawy, Amera and Jhangiani, Shalini N and Coban Akdemir, Zeynep H and Gambin, Tomasz and Sorte, Hanne S and Heiberg, Arvid and McEvoy-Venneri, Jennifer and James, Kiely N and Stanley, Valentina and Belandres, Denice and Guipponi, Michel and Santoni, Federico A and Ahangari, Najmeh and Tara, Fatemeh and Doosti, Mohammad and Iwaszkiewicz, Justyna and Zoete, Vincent and Backe, Paul Hoff and Hamamy, Hanan and Gleeson, Joseph G and Lupski, James R and Karimiani, Ehsan Ghayoor and Antonarakis, Stylianos E} } @article {504, title = {CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris.}, journal = {J Am Acad Dermatol}, volume = {79}, year = {2018}, month = {2018 Sep}, pages = {487-494}, abstract = {

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

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

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

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

LIMITATIONS: Relatively small sample size.

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

}, keywords = {Age of Onset, CARD Signaling Adaptor Proteins, Child, Child, Preschool, Dermatologic Agents, Facial Dermatoses, Genetic Testing, Guanylate Cyclase, Humans, Infant, Infant, Newborn, Membrane Proteins, Phenotype, Pityriasis Rubra Pilaris, Psoriasis, Retreatment, Skin Diseases, Papulosquamous, Ustekinumab}, issn = {1097-6787}, doi = {10.1016/j.jaad.2018.02.034}, author = {Craiglow, Brittany G and Boyden, Lynn M and Hu, Ronghua and Virtanen, Marie and Su, John and Rodriguez, Gabriela and McCarthy, Catherine and Luna, Paula and Larralde, Margarita and Humphrey, Stephen and Holland, Kristen E and Hogeling, Marcia and Hidalgo-Matlock, Benjamin and Ferrari, Bruno and Fernandez-Faith, Esteban and Drolet, Beth and Cordoro, Kelly M and Bowcock, Anne M and Antaya, Richard J and Ashack, Kurt and Ashack, Richard J and Lifton, Richard P and Milstone, Leonard M and Paller, Amy S and Choate, Keith A} } @article {487, title = {Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness.}, journal = {Skelet Muscle}, volume = {8}, year = {2018}, month = {2018 07 30}, pages = {23}, abstract = {

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

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

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

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

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Dystroglycans, Female, Genetic Predisposition to Disease, Genetic Variation, Glycosylation, Heterozygote, Homozygote, Humans, Male, Middle Aged, Muscle Proteins, Muscular Dystrophies, Limb-Girdle, Mutation, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {2044-5040}, doi = {10.1186/s13395-018-0170-1}, author = {Johnson, Katherine and Bertoli, Marta and Phillips, Lauren and Topf, Ana and Van den Bergh, Peter and Vissing, John and Witting, Nanna and Nafissi, Shahriar and Jamal-Omidi, Shirin and {\L}usakowska, Anna and Kostera-Pruszczyk, Anna and Potulska-Chromik, Anna and Deconinck, Nicolas and Wallgren-Pettersson, Carina and Strang-Karlsson, Sonja and Colomer, Jaume and Claeys, Kristl G and De Ridder, Willem and Baets, Jonathan and von der Hagen, Maja and Fern{\'a}ndez-Torr{\'o}n, Roberto and Zulaica Ijurco, Miren and Espinal Valencia, Juan Bautista and Hahn, Andreas and Durmus, Hacer and Willis, Tracey and Xu, Liwen and Valkanas, Elise and Mullen, Thomas E and Lek, Monkol and MacArthur, Daniel G and Straub, Volker} } @article {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 {431, title = {Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 09}, pages = {1022-1029}, abstract = {

PURPOSE: CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30\% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome.

METHODS: We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome.

RESULTS: Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6\%), whereas 4 (14.3\%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5\%) individual. The remaining eight (28.6\%) individuals were not found to have pathogenic variants by WES.

CONCLUSION: These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.

}, keywords = {Adolescent, Adult, Carrier Proteins, CHARGE Syndrome, Child, Child, Preschool, Cohort Studies, DNA Helicases, DNA-Binding Proteins, E1A-Associated p300 Protein, Epigenesis, Genetic, Female, Genetic Testing, Humans, Infant, Male, Mutation, Neoplasm Proteins, Phenotype, Repressor Proteins, RNA Splicing Factors}, issn = {1530-0366}, doi = {10.1038/gim.2017.233}, author = {Moccia, Amanda and Srivastava, Anshika and Skidmore, Jennifer M and Bernat, John A and Wheeler, Marsha and Chong, Jessica X and Nickerson, Deborah and Bamshad, Michael and Hefner, Margaret A and Martin, Donna M and Bielas, Stephanie L} } @article {500, title = {Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {753-768}, abstract = {

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

}, keywords = {Adolescent, Adult, Carrier Proteins, Channelopathies, Child, Child, Preschool, Developmental Disabilities, Female, Genetic Markers, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Phenotype, Sodium Channels, Young Adult}, issn = {1432-1203}, doi = {10.1007/s00439-018-1929-5}, author = {Bramswig, Nuria C and Bertoli-Avella, Aida M and Albrecht, Beate and Al Aqeel, Aida I and Alhashem, Amal and Al-Sannaa, Nouriya and Bah, Maissa and Br{\"o}hl, Katharina and Depienne, Christel and Dorison, Nathalie and Doummar, Diane and Ehmke, Nadja and Elbendary, Hasnaa M and Gorokhova, Svetlana and H{\'e}ron, Delphine and Horn, Denise and James, Kiely and Keren, Boris and Kuechler, Alma and Ismail, Samira and Issa, Mahmoud Y and Marey, Isabelle and Mayer, Mich{\`e}le and McEvoy-Venneri, Jennifer and Megarbane, Andre and Mignot, Cyril and Mohamed, Sarar and Nava, Caroline and Philip, Nicole and Ravix, Cecile and Rolfs, Arndt and Sadek, Abdelrahim Abdrabou and Segebrecht, Lara and Stanley, Valentina and Trautman, Camille and Valence, Stephanie and Villard, Laurent and Wieland, Thomas and Engels, Hartmut and Strom, Tim M and Zaki, Maha S and Gleeson, Joseph G and L{\"u}decke, Hermann-Josef and Bauer, Peter and Wieczorek, Dagmar} } @article {542, title = {Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome.}, journal = {Mol Genet Genomic Med}, volume = {6}, year = {2018}, month = {2018 03}, pages = {230-248}, abstract = {

BACKGROUND: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage.

METHODS: In the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations.

RESULTS: We found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4~years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20~years old. All patients presented developmental coxa vara and seven patients (~22\%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene.

CONCLUSION: With this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense-mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis.

}, keywords = {Adolescent, Adult, Arthropathy, Neurogenic, Child, Child, Preschool, Coxa Vara, Exons, Female, Genetic Association Studies, Hand Deformities, Congenital, Humans, Male, Middle Aged, Mutation, Proteoglycans, Retrospective Studies, Sequence Deletion, Synovitis, Whole Exome Sequencing}, issn = {2324-9269}, doi = {10.1002/mgg3.364}, author = {Yilmaz, Saliha and Uluda{\u g} Alkaya, Dilek and Kasapcopur, Ozgur and Barut, Kenan and Akdemir, Ekin S and Celen, Cemre and Youngblood, Mark W and Yasuno, Katsuhito and Bilguvar, Kaya and G{\"u}nel, Murat and Tuysuz, Beyhan} } @article {545, title = {A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0191224}, abstract = {

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

}, keywords = {Amino Acid Sequence, Amino Acid Substitution, Animals, Animals, Newborn, Biomarkers, Tumor, Child, Consanguinity, Conserved Sequence, Exons, Extracellular Matrix Proteins, Fraser Syndrome, Gene Expression Regulation, Developmental, Homozygote, Humans, Male, Mice, Models, Animal, Models, Molecular, Mutation, Missense, Pedigree, Sequence Homology, Amino Acid, Urogenital Abnormalities, Urogenital System, Vesico-Ureteral Reflux}, issn = {1932-6203}, doi = {10.1371/journal.pone.0191224}, author = {van der Ven, Amelie T and Kobbe, Birgit and Kohl, Stefan and Shril, Shirlee and Pogoda, Hans-Martin and Imhof, Thomas and Ityel, Hadas and Vivante, Asaf and Chen, Jing and Hwang, Daw-Yang and Connaughton, Dervla M and Mann, Nina and Widmeier, Eugen and Taglienti, Mary and Schmidt, Johanna Magdalena and Nakayama, Makiko and Senguttuvan, Prabha and Kumar, Selvin and Tasic, Velibor and Kehinde, Elijah O and Mane, Shrikant M and Lifton, Richard P and Soliman, Neveen and Lu, Weining and Bauer, Stuart B and Hammerschmidt, Matthias and Wagener, Raimund and Hildebrandt, Friedhelm} } @article {523, title = {Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {689-703}, abstract = {

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

}, keywords = {Anodontia, Cell Adhesion Molecules, Child, Child, Preschool, Female, Genetic Markers, Humans, Male, Mutation, Pedigree, Phenotype, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Turkey, Wnt Proteins}, issn = {1432-1203}, doi = {10.1007/s00439-018-1907-y}, author = {Du, Renqian and Dinckan, Nuriye and Song, Xiaofei and Coban-Akdemir, Zeynep and Jhangiani, Shalini N and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Petty, Lauren E and Muzny, Donna M and Below, Jennifer E and Boerwinkle, Eric and Wu, Nan and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Letra, Ariadne and Uyguner, Z Oya} } @article {629, title = {A novel pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {4}, year = {2018}, month = {2018 02}, abstract = {

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent attacks of dyskinetic movements without alteration of consciousness that are often triggered by the initiation of voluntary movements. Whole-exome sequencing has revealed a cluster of pathogenic variants in (proline-rich transmembrane protein), a gene with a function in synaptic regulation that remains poorly understood. Here, we report the discovery of a novel pathogenic variant inherited in an autosomal dominant pattern in a family with PKD and benign familial infantile seizures (BFIS). After targeted Sanger sequencing did not identify the presence of previously described pathogenic variants, we carried out whole-exome sequencing in the proband and her affected paternal grandfather. This led to the discovery of a novel variant, NM_001256442:exon3:c.C959T/NP_660282.2:p.A320V, altering an evolutionarily conserved alanine at the amino acid position 320 located in the M2 transmembrane region. Sanger sequencing further confirmed the presence of this variant in four affected family members (paternal grandfather, father, brother, and proband) and its absence in two unaffected ones (paternal grandmother and mother). This newly found variant further reinforces the importance of in PKD, BFIS, and possibly other movement disorders. Future functional studies using animal models and human pluripotent stem cell models will provide new insights into the role of and the significance of this variant in regulating neural development and/or function.

}, keywords = {Amino Acid Sequence, Base Sequence, Child, Chromosome Segregation, Conserved Sequence, Dystonia, Epilepsy, Benign Neonatal, Evolution, Molecular, Family, Female, Humans, Infant, Inheritance Patterns, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree}, issn = {2373-2873}, doi = {10.1101/mcs.a002287}, author = {Lu, Jacqueline G and Bishop, Juliet and Cheyette, Sarah and Zhulin, Igor B and Guo, Su and Sobreira, Nara and Brenner, Steven E} } @article {465, title = {The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 06 15}, pages = {2064-2075}, abstract = {

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

}, keywords = {Animals, Child, Child, Preschool, Epithelium, Extracellular Matrix Proteins, Female, Hernias, Diaphragmatic, Congenital, Humans, Infant, Infant, Newborn, Male, Mice, Mice, Knockout, Mutation, Pregnancy, Receptors, Interleukin}, issn = {1460-2083}, doi = {10.1093/hmg/ddy110}, author = {Jordan, Valerie K and Beck, Tyler F and Hernandez-Garcia, Andres and Kundert, Peter N and Kim, Bum-Jun and Jhangiani, Shalini N and Gambin, Tomasz and Starkovich, Molly and Punetha, Jaya and Paine, Ingrid S and Posey, Jennifer E and Li, Alexander H and Muzny, Donna and Hsu, Chih-Wei and Lashua, Amber J and Sun, Xin and Fernandes, Caraciolo J and Dickinson, Mary E and Lally, Kevin P and Gibbs, Richard A and Boerwinkle, Eric and Lupski, James R and Scott, Daryl A} } @article {464, title = {Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {985-994}, abstract = {

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Autism Spectrum Disorder, Cell Line, Child, Exons, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Humans, Intellectual Disability, Male, Middle Aged, Mutation, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Pedigree, Phenotype, RNA, Messenger, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.004}, author = {Cheng, Hanyin and Dharmadhikari, Avinash V and Varland, Sylvia and Ma, Ning and Domingo, Deepti and Kleyner, Robert and Rope, Alan F and Yoon, Margaret and Stray-Pedersen, Asbj{\o}rg and Posey, Jennifer E and Crews, Sarah R and Eldomery, Mohammad K and Akdemir, Zeynep Coban and Lewis, Andrea M and Sutton, Vernon R and Rosenfeld, Jill A and Conboy, Erin and Agre, Katherine and Xia, Fan and Walkiewicz, Magdalena and Longoni, Mauro and High, Frances A and van Slegtenhorst, Marjon A and Mancini, Grazia M S and Finnila, Candice R and van Haeringen, Arie and den Hollander, Nicolette and Ruivenkamp, Claudia and Naidu, Sakkubai and Mahida, Sonal and Palmer, Elizabeth E and Murray, Lucinda and Lim, Derek and Jayakar, Parul and Parker, Michael J and Giusto, Stefania and Stracuzzi, Emanuela and Romano, Corrado and Beighley, Jennifer S and Bernier, Raphael A and K{\"u}ry, S{\'e}bastien and Nizon, Mathilde and Corbett, Mark A and Shaw, Marie and Gardner, Alison and Barnett, Christopher and Armstrong, Ruth and Kassahn, Karin S and Van Dijck, Anke and Vandeweyer, Geert and Kleefstra, Tjitske and Schieving, Jolanda and Jongmans, Marjolijn J and de Vries, Bert B A and Pfundt, Rolph and Kerr, Bronwyn and Rojas, Samantha K and Boycott, Kym M and Person, Richard and Willaert, Rebecca and Eichler, Evan E and Kooy, R Frank and Yang, Yaping and Wu, Joseph C and Lupski, James R and Arnesen, Thomas and Cooper, Gregory M and Chung, Wendy K and Gecz, Jozef and Stessman, Holly A F and Meng, Linyan and Lyon, Gholson J} } @article {485, title = {A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Jul}, pages = {471-478}, abstract = {

Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

}, keywords = {Adolescent, Adult, Animals, Child, Disease Models, Animal, Ear, Inner, Female, Genes, Dominant, Genes, Recessive, Hearing Loss, Hearing Loss, Sensorineural, Homozygote, Humans, LIM-Homeodomain Proteins, Male, Mice, Mutation, Missense, Pedigree, Transcription Factors, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-018-1899-7}, author = {Schrauwen, Isabelle and Chakchouk, Imen and Liaqat, Khurram and Jan, Abid and Nasir, Abdul and Hussain, Shabir and Nickerson, Deborah A and Bamshad, Michael J and Ullah, Asmat and Ahmad, Wasim and Leal, Suzanne M} } @article {441, title = {Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and~nephrocalcinosis.}, journal = {Kidney Int}, volume = {93}, year = {2018}, month = {2018 01}, pages = {204-213}, abstract = {

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4\% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8\% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

}, keywords = {Adolescent, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Mutation, Nephrocalcinosis, Nephrolithiasis, Pedigree, Phenotype, Predictive Value of Tests, Prognosis, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Whole Exome Sequencing, Young Adult}, issn = {1523-1755}, doi = {10.1016/j.kint.2017.06.025}, author = {Daga, Ankana and Majmundar, Amar J and Braun, Daniela A and Gee, Heon Yung and Lawson, Jennifer A and Shril, Shirlee and Jobst-Schwan, Tilman and Vivante, Asaf and Schapiro, David and Tan, Weizhen and Warejko, Jillian K and Widmeier, Eugen and Nelson, Caleb P and Fathy, Hanan M and Gucev, Zoran and Soliman, Neveen A and Hashmi, Seema and Halbritter, Jan and Halty, Margarita and Kari, Jameela A and El-Desoky, Sherif and Ferguson, Michael A and Somers, Michael J G and Traum, Avram Z and Stein, Deborah R and Daouk, Ghaleb H and Rodig, Nancy M and Katz, Avi and Hanna, Christian and Schwaderer, Andrew L and Sayer, John A and Wassner, Ari J and Mane, Shrikant and Lifton, Richard P and Milosevic, Danko and Tasic, Velibor and Baum, Michelle A and Hildebrandt, Friedhelm} } @article {497, title = {Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43\% of 35 Families With Midaortic Syndrome.}, journal = {Hypertension}, volume = {71}, year = {2018}, month = {2018 04}, pages = {691-699}, abstract = {

Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9\%), we detected likely causal dominant mutations. In 15 of 35 (42.9\%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (, , , , and ). Ten of the 15 mutations have not previously been reported. This is the first report of , , or mutations in individuals with MAS. Mutations were detected in (6/15 families), (4/15 families), (3/15 families), and one family each for and Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS.

}, keywords = {Adolescent, Aorta, Abdominal, Aortic Valve Stenosis, Child, Child, Preschool, Cohort Studies, Female, Genetic Association Studies, Humans, Hypertension, Jagged-1 Protein, Male, Mutation, Neurofibromatoses, Neurofibromin 1, Pedigree, Syndrome, United States, Whole Exome Sequencing}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.10296}, author = {Warejko, Jillian K and Schueler, Markus and Vivante, Asaf and Tan, Weizhen and Daga, Ankana and Lawson, Jennifer A and Braun, Daniela A and Shril, Shirlee and Amann, Kassaundra and Somers, Michael J G and Rodig, Nancy M and Baum, Michelle A and Daouk, Ghaleb and Traum, Avram Z and Kim, Heung Bae and Vakili, Khashayar and Porras, Diego and Lock, James and Rivkin, Michael J and Chaudry, Gulraiz and Smoot, Leslie B and Singh, Michael N and Smith, Edward R and Mane, Shrikant M and Lifton, Richard P and Stein, Deborah R and Ferguson, Michael A and Hildebrandt, Friedhelm} } @article {446, title = {WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 01 04}, pages = {27-43}, abstract = {

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, \~{}70\% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

}, keywords = {Adolescent, Adult, Base Sequence, Child, Child, Preschool, Chromosome Segregation, Craniofacial Abnormalities, Diagnosis, Differential, Dwarfism, Female, Genes, Dominant, Genetic Association Studies, Genetic Heterogeneity, Humans, Limb Deformities, Congenital, Male, Middle Aged, Mutation, Missense, Phenotype, Urogenital Abnormalities, Wnt Signaling Pathway}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.10.002}, author = {White, Janson J and Mazzeu, Juliana F and Coban-Akdemir, Zeynep and Bayram, Yavuz and Bahrambeigi, Vahid and Hoischen, Alexander and van Bon, Bregje W M and Gezdirici, Alper and Gulec, Elif Yilmaz and Ramond, Francis and Touraine, Renaud and Thevenon, Julien and Shinawi, Marwan and Beaver, Erin and Heeley, Jennifer and Hoover-Fong, Julie and Durmaz, Ceren D and Karabulut, Halil Gurhan and Marzioglu-Ozdemir, Ebru and Cayir, Atilla and Duz, Mehmet B and Seven, Mehmet and Price, Susan and Ferreira, Barbara Merfort and Vianna-Morgante, Angela M and Ellard, Sian and Parrish, Andrew and Stals, Karen and Flores-Daboub, Josue and Jhangiani, Shalini N and Gibbs, Richard A and Brunner, Han G and Sutton, V Reid and Lupski, James R and Carvalho, Claudia M B} } @article {371, title = {Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency.}, journal = {Mitochondrion}, volume = {34}, year = {2017}, month = {2017 05}, pages = {84-90}, abstract = {

We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.

}, keywords = {Child, Child, Preschool, Congenital Abnormalities, Gene Expression, Humans, Infant, Infant, Newborn, Male, Mitochondrial Proteins, Oxidative Phosphorylation, Peptide Elongation Factor G, RNA Splice Sites}, issn = {1872-8278}, doi = {10.1016/j.mito.2017.02.004}, author = {Simon, Mariella T and Ng, Bobby G and Friederich, Marisa W and Wang, Raymond Y and Boyer, Monica and Kircher, Martin and Collard, Renata and Buckingham, Kati J and Chang, Richard and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Van Hove, Johan L K and Freeze, Hudson H and Abdenur, Jose E} } @article {637, title = {Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Jul}, pages = {e1006905}, abstract = {

Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.

}, keywords = {Alleles, Animals, Animals, Genetically Modified, Calcium Channels, Cerebellar Ataxia, Child, Child, Preschool, Drosophila melanogaster, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Microscopy, Electron, Transmission, Mutation, Missense, Neurodegenerative Diseases, Neuroimaging, Phenotype, Point Mutation}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006905}, author = {Luo, Xi and Rosenfeld, Jill A and Yamamoto, Shinya and Harel, Tamar and Zuo, Zhongyuan and Hall, Melissa and Wierenga, Klaas J and Pastore, Matthew T and Bartholomew, Dennis and Delgado, Mauricio R and Rotenberg, Joshua and Lewis, Richard Alan and Emrick, Lisa and Bacino, Carlos A and Eldomery, Mohammad K and Coban Akdemir, Zeynep and Xia, Fan and Yang, Yaping and Lalani, Seema R and Lotze, Timothy and Lupski, James R and Lee, Brendan and Bellen, Hugo J and Wangler, Michael F} } @article {449, title = {Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO.}, journal = {J Med Genet}, volume = {54}, year = {2017}, month = {2017 01}, pages = {47-53}, abstract = {

BACKGROUND: The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects.

METHODS: We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis.

RESULTS: We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother.

CONCLUSIONS: We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.

}, keywords = {Child, Child, Preschool, Developmental Disabilities, DNA-Binding Proteins, Exome, Heart Defects, Congenital, Heart Ventricles, Humans, Infant, Male, Nuclear Matrix-Associated Proteins, Octamer Transcription Factors, RNA-Binding Proteins}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-104039}, author = {Scott, Daryl A and Hernandez-Garcia, Andres and Azamian, Mahshid S and Jordan, Valerie K and Kim, Bum Jun and Starkovich, Molly and Zhang, Jinglan and Wong, Lee-Jun and Darilek, Sandra A and Breman, Amy M and Yang, Yaping and Lupski, James R and Jiwani, Amyn K and Das, Bibhuti and Lalani, Seema R and Iglesias, Alejandro D and Rosenfeld, Jill A and Xia, Fan} } @article {426, title = {Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Nov}, pages = {1593-1601}, abstract = {

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8\%, including a recessive founder mutation in GDF1 accounting for \~{}5\% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for \~{}11\% of Shone complex, and dominant FLT4 mutations accounting for 2.3\% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8\% of cases, including \~{}3\% of isolated CHD patients and \~{}28\% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70\% probability of being disease related. DNMs in \~{}440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

}, keywords = {Adult, Autistic Disorder, Cardiac Myosins, Case-Control Studies, Child, Exome, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Growth Differentiation Factor 1, Heart Defects, Congenital, Heterozygote, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Mutation, Myosin Heavy Chains, Pedigree, Risk, Vascular Endothelial Growth Factor Receptor-3}, issn = {1546-1718}, doi = {10.1038/ng.3970}, author = {Jin, Sheng Chih and Homsy, Jason and Zaidi, Samir and Lu, Qiongshi and Morton, Sarah and DePalma, Steven R and Zeng, Xue and Qi, Hongjian and Chang, Weni and Sierant, Michael C and Hung, Wei-Chien and Haider, Shozeb and Zhang, Junhui and Knight, James and Bjornson, Robert D and Castaldi, Christopher and Tikhonoa, Irina R and Bilguvar, Kaya and Mane, Shrikant M and Sanders, Stephan J and Mital, Seema and Russell, Mark W and Gaynor, J William and Deanfield, John and Giardini, Alessandro and Porter, George A and Srivastava, Deepak and Lo, Cecelia W and Shen, Yufeng and Watkins, W Scott and Yandell, Mark and Yost, H Joseph and Tristani-Firouzi, Martin and Newburger, Jane W and Roberts, Amy E and Kim, Richard and Zhao, Hongyu and Kaltman, Jonathan R and Goldmuntz, Elizabeth and Chung, Wendy K and Seidman, Jonathan G and Gelb, Bruce D and Seidman, Christine E and Lifton, Richard P and Brueckner, Martina} } @article {636, title = {Copy Number Changes Identified Using Whole Exome Sequencing in Nonsyndromic Cleft Lip and Palate in a Honduran Population.}, journal = {Birth Defects Res}, volume = {109}, year = {2017}, month = {2017 Oct 02}, pages = {1257-1267}, abstract = {

BACKGROUND: The majority of cleft lip with or without cleft palate cases appear as an isolated, nonsyndromic entity (NSCLP). With the advent of next generation sequencing, whole exome sequencing (WES) has been used to identify single nucleotide variants and insertion/deletions which cause or increase the risk of NSCLP. However, to our knowledge, there are no published studies using WES in NSCLP to investigate copy number changes (CNCs), which are a major component of human genetic variation. Our study aimed to identify CNCs associated with NSCLP in a Honduran population using WES.

METHODS: WES was performed on two to four members of 27 multiplex Honduran families. CNCs were identified using two algorithms, CoNIFER and XHMM. Priority was given to CNCs that were identified in more than one patient and had variant frequencies of less than 5\% in reference data sets.

RESULTS: WES completion was defined as >90\% of the WES target at >8 {\texttimes} coverage and >80\% of the WES target at >20 {\texttimes} coverage. Twenty-four CNCs that met our inclusion criteria were identified by both CoNIFER and XHMM. These CNCs were confirmed using quantitative PCR. Pedigree analysis produced three CNCs corresponding to ADH7, AHR, and CRYZ segregating with NSCLP. Two of the three CNCs implicate genes, AHR and ADH7, whose known biological functions could plausibly play a role in NSCLP.

CONCLUSION: WES can be used to detect candidate CNCs that may be involved in the pathophysiology of NSCLP. Birth Defects Research 109:1257-1267, 2017. {\textcopyright} 2017 Wiley Periodicals, Inc.

}, keywords = {Adolescent, Adult, Alcohol Dehydrogenase, Alleles, Basic Helix-Loop-Helix Transcription Factors, Child, Child, Preschool, Cleft Lip, Cleft Palate, DNA Copy Number Variations, Family, Female, Gene Frequency, Genetic Variation, High-Throughput Nucleotide Sequencing, Honduras, Humans, Male, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Receptors, Aryl Hydrocarbon, Whole Exome Sequencing}, issn = {2472-1727}, doi = {10.1002/bdr2.1063}, author = {Cai, Yi and Patterson, Karynne E and Reinier, Frederic and Keesecker, Sarah E and Blue, Elizabeth and Bamshad, Michael and Haddad, Joseph} } @article {335, title = {De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {352-363}, abstract = {

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

}, keywords = {Adolescent, Animals, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Down-Regulation, Female, Gene Deletion, Humans, Infant, Intellectual Disability, Male, Microcephaly, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.01.003}, author = {K{\"u}ry, S{\'e}bastien and Besnard, Thomas and Ebstein, Fr{\'e}d{\'e}ric and Khan, Tahir N and Gambin, Tomasz and Douglas, Jessica and Bacino, Carlos A and Craigen, William J and Sanders, Stephan J and Lehmann, Andrea and Latypova, X{\'e}nia and Khan, Kamal and Pacault, Mathilde and Sacharow, Stephanie and Glaser, Kimberly and Bieth, Eric and Perrin-Sabourin, Laurence and Jacquemont, Marie-Line and Cho, Megan T and Roeder, Elizabeth and Denomm{\'e}-Pichon, Anne-Sophie and Monaghan, Kristin G and Yuan, Bo and Xia, Fan and Simon, Sylvain and Bonneau, Dominique and Parent, Philippe and Gilbert-Dussardier, Brigitte and Odent, Sylvie and Toutain, Annick and Pasquier, Laurent and Barbouth, Deborah and Shaw, Chad A and Patel, Ankita and Smith, Janice L and Bi, Weimin and Schmitt, S{\'e}bastien and Deb, Wallid and Nizon, Mathilde and Mercier, Sandra and Vincent, Marie and Rooryck, Caroline and Malan, Val{\'e}rie and Brice{\~n}o, Ignacio and G{\'o}mez, Alberto and Nugent, Kimberly M and Gibson, James B and Cogn{\'e}, Benjamin and Lupski, James R and Stessman, Holly A F and Eichler, Evan E and Retterer, Kyle and Yang, Yaping and Redon, Richard and Katsanis, Nicholas and Rosenfeld, Jill A and Kloetzel, Peter-Michael and Golzio, Christelle and B{\'e}zieau, St{\'e}phane and Stankiewicz, Pawe{\l} and Isidor, Bertrand} } @article {424, title = {De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {716-724}, abstract = {

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in~vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

}, keywords = {Adenosine Triphosphatases, Adolescent, Amino Acids, Cell Line, Cell Line, Tumor, Central Nervous System, Child, Child, Preschool, Developmental Disabilities, Female, HEK293 Cells, Humans, Intellectual Disability, Male, Mutation, Missense, RNA, RNA Helicases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.014}, author = {Lessel, Davor and Schob, Claudia and K{\"u}ry, S{\'e}bastien and Reijnders, Margot R F and Harel, Tamar and Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Denecke, Jonas and Edvardson, Shimon and Colin, Estelle and Stegmann, Alexander P A and Gerkes, Erica H and Tessarech, Marine and Bonneau, Dominique and Barth, Magalie and Besnard, Thomas and Cogn{\'e}, Benjamin and Revah-Politi, Anya and Strom, Tim M and Rosenfeld, Jill A and Yang, Yaping and Posey, Jennifer E and Immken, LaDonna and Oundjian, Nelly and Helbig, Katherine L and Meeks, Naomi and Zegar, Kelsey and Morton, Jenny and Schieving, Jolanda H and Claasen, Ana and Huentelman, Matthew and Narayanan, Vinodh and Ramsey, Keri and Brunner, Han G and Elpeleg, Orly and Mercier, Sandra and B{\'e}zieau, St{\'e}phane and Kubisch, Christian and Kleefstra, Tjitske and Kindler, Stefan and Lupski, James R and Kreienkamp, Hans-J{\"u}rgen} } @article {633, title = {De novo mutations in HNRNPU result in a neurodevelopmental syndrome.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Nov}, pages = {3003-3012}, abstract = {

Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterogeneous-Nuclear Ribonucleoprotein U, Heterozygote, Humans, Infant, Intellectual Disability, Male, Mutation, Neurodevelopmental Disorders, Phenotype, Seizures, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38492}, author = {Yates, T Michael and Vasudevan, Pradeep C and Chandler, Kate E and Donnelly, Deirdre E and Stark, Zornitza and Sadedin, Simon and Willoughby, Josh and Balasubramanian, Meena} } @article {386, title = {De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 08 29}, pages = {E7341-E7347}, abstract = {

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95\% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, = 2.4 {\texttimes} 10). had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10\% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near increased the penetrance of mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

}, keywords = {Adult, Animals, Bone Morphogenetic Proteins, Child, Child, Preschool, Cranial Sutures, Craniosynostoses, Exome, Female, Humans, Male, MAP Kinase Signaling System, Mutation, Osteogenesis, Penetrance, Phenotype, ras Proteins, Sequence Analysis, DNA, Signal Transduction, Smad6 Protein, Whole Exome Sequencing}, issn = {1091-6490}, doi = {10.1073/pnas.1709255114}, author = {Timberlake, Andrew T and Furey, Charuta G and Choi, Jungmin and Nelson-Williams, Carol and Loring, Erin and Galm, Amy and Kahle, Kristopher T and Steinbacher, Derek M and Larysz, Dawid and Persing, John A and Lifton, Richard P} } @article {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 {365, title = {Diagnosis of Chronic Intestinal Pseudo-obstruction and Megacystis by Sequencing the ACTG2 Gene.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {65}, year = {2017}, month = {2017 10}, pages = {384-387}, abstract = {

OBJECTIVES: The diagnosis of chronic intestinal pseudo-obstruction has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the actin γ-2 (ACTG2) gene for diagnosis. In addition, the goal was to determine how often a mutation would be found in our randomly collected cohort of probands and those probands published previously.

METHODS: Whole exome sequencing was performed in 4 probands with chronic intestinal pseudo-obstruction. Subsequently, only the ACTG2 gene was sequenced in another 24 probands (total 28). We analyzed published data of 83 probands and our 28 (total 111) and determined how many had pathogenic variants and the precise genotype.

RESULTS: Whole exome and Sanger sequencing revealed a pathogenic variant in the ACTG2 gene in 4 out of 28 of our probands and in 45 out of 83 published probands (49/111 [44.1\%]). Moreover, a mutational hotspot in the ACTG2 gene was recognized. Genetic heterogeneity is evident.

CONCLUSIONS: Pooled gene sequencing results from 1 individual in each of 111 families enabled a precise diagnosis of an ACTG2 mutation in 49 (44\%). The benefit to patients and families of early confirmation of a motility disorder not only helps avoid unnecessary intervention, but also enables institution of appropriate treatments and avoidance of secondary disorders such as malnutrition and poor growth. Knowledge of a pathogenic variant in a parent, with a 50\% risk of recurrence, provides an opportunity for genetic counseling.

}, keywords = {Actins, Adult, Child, Child, Preschool, Chronic Disease, Duodenum, Female, Fetal Diseases, Genetic Markers, Genetic Testing, Humans, Infant, Infant, Newborn, Intestinal Pseudo-Obstruction, Male, Mutation, Sequence Analysis, DNA, Urinary Bladder, Whole Exome Sequencing}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000001608}, author = {Milunsky, Aubrey and Baldwin, Clinton and Zhang, Xiaoying and Primack, Daniel and Curnow, Adrian and Milunsky, Jeff} } @article {361, title = {Dual molecular diagnosis contributes to atypical Prader-Willi phenotype in monozygotic twins.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Sep}, pages = {2451-2455}, abstract = {

We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re-evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci.

}, keywords = {Adolescent, Base Sequence, Child, Chromosome Deletion, Chromosomes, Human, Pair 15, Comparative Genomic Hybridization, Exome, Facies, Female, Humans, Hyperventilation, Intellectual Disability, Obesity, Pathology, Molecular, Phenotype, Prader-Willi Syndrome, Transcription Factor 4, Twins, Monozygotic}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38315}, author = {Jehee, Fernanda S and de Oliveira, Valdirene T and Gurgel-Giannetti, Juliana and Pietra, Rafaella X and Rubatino, Fernando V M and Carobin, Nat{\'a}lia V and Vianna, Gabrielle S and de Freitas, Mariana L and Fernandes, Karla S and Ribeiro, Beatriz S V and Br{\"u}ggenwirth, Hennie T and Ali-Amin, Roza and White, Janson J and Akdemir, Zeynep C and Jhangiani, Shalini N and Gibbs, Richard A and Lupski, James R and Varela, Monica C and Koiffmann, C{\'e}lia and Rosenberg, Carla and Carvalho, Claudia M B} } @article {381, title = {Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Nov}, pages = {2906-2911}, abstract = {

Transport of activated nucleotide-sugars into the Golgi is critical for proper glycosylation and mutations in these transporters cause a group of rare genetic disorders termed congenital disorders of glycosylation. We performed exome sequencing on an individual with a profound neurological presentation and identified rare compound heterozygous mutations, p.Thr156Arg and p.Glu196Lys, in the CMP-sialic acid transporter, SLC35A1. Patient primary fibroblasts and serum showed a considerable decrease in the amount of N- and O-glycans terminating in sialic acid. Direct measurement of CMP-sialic acid transport into the Golgi showed a substantial decrease in overall rate of transport. Here we report the identification of the third patient with CMP-sialic acid transporter deficiency, who presented with severe neurological phenotype, but without hematological abnormalities.

}, keywords = {Animals, Brain Diseases, Child, CHO Cells, Cricetinae, Cricetulus, Female, Flow Cytometry, Golgi Apparatus, Humans, Mutation, N-Acetylneuraminic Acid, Nucleotide Transport Proteins, Whole Exome Sequencing}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38412}, author = {Ng, Bobby G and Asteggiano, Carla G and Kircher, Martin and Buckingham, Kati J and Raymond, Kimiyo and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Ensslen, Matthias and Freeze, Hudson H} } @article {57, title = {Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2.}, journal = {Genet Med}, volume = {19}, year = {2017}, month = {2017 01}, pages = {13-19}, abstract = {

PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.

METHODS: Twenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.

RESULTS: Three patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5\%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4\%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.

CONCLUSION: The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromatin, DNA Copy Number Variations, Female, Forkhead Transcription Factors, Humans, Infant, Male, Methyl-CpG-Binding Protein 2, Mutation, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases, Rett Syndrome, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/gim.2016.42}, author = {Sajan, Samin A and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and Glaze, Daniel G and Kaufmann, Walter E and Skinner, Steven A and Annese, Fran and Friez, Michael J and Lane, Jane and Percy, Alan K and Neul, Jeffrey L} } @article {635, title = {Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43\% of cases.}, journal = {Pediatr Nephrol}, volume = {32}, year = {2017}, month = {2017 Dec}, pages = {2273-2282}, abstract = {

BACKGROUND: Rhabdomyolysis is a clinical emergency that may cause acute kidney injury (AKI). It can be acquired or due to monogenic mutations. Around 60 different rare monogenic forms of rhabdomyolysis have been reported to date. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to nonspecific presentation, the high number of causative genes, and current lack of data on the prevalence of monogenic forms.

METHODS: We employed whole exome sequencing (WES) to reveal the percentage of rhabdomyolysis cases explained by single-gene (monogenic) mutations in one of 58 candidate genes. We investigated a cohort of 21 unrelated families with rhabdomyolysis, in whom no underlying etiology had been previously established.

RESULTS: Using WES, we identified causative mutations in candidate genes in nine of the 21 families (43\%). We detected disease-causing mutations in eight of 58 candidate genes, grouped into the following categories: (1) disorders of fatty acid metabolism (CPT2), (2) disorders of glycogen metabolism (PFKM and PGAM2), (3) disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A), and (4) disorders of purine metabolism (AHCY).

CONCLUSIONS: Our findings demonstrate a very high detection rate for monogenic etiologies using WES and reveal broad genetic heterogeneity for rhabdomyolysis. These results highlight the importance of molecular genetic diagnostics for establishing an etiologic diagnosis. Because these patients are at risk for recurrent episodes of rhabdomyolysis and subsequent risk for AKI, WES allows adequate prophylaxis and treatment for these patients and their family members and enables a personalized medicine approach.

}, keywords = {Adolescent, Adult, Arabs, Child, Exome, Genetic Predisposition to Disease, Humans, Jews, Mutation, Rhabdomyolysis, Whole Exome Sequencing}, issn = {1432-198X}, doi = {10.1007/s00467-017-3755-8}, author = {Vivante, Asaf and Ityel, Hadas and Pode-Shakked, Ben and Chen, Jing and Shril, Shirlee and van der Ven, Amelie T and Mann, Nina and Schmidt, Johanna Magdalena and Segel, Reeval and Aran, Adi and Zeharia, Avraham and Staretz-Chacham, Orna and Bar-Yosef, Omer and Raas-Rothschild, Annick and Landau, Yuval E and Lifton, Richard P and Anikster, Yair and Hildebrandt, Friedhelm} } @article {368, title = {An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a mutation.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {3}, year = {2017}, month = {2017 03}, pages = {a000984}, abstract = {

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in and , we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.

}, keywords = {Child, Child, Preschool, Cohort Studies, Exome, Eye Diseases, Hereditary, Facial Paralysis, Female, Humans, Infant, Male, Malformations of Cortical Development, Mobius Syndrome, Muscular Diseases, Mutation, Ocular Motility Disorders, Ophthalmoplegia, Orbital Diseases, Pedigree, Tubulin, Whole Exome Sequencing}, issn = {2373-2873}, doi = {10.1101/mcs.a000984}, author = {Patel, Ronak M and Liu, David and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Lu, James T and Sutton, V Reid and Fernbach, Susan D and Azamian, Mahshid and White, Lisa and Edmond, Jane C and Paysse, Evelyn A and Belmont, John W and Muzny, Donna and Lupski, James R and Gibbs, Richard A and Lewis, Richard Alan and Lee, Brendan H and Lalani, Seema R and Campeau, Philippe M} } @article {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 {369, title = {Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.}, journal = {Hum Genet}, volume = {136}, year = {2017}, month = {2017 04}, pages = {377-386}, abstract = {

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.

}, keywords = {Adolescent, Autism Spectrum Disorder, Carrier Proteins, Child, Child, Preschool, Cohort Studies, DNA Copy Number Variations, Facies, Female, Haploinsufficiency, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Ubiquitin-Protein Ligases}, issn = {1432-1203}, doi = {10.1007/s00439-017-1763-1}, author = {Zhang, Jing and Gambin, Tomasz and Yuan, Bo and Szafranski, Przemyslaw and Rosenfeld, Jill A and Balwi, Mohammed Al and Alswaid, Abdulrahman and Al-Gazali, Lihadh and Shamsi, Aisha M Al and Komara, Makanko and Ali, Bassam R and Roeder, Elizabeth and McAuley, Laura and Roy, Daniel S and Manchester, David K and Magoulas, Pilar and King, Lauren E and Hannig, Vickie and Bonneau, Dominique and Denomm{\'e}-Pichon, Anne-Sophie and Charif, Majida and Besnard, Thomas and B{\'e}zieau, St{\'e}phane and Cogn{\'e}, Benjamin and Andrieux, Joris and Zhu, Wenmiao and He, Weimin and Vetrini, Francesco and Ward, Patricia A and Cheung, Sau Wai and Bi, Weimin and Eng, Christine M and Lupski, James R and Yang, Yaping and Patel, Ankita and Lalani, Seema R and Xia, Fan and Stankiewicz, Pawe{\l}} } @article {388, title = {Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Aug 03}, pages = {267-273}, abstract = {

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in~all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5{\textquoteright}- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

}, keywords = {Adolescent, Adult, Atrophy, Brain, Brain Diseases, Cell Nucleolus, Child, Chromatin, DNA-Binding Proteins, Female, Humans, Male, Neurodegenerative Diseases, Pol1 Transcription Initiation Complex Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Ribosomal, 18S, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.07.002}, author = {Edvardson, Simon and Nicolae, Claudia M and Agrawal, Pankaj B and Mignot, Cyril and Payne, Katelyn and Prasad, Asuri Narayan and Prasad, Chitra and Sadler, Laurie and Nava, Caroline and Mullen, Thomas E and Begtrup, Amber and Baskin, Berivan and Powis, Z{\"o}e and Shaag, Avraham and Keren, Boris and Moldovan, George-Lucian and Elpeleg, Orly} } @article {391, title = {Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 10}, pages = {1365-1371}, abstract = {

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to β-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

}, keywords = {Actins, Adolescent, Child, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, DNA Helicases, DNA-Binding Proteins, Exome, Face, Female, Hand Deformities, Congenital, Heterozygote, Humans, Intellectual Disability, Male, Micrognathism, Multiprotein Complexes, Mutation, Missense, Nuclear Proteins, Protein Binding, Transcription Factors}, issn = {1098-1004}, doi = {10.1002/humu.23282}, author = {Marom, Ronit and Jain, Mahim and Burrage, Lindsay C and Song, I-Wen and Graham, Brett H and Brown, Chester W and Stevens, Servi J C and Stegmann, Alexander P A and Gunter, Andrew T and Kaplan, Julie D and Gavrilova, Ralitza H and Shinawi, Marwan and Rosenfeld, Jill A and Bae, Yangjin and Tran, Alyssa A and Chen, Yuqing and Lu, James T and Gibbs, Richard A and Eng, Christine and Yang, Yaping and Rousseau, Justine and de Vries, Bert B A and Campeau, Philippe M and Lee, Brendan} } @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 {382, title = {Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Sep 07}, pages = {441-450}, abstract = {

Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.

}, keywords = {Adolescent, Animals, Cerebellar Diseases, Child, Child, Preschool, Female, GTPase-Activating Proteins, HeLa Cells, Homozygote, Humans, Male, Microcephaly, Mutation, Pedigree, Phenotype, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.07.015}, author = {Marin-Valencia, Isaac and Gerondopoulos, Andreas and Zaki, Maha S and Ben-Omran, Tawfeg and Almureikhi, Mariam and Demir, Ercan and Guemez-Gamboa, Alicia and Gregor, Anne and Issa, Mahmoud Y and Appelhof, Bart and Roosing, Susanne and Musaev, Damir and Rosti, Basak and Wirth, Sara and Stanley, Valentina and Baas, Frank and Barr, Francis A and Gleeson, Joseph G} } @article {421, title = {Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness.}, journal = {Orphanet J Rare Dis}, volume = {12}, year = {2017}, month = {2017 11 17}, pages = {173}, abstract = {

BACKGROUND: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250~ng DNA was completed using an Illumina exome capture and a 38~Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants.

RESULTS: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13~T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease.

CONCLUSIONS: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, alpha-Glucosidases, Child, Child, Preschool, Cohort Studies, Female, Genetic Variation, Glycogen Storage Disease Type II, Humans, Male, Middle Aged, Muscle Weakness, Muscular Dystrophies, Limb-Girdle, Whole Exome Sequencing, Young Adult}, issn = {1750-1172}, doi = {10.1186/s13023-017-0722-1}, author = {Johnson, Katherine and Topf, Ana and Bertoli, Marta and Phillips, Lauren and Claeys, Kristl G and Stojanovic, Vidosava Rakocevic and Peri{\'c}, Stojan and Hahn, Andreas and Maddison, Paul and Akay, Ela and Bastian, Alexandra E and {\L}usakowska, Anna and Kostera-Pruszczyk, Anna and Lek, Monkol and Xu, Liwen and MacArthur, Daniel G and Straub, Volker} } @article {427, title = {Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Oct}, pages = {2763-2771}, abstract = {

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, Child, Female, Humans, Male, Mobius Syndrome, Muscular Diseases, Mutation, Pedigree, Pierre Robin Syndrome, Prognosis, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38375}, author = {Telegrafi, Aida and Webb, Bryn D and Robbins, Sarah M and Speck-Martins, Carlos E and FitzPatrick, David and Fleming, Leah and Redett, Richard and Dufke, Andreas and Houge, Gunnar and van Harssel, Jeske J T and Verloes, Alain and Robles, Angela and Manoli, Irini and Engle, Elizabeth C and Jabs, Ethylin W and Valle, David and Carey, John and Hoover-Fong, Julie E and Sobreira, Nara L M} } @article {359, title = {Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails.}, journal = {J Hum Genet}, volume = {62}, year = {2017}, month = {2017 Apr}, pages = {465-471}, abstract = {

Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.

}, keywords = {Abnormalities, Multiple, Adult, Carrier Proteins, Child, Child, Preschool, Diagnosis, Differential, Eczema, Eye Abnormalities, Face, Facies, Female, Growth Disorders, Hand Deformities, Congenital, Humans, Intellectual Disability, Karyotype, Limb Deformities, Congenital, Male, Microcephaly, Micrognathism, Mutation, Neck, Pathology, Molecular, Sequence Analysis, DNA, Ubiquitin-Protein Ligases}, issn = {1435-232X}, doi = {10.1038/jhg.2016.151}, author = {Kariminejad, Ariana and Ajeawung, Norbert Fonya and Bozorgmehr, Bita and Dionne-Laporte, Alexandre and Molidperee, Sirinart and Najafi, Kimia and Gibbs, Richard A and Lee, Brendan H and Hennekam, Raoul C and Campeau, Philippe M} } @article {389, title = {MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Sep}, pages = {2415-2421}, abstract = {

Multiple Epiphyseal Dysplasia (MED) is a relatively mild skeletal dysplasia characterized by mild short stature, joint pain, and early-onset osteoarthropathy. Dominantly inherited mutations in COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2, account for the molecular basis of disease in about 80-85\% of the cases. In two families with recurrent MED of an unknown molecular basis, we used exome sequencing and candidate gene analysis to identify homozygosity for recessively inherited missense mutations in CANT1, which encodes calcium-activated nucleotidase 1. The MED phenotype is thus allelic to the more severe Desbuquois dysplasia phenotype and the results identify CANT1 as a second locus for recessively inherited MED.

}, keywords = {Adult, Base Sequence, Child, Child, Preschool, Exome, Female, Genes, Recessive, Humans, Male, Mutation, Missense, Nucleotidases, Osteochondrodysplasias, Pedigree, Radiography}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38349}, author = {Balasubramanian, Karthika and Li, Bing and Krakow, Deborah and Nevarez, Lisette and Ho, Patric J and Ainsworth, Julia A and Nickerson, Deborah A and Bamshad, Michael J and Immken, LaDonna and Lachman, Ralph S and Cohn, Daniel H} } @article {338, title = {Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {117-127}, abstract = {

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in~situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in \~{}0.1\% of individuals with unexplained neurodevelopmental disorders.

}, keywords = {Adolescent, Adult, Amino Acid Substitution, Ataxia, Child, Child, Preschool, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, Developmental Disabilities, Exome, Face, Female, Gene Expression Regulation, Genes, Reporter, HEK293 Cells, Humans, Intellectual Disability, Language Development Disorders, Male, Models, Molecular, Mosaicism, Mutation, Neurodevelopmental Disorders, Protein Transport, Syndrome, Transcription Factors, Transcription, Genetic}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.012}, author = {Harms, Frederike Leonie and Girisha, Katta M and Hardigan, Andrew A and Kort{\"u}m, Fanny and Shukla, Anju and Alawi, Malik and Dalal, Ashwin and Brady, Lauren and Tarnopolsky, Mark and Bird, Lynne M and Ceulemans, Sophia and Bebin, Martina and Bowling, Kevin M and Hiatt, Susan M and Lose, Edward J and Primiano, Michelle and Chung, Wendy K and Juusola, Jane and Akdemir, Zeynep C and Bainbridge, Matthew and Charng, Wu-Lin and Drummond-Borg, Margaret and Eldomery, Mohammad K and El-Hattab, Ayman W and Saleh, Mohammed A M and B{\'e}zieau, St{\'e}phane and Cogn{\'e}, Benjamin and Isidor, Bertrand and K{\"u}ry, S{\'e}bastien and Lupski, James R and Myers, Richard M and Cooper, Gregory M and Kutsche, Kerstin} } @article {422, title = {Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {815-823}, abstract = {

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo~FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70~kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.

}, keywords = {Adolescent, Adult, Bone and Bones, Bone Diseases, Developmental, Cartilage, Child, Child, Preschool, Exome, Female, Fibronectins, Fractures, Bone, Humans, Male, Mutation, Osteochondrodysplasias, Phenotype, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.019}, author = {Lee, Chae Syng and Fu, He and Baratang, Nissan and Rousseau, Justine and Kumra, Heena and Sutton, V Reid and Niceta, Marcello and Ciolfi, Andrea and Yamamoto, Guilherme and Bertola, D{\'e}bora and Marcelis, Carlo L and Lugtenberg, Dorien and Bartuli, Andrea and Kim, Choel and Hoover-Fong, Julie and Sobreira, Nara and Pauli, Richard and Bacino, Carlos and Krakow, Deborah and Parboosingh, Jillian and Yap, Patrick and Kariminejad, Ariana and McDonald, Marie T and Aracena, Mariana I and Lausch, Ekkehart and Unger, Sheila and Superti-Furga, Andrea and Lu, James T and Cohn, Dan H and Tartaglia, Marco and Lee, Brendan H and Reinhardt, Dieter P and Campeau, Philippe M} } @article {493, title = {Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {856-865}, abstract = {

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs102] and c.920delG [p.Gly307Alafs11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

}, keywords = {Acyltransferases, Adolescent, Adult, Alleles, Atrophy, Bone Diseases, Metabolic, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Epilepsy, Exome, Female, Fibroblasts, Glycosylphosphatidylinositols, Humans, Male, Membrane Glycoproteins, Muscle Hypotonia, Mutation, Pedigree, RNA, Messenger, Seizures}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.020}, author = {Nguyen, Thi Tuyet Mai and Murakami, Yoshiko and Sheridan, Eamonn and Ehresmann, Sophie and Rousseau, Justine and St-Denis, Anik and Chai, Guoliang and Ajeawung, Norbert F and Fairbrother, Laura and Reimschisel, Tyler and Bateman, Alexandra and Berry-Kravis, Elizabeth and Xia, Fan and Tardif, Jessica and Parry, David A and Logan, Clare V and Diggle, Christine and Bennett, Christopher P and Hattingh, Louise and Rosenfeld, Jill A and Perry, Michael Scott and Parker, Michael J and Le Deist, Fran{\c c}oise and Zaki, Maha S and Ignatius, Erika and Isohanni, Pirjo and L{\"o}nnqvist, Tuula and Carroll, Christopher J and Johnson, Colin A and Gleeson, Joseph G and Kinoshita, Taroh and Campeau, Philippe M} } @article {387, title = {Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, abstract = {

BACKGROUND: Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous disease and, although increasingly recognized in clinical practice, there is a lack of widely accepted diagnostic criteria. We sought to identify novel genetic causes of LVNC and describe genotype-phenotype correlations.

METHODS AND RESULTS: A total of 190 patients from 174 families with left ventricular hypertrabeculation (LVHT) or LVNC were referred for cardiac magnetic resonance and whole-exome sequencing. A total of 425 control individuals were included to identify variants of interest (VOIs). We found an excess of 138 VOIs in 102 (59\%) unrelated patients in 54 previously identified LVNC or other known cardiomyopathy genes. VOIs were found in 68 of 90 probands with LVNC and 34 of 84 probands with LVHT (76\% and 40\%, respectively; <0.001). We identified 0, 1, and >=2 VOIs in 72, 74, and 28 probands, respectively. We found increasing number of VOIs in a patient strongly correlated with several markers of disease severity, including ratio of noncompacted to compacted myocardium (<0.001) and left ventricular ejection fraction (=0.01). The presence of sarcomeric gene mutations was associated with increased occurrence of late gadolinium enhancement (=0.004).

CONCLUSIONS: LVHT and LVNC likely represent a continuum of genotypic disease with differences in severity and variable phenotype explained, in part, by the number of VOIs and whether mutations are present in sarcomeric or nonsarcomeric genes. Presence of VOIs is common in patients with LVHT. Our findings expand the current clinical and genetic diagnostic approaches for patients with LVHT and LVNC.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Cardiac Myosins, Carrier Proteins, Child, Connectin, Female, Genetic Association Studies, Genetic Variation, Heart Ventricles, Humans, LIM Domain Proteins, Magnetic Resonance Imaging, Cine, Male, Middle Aged, Muscle Proteins, Myocardium, Myosin Heavy Chains, Prospective Studies, Severity of Illness Index, Tropomyosin, Ventricular Dysfunction, Left, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.117.001763}, author = {Miszalski-Jamka, Karol and Jefferies, John L and Mazur, Wojciech and G{\l}owacki, Jan and Hu, Jianhong and Lazar, Monika and Gibbs, Richard A and Liczko, Jacek and K{\l}y{\'s}, Jan and Venner, Eric and Muzny, Donna M and Rycaj, Jaros{\l}aw and Bia{\l}kowski, Jacek and Kluczewska, Ewa and Kalarus, Zbigniew and Jhangiani, Shalini and Al-Khalidi, Hussein and Kukulski, Tomasz and Lupski, James R and Craigen, William J and Bainbridge, Matthew N} } @article {396, title = {A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Aug}, pages = {2246-2250}, abstract = {

GMPPA encodes the GDP-mannose pyrophosphorylase A protein (GMPPA). The function of GMPPA is not well defined, however it is a homolog of GMPPB which catalyzes the reaction that converts mannose-1-phosphate and guanosine-5{\textquoteright}-triphosphate to GDP-mannose. Previously, biallelic mutations in GMPPA were reported to cause a disorder characterized by achalasia, alacrima, neurological deficits, and intellectual disability. In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP-mannose in lymphoblasts on high performance liquid chromatography. Based on our findings and the previous report describing patients with an overlapping phenotype, we conclude that this novel variant in GMPPA, identified by exome sequencing in the proband and her affected sister, is the genetic cause of their phenotype and may expand the known phenotype of this recently described glycosylation disorder.

}, keywords = {Abnormalities, Multiple, Child, Child, Preschool, Craniofacial Abnormalities, Epilepsy, Exome, Facies, Female, Heterozygote, Humans, Intellectual Disability, Microcephaly, Muscular Atrophy, Mutation, Missense, Nucleotidyltransferases, Pedigree, Phenotype, Seizures}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38292}, author = {Gold, Wendy A and Sobreira, Nara and Wiame, Elsa and Marbaix, Alexandre and Van Schaftingen, Emile and Franzka, Patricia and Riley, Lisa G and Worgan, Lisa and H{\"u}bner, Christian A and Christodoulou, John and Ad{\`e}s, Lesley C} } @article {454, title = {P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye.}, journal = {Hum Mol Genet}, volume = {26}, year = {2017}, month = {2017 06 15}, pages = {2207-2217}, abstract = {

Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient. Similar to P4ha1 null mice, which die prenatally, the muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane. Patients were compound heterozygous for frameshift and splice site mutations leading to reduced, but not absent, P4HA1 protein level and C-P4H activity in dermal fibroblasts compared to age-matched control samples. Differential scanning calorimetry revealed reduced thermal stability of collagen in patient-derived dermal fibroblasts versus age-matched control samples. Mutations affecting the family of C-P4Hs, and in particular C-P4H-I, should be considered in patients presenting with congenital connective tissue/myopathy overlap disorders with joint hypermobility, contractures, mild skeletal dysplasia and high myopia.

}, keywords = {Animals, Basement Membrane, Bone and Bones, Child, Collagen Type IV, Connective Tissue, Humans, Male, Mice, Mice, Knockout, Muscles, Mutation, Osteochondrodysplasias, Procollagen-Proline Dioxygenase, Prolyl Hydroxylases, Tendons}, issn = {1460-2083}, doi = {10.1093/hmg/ddx110}, author = {Zou, Yaqun and Donkervoort, Sandra and Salo, Antti M and Foley, A Reghan and Barnes, Aileen M and Hu, Ying and Makareeva, Elena and Leach, Meganne E and Mohassel, Payam and Dastgir, Jahannaz and Deardorff, Matthew A and Cohn, Ronald D and DiNonno, Wendy O and Malfait, Fransiska and Lek, Monkol and Leikin, Sergey and Marini, Joan C and Myllyharju, Johanna and B{\"o}nnemann, Carsten G} } @article {433, title = {Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 12}, pages = {1335-1344}, abstract = {

Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.

}, keywords = {Abnormalities, Multiple, Case-Control Studies, Child, DNA Methylation, Face, Female, Hematologic Diseases, Histone-Lysine N-Methyltransferase, Humans, Loss of Function Mutation, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Vestibular Diseases}, issn = {1476-5438}, doi = {10.1038/s41431-017-0023-0}, author = {Sobreira, Nara and Brucato, Martha and Zhang, Li and Ladd-Acosta, Christine and Ongaco, Chrissie and Romm, Jane and Doheny, Kimberly F and Mingroni-Netto, Regina C and Bertola, D{\'e}bora and Kim, Chong A and Perez, Ana Ba and Melaragno, Maria I and Valle, David and Meloni, Vera A and Bjornsson, Hans T} } @article {442, title = {Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 08 14}, pages = {73}, abstract = {

BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.

METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.

RESULTS: We demonstrate greater than expected phenotypic heterogeneity, including 33\% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.

CONCLUSIONS: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

}, keywords = {Adolescent, Adult, CDC2 Protein Kinase, Child, Child, Preschool, Face, Female, Heart Defects, Congenital, Humans, Infant, Intellectual Disability, Male, Mutation, Phenotype, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-017-0463-8}, author = {Bostwick, Bret L and McLean, Scott and Posey, Jennifer E and Streff, Haley E and Gripp, Karen W and Blesson, Alyssa and Powell-Hamilton, Nina and Tusi, Jessica and Stevenson, David A and Farrelly, Ellyn and Hudgins, Louanne and Yang, Yaping and Xia, Fan and Wang, Xia and Liu, Pengfei and Walkiewicz, Magdalena and McGuire, Marianne and Grange, Dorothy K and Andrews, Marisa V and Hummel, Marybeth and Madan-Khetarpal, Suneeta and Infante, Elena and Coban-Akdemir, Zeynep and Miszalski-Jamka, Karol and Jefferies, John L and Rosenfeld, Jill A and Emrick, Lisa and Nugent, Kimberly M and Lupski, James R and Belmont, John W and Lee, Brendan and Lalani, Seema R} } @article {399, title = {Phenotypic spectrum of autosomal recessive congenital ichthyosis due to PNPLA1 mutation.}, journal = {Br J Dermatol}, volume = {177}, year = {2017}, month = {2017 07}, pages = {319-322}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Heterozygote, Homozygote, Humans, Ichthyosis, Infant, Lipase, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Young Adult}, issn = {1365-2133}, doi = {10.1111/bjd.15570}, author = {Boyden, L M and Craiglow, B G and Hu, R H and Zhou, J and Browning, J and Eichenfield, L and Lim, Y L and Luu, M and Randolph, L M and Ginarte, M and Fachal, L and Rodriguez-Pazos, L and Vega, A and Kramer, D and Yosipovitch, G and Vahidnezhad, H and Youssefian, L and Uitto, J and Lifton, R P and Paller, A S and Milstone, L M and Choate, K A} } @article {27, title = {Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.}, journal = {J Allergy Clin Immunol}, volume = {139}, year = {2017}, month = {2017 Jan}, pages = {232-245}, abstract = {

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.

OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.

METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.

RESULTS: A likely molecular diagnosis was achieved in 110 (40\%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30~Kb that would not have been detected with conventional diagnostic CNV arrays.

CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

}, keywords = {Adolescent, Adult, Aged, Child, Child, Preschool, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Infant, Male, Middle Aged, Young Adult}, issn = {1097-6825}, doi = {10.1016/j.jaci.2016.05.042}, author = {Stray-Pedersen, Asbj{\o}rg and Sorte, Hanne S{\o}rmo and Samarakoon, Pubudu and Gambin, Tomasz and Chinn, Ivan K and Coban Akdemir, Zeynep H and Erichsen, Hans Christian and Forbes, Lisa R and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Muzny, Donna M and R{\o}dningen, Olaug Kristin and Sheng, Ying and Nicholas, Sarah K and Noroski, Lenora M and Seeborg, Filiz O and Davis, Carla M and Canter, Debra L and Mace, Emily M and Vece, Timothy J and Allen, Carl E and Abhyankar, Harshal A and Boone, Philip M and Beck, Christine R and Wiszniewski, Wojciech and Fevang, B{\o}rre and Aukrust, P{\r a}l and Tj{\o}nnfjord, Geir E and Gedde-Dahl, Tobias and Hjorth-Hansen, Henrik and Dybedal, Ingunn and Nord{\o}y, Ingvild and J{\o}rgensen, Silje F and Abrahamsen, Tore G and {\O}verland, Torstein and Bechensteen, Anne Grete and Skogen, Vegard and Osnes, Liv T N and Kulseth, Mari Ann and Prescott, Trine E and Rustad, Cecilie F and Heimdal, Ketil R and Belmont, John W and Rider, Nicholas L and Chinen, Javier and Cao, Tram N and Smith, Eric A and Caldirola, Maria Soledad and Bezrodnik, Liliana and Lugo Reyes, Saul Oswaldo and Espinosa Rosales, Francisco J and Guerrero-Cursaru, Nina Denisse and Pedroza, Luis Alberto and Poli, Cecilia M and Franco, Jose L and Trujillo Vargas, Claudia M and Aldave Becerra, Juan Carlos and Wright, Nicola and Issekutz, Thomas B and Issekutz, Andrew C and Abbott, Jordan and Caldwell, Jason W and Bayer, Diana K and Chan, Alice Y and Aiuti, Alessandro and Cancrini, Caterina and Holmberg, Eva and West, Christina and Burstedt, Magnus and Karaca, Ender and Yesil, G{\"o}zde and Artac, Hasibe and Bayram, Yavuz and Atik, Mehmed Musa and Eldomery, Mohammad K and Ehlayel, Mohammad S and Jolles, Stephen and Flat{\o}, Berit and Bertuch, Alison A and Hanson, I Celine and Zhang, Victor W and Wong, Lee-Jun and Hu, Jianhong and Walkiewicz, Magdalena and Yang, Yaping and Eng, Christine M and Boerwinkle, Eric and Gibbs, Richard A and Shearer, William T and Lyle, Robert and Orange, Jordan S and Lupski, James R} } @article {355, title = {PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.}, journal = {Brain}, volume = {140}, year = {2017}, month = {2017 Apr 01}, pages = {940-952}, abstract = {

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

}, keywords = {Adolescent, Brain, Carrier Proteins, Cell Differentiation, Cell Movement, Cerebral Cortex, Child, Child, Preschool, Cytoskeleton, Developmental Disabilities, Female, Genes, Recessive, Heredodegenerative Disorders, Nervous System, Humans, Infant, Male, Microcephaly, Microtubules, Mutation, Pedigree, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awx014}, author = {Zollo, Massimo and Ahmed, Mustafa and Ferrucci, Veronica and Salpietro, Vincenzo and Asadzadeh, Fatemeh and Carotenuto, Marianeve and Maroofian, Reza and Al-Amri, Ahmed and Singh, Royana and Scognamiglio, Iolanda and Mojarrad, Majid and Musella, Luca and Duilio, Angela and Di Somma, Angela and Karaca, Ender and Rajab, Anna and Al-Khayat, Aisha and Mohan Mohapatra, Tribhuvan and Eslahi, Atieh and Ashrafzadeh, Farah and Rawlins, Lettie E and Prasad, Rajniti and Gupta, Rashmi and Kumari, Preeti and Srivastava, Mona and Cozzolino, Flora and Kumar Rai, Sunil and Monti, Maria and Harlalka, Gaurav V and Simpson, Michael A and Rich, Philip and Al-Salmi, Fatema and Patton, Michael A and Chioza, Barry A and Efthymiou, Stephanie and Granata, Francesca and Di Rosa, Gabriella and Wiethoff, Sarah and Borgione, Eugenia and Scuderi, Carmela and Mankad, Kshitij and Hanna, Michael G and Pucci, Piero and Houlden, Henry and Lupski, James R and Crosby, Andrew H and Baple, Emma L} } @article {334, title = {A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {343-351}, abstract = {

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who~underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p~= 1.25~{\texttimes} 10). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.

}, keywords = {Alleles, Amino Acid Sequence, Brain, Cataract, Child, Child, Preschool, Female, Genetic Variation, Genome-Wide Association Study, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Missense, Neoplasm Proteins, Pedigree, Phenotype, Repressor Proteins, Spasms, Infantile}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.12.013}, author = {Schoch, Kelly and Meng, Linyan and Szelinger, Szabolcs and Bearden, David R and Stray-Pedersen, Asbjorg and Busk, Oyvind L and Stong, Nicholas and Liston, Eriskay and Cohn, Ronald D and Scaglia, Fernando and Rosenfeld, Jill A and Tarpinian, Jennifer and Skraban, Cara M and Deardorff, Matthew A and Friedman, Jeremy N and Akdemir, Zeynep Coban and Walley, Nicole and Mikati, Mohamad A and Kranz, Peter G and Jasien, Joan and McConkie-Rosell, Allyn and McDonald, Marie and Wechsler, Stephanie Burns and Freemark, Michael and Kansagra, Sujay and Freedman, Sharon and Bali, Deeksha and Millan, Francisca and Bale, Sherri and Nelson, Stanley F and Lee, Hane and Dorrani, Naghmeh and Goldstein, David B and Xiao, Rui and Yang, Yaping and Posey, Jennifer E and Martinez-Agosto, Julian A and Lupski, James R and Wangler, Michael F and Shashi, Vandana} } @article {356, title = {Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.}, journal = {Am J Med Genet B Neuropsychiatr Genet}, volume = {174}, year = {2017}, month = {2017 Jun}, pages = {381-389}, abstract = {

Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5\% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8\%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. {\textcopyright} 2017 Wiley Periodicals, Inc.

}, keywords = {Adult, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Biomarkers, Child, Exome, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Missense, Phenotype}, issn = {1552-485X}, doi = {10.1002/ajmg.b.32527}, author = {Kim, Daniel Seung and Burt, Amber A and Ranchalis, Jane E and Wilmot, Beth and Smith, Joshua D and Patterson, Karynne E and Coe, Bradley P and Li, Yatong K and Bamshad, Michael J and Nikolas, Molly and Eichler, Evan E and Swanson, James M and Nigg, Joel T and Nickerson, Deborah A and Jarvik, Gail P} } @article {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 {19, title = {Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.}, journal = {Genet Med}, volume = {19}, year = {2017}, month = {2017 Apr}, pages = {412-420}, abstract = {

PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

RESULTS: In approximately 5\% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.

CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.

}, keywords = {Adolescent, Child, Child, Preschool, DNA Copy Number Variations, Exome Sequencing, Female, Forkhead Transcription Factors, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-beta, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Nuclear Proteins, PAX2 Transcription Factor, Pedigree, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatases, Repressor Proteins, Urogenital Abnormalities, Vesico-Ureteral Reflux, Young Adult}, issn = {1530-0366}, doi = {10.1038/gim.2016.131}, author = {Bekheirnia, Mir Reza and Bekheirnia, Nasim and Bainbridge, Matthew N and Gu, Shen and Coban Akdemir, Zeynep Hande and Gambin, Tomek and Janzen, Nicolette K and Jhangiani, Shalini N and Muzny, Donna M and Michael, Mini and Brewer, Eileen D and Elenberg, Ewa and Kale, Arundhati S and Riley, Alyssa A and Swartz, Sarah J and Scott, Daryl A and Yang, Yaping and Srivaths, Poyyapakkam R and Wenderfer, Scott E and Bodurtha, Joann and Applegate, Carolyn D and Velinov, Milen and Myers, Angela and Borovik, Lior and Craigen, William J and Hanchard, Neil A and Rosenfeld, Jill A and Lewis, Richard Alan and Gonzales, Edmond T and Gibbs, Richard A and Belmont, John W and Roth, David R and Eng, Christine and Braun, Michael C and Lupski, James R and Lamb, Dolores J} } @article {20, title = {ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment.}, journal = {Proc Natl Acad Sci U S A}, volume = {113}, year = {2016}, month = {2016 Oct 04}, pages = {11289-11293}, abstract = {

Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient{\textquoteright}s liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.

}, keywords = {Ataxia, Bile Acids and Salts, Child, Cognitive Dysfunction, Homozygote, Humans, Infant, Infant, Newborn, Liver, Liver Cirrhosis, Loss of Function Mutation, Male, Mutation, Oxidation-Reduction, Oxidoreductases, Transaminases}, issn = {1091-6490}, doi = {10.1073/pnas.1613228113}, author = {Vilarinho, S{\'\i}lvia and Sari, Sinan and Mazzacuva, Francesca and Bilguvar, Kaya and Esendagli-Yilmaz, G{\"u}ldal and Jain, Dhanpat and Akyol, G{\"u}len and Dalgi{\c c}, Buket and G{\"u}nel, Murat and Clayton, Peter T and Lifton, Richard P} } @article {113, title = {Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.}, journal = {Endocrine}, volume = {51}, year = {2016}, month = {2016 Feb}, pages = {236-44}, abstract = {

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 {\texttimes} 23.9 {\texttimes} 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 {\texttimes} 58.1 {\texttimes} 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

}, keywords = {Adenoma, Child, Genetic Diseases, X-Linked, Gigantism, Humans, Male, Pituitary Neoplasms, Treatment Outcome}, issn = {1559-0100}, doi = {10.1007/s12020-015-0804-6}, author = {Naves, Luciana A and Daly, Adrian F and Dias, Luiz Augusto and Yuan, Bo and Zakir, Juliano Coelho Oliveira and Barra, Gustavo Barcellos and Palmeira, Leonor and Villa, Chiara and Trivellin, Giampaolo and J{\'u}nior, Armindo Jreige and Neto, Flor{\^e}ncio Figueiredo Cavalcante and Liu, Pengfei and Pellegata, Natalia S and Stratakis, Constantine A and Lupski, James R and Beckers, Albert} } @article {118, title = {Assessment of estimated retinal atrophy progression in Stargardt macular dystrophy using spectral-domain optical coherence tomography.}, journal = {Br J Ophthalmol}, volume = {100}, year = {2016}, month = {2016 Jul}, pages = {956-962}, abstract = {

AIMS: To estimate disease progression based on analysis of macular volume measured by spectral-domain optical coherence tomography (SD-OCT) in patients affected by Stargardt macular dystrophy (STGD1) and to evaluate the influence of software errors on these measurements.

METHODS: 58 eyes of 29 STGD1 patients were included. Numbers and types of algorithm errors were recorded and manually corrected. In a subgroup of 36 eyes of 18 patients with at least two examinations over time, total macular volume (TMV) and volumes of all nine Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields were obtained. Random effects models were used to estimate the rate of change per year for the population, and empirical Bayes slopes were used to estimate yearly decline in TMV for individual eyes.

RESULTS: 6958 single B-scans from 190 macular cube scans were analysed. 2360 (33.9\%) showed algorithm errors. Mean observation period for follow-up data was 15 months (range 3-40). The median (IQR) change in TMV using the empirical Bayes estimates for the individual eyes was -0.103 (-0.145, -0.059) mm per year. The mean ({\textpm}SD) TMV was 6.321{\textpm}1.000 mm at baseline, and rate of decline was -0.118 mm per year (p=0.003). Yearly mean volume change was -0.004 mm in the central subfield (mean baseline=0.128 mm), -0.032 mm in the inner (mean baseline=1.484 mm) and -0.079 mm in the outer ETDRS subfields (mean baseline=5.206 mm).

CONCLUSIONS: SD-OCT measurements allow monitoring the decline in retinal volume in STGD1; however, they require significant manual correction of software errors.

}, keywords = {Adolescent, Adult, Aged, Child, Disease Progression, Female, Humans, Macula Lutea, Macular Degeneration, Male, Middle Aged, Reproducibility of Results, Retrospective Studies, Tomography, Optical Coherence, Visual Acuity, Young Adult}, issn = {1468-2079}, doi = {10.1136/bjophthalmol-2015-307035}, author = {Strauss, Rupert W and Mu{\~n}oz, Beatriz and Wolfson, Yulia and Sophie, Raafay and Fletcher, Emily and Bittencourt, Millena G and Scholl, Hendrik P N} } @article {58, title = {Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 07 01}, pages = {836-845}, abstract = {

IMPORTANCE: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality.

OBJECTIVE: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.

DESIGN, SETTING, AND PARTICIPANTS: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children{\textquoteright}s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.

RESULTS: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.

CONCLUSIONS AND RELEVANCE: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.

}, keywords = {Adolescent, Adult, Amino Acids, Animals, Cells, Cultured, Cerebral Cortex, Child, Child, Preschool, Developmental Disabilities, Embryo, Mammalian, Female, Gene Expression Regulation, Genetic Association Studies, Humans, Intercellular Signaling Peptides and Proteins, Male, Malformations of Cortical Development, Mechanistic Target of Rapamycin Complex 1, Megalencephaly, Mosaicism, Multiprotein Complexes, Mutation, Nerve Tissue Proteins, Neurons, Rats, Retrospective Studies, TOR Serine-Threonine Kinases, Young Adult}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2016.0363}, author = {Mirzaa, Ghayda M and Campbell, Catarina D and Solovieff, Nadia and Goold, Carleton and Jansen, Laura A and Menon, Suchithra and Timms, Andrew E and Conti, Valerio and Biag, Jonathan D and Adams, Carissa and Boyle, Evan August and Collins, Sarah and Ishak, Gisele and Poliachik, Sandra and Girisha, Katta M and Yeung, Kit San and Chung, Brian Hon Yin and Rahikkala, Elisa and Gunter, Sonya A and McDaniel, Sharon S and Macmurdo, Colleen Forsyth and Bernstein, Jonathan A and Martin, Beth and Leary, Rebecca and Mahan, Scott and Liu, Shanming and Weaver, Molly and Doerschner, Michael and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Shendure, Jay and Saneto, Russell P and Novotny, Edward J and Wilson, Christopher J and Sellers, William R and Morrissey, Michael and Hevner, Robert F and Ojemann, Jeffrey G and Guerrini, Renzo and Murphy, Leon O and Winckler, Wendy and Dobyns, William B} } @article {49, title = {Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Jun 02}, pages = {1146-1158}, abstract = {

Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in~vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.

}, keywords = {Adolescent, Adult, Cerebellar Ataxia, Child, Chromosome Aberrations, Chromosomes, Human, Pair 7, Exome, Female, Genetic Linkage, Genotype, High-Throughput Nucleotide Sequencing, Humans, Intracellular Signaling Peptides and Proteins, Loss of Heterozygosity, Male, Middle Aged, Mutation, Missense, Pancytopenia, Pedigree, Proteins, Tumor Suppressor Proteins, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.009}, author = {Chen, Dong-Hui and Below, Jennifer E and Shimamura, Akiko and Keel, Sioban B and Matsushita, Mark and Wolff, John and Sul, Youngmee and Bonkowski, Emily and Castella, Maria and Taniguchi, Toshiyasu and Nickerson, Deborah and Papayannopoulou, Thalia and Bird, Thomas D and Raskind, Wendy H} } @article {37, title = {Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Aug 04}, pages = {501-10}, abstract = {

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

}, keywords = {Alleles, Apoptosis, Centrosome, Child, Child, Preschool, Cytokinesis, Female, Genes, Recessive, Humans, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Male, Microcephaly, Mitosis, Mutation, Missense, Pedigree, Protein Serine-Threonine Kinases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.07.004}, author = {Li, Hongda and Bielas, Stephanie L and Zaki, Maha S and Ismail, Samira and Farfara, Dorit and Um, Kyongmi and Rosti, Rasim O and Scott, Eric C and Tu, Shu and Chi, Neil C and Gabriel, Stacey and Erson-Omay, Emine Z and Ercan-Sencicek, A Gulhan and Yasuno, Katsuhito and {\c C}a{\u g}layan, Ahmet Okay and Kaymak{\c c}alan, Hande and Ekici, Bar{\i}{\c s} and Bilguvar, Kaya and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {99, title = {Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Jan 07}, pages = {202-9}, abstract = {

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. UNC80 is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Loss-of-function mutations of NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF). We report four individuals from three unrelated families who have homozygous missense or compound heterozygous truncating mutations in UNC80 and persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability. Compared to control cells, HEK293T cells transfected with an expression plasmid containing the c.5098C>T (p.Pro1700Ser) UNC80 mutation found in one individual showed markedly decreased NALCN channel currents. Our findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health.

}, keywords = {Adolescent, Alleles, Brain Diseases, Carrier Proteins, Child, Child, Preschool, Female, Growth Disorders, Humans, Intellectual Disability, Membrane Proteins, Muscle Hypotonia, Mutation, Severity of Illness Index}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.11.004}, author = {Stray-Pedersen, Asbj{\o}rg and Cobben, Jan-Maarten and Prescott, Trine E and Lee, Sora and Cang, Chunlei and Aranda, Kimberly and Ahmed, Sohnee and Alders, Marielle and Gerstner, Thorsten and Aslaksen, Kathinka and T{\'e}treault, Martine and Qin, Wen and Hartley, Taila and Jhangiani, Shalini N and Muzny, Donna M and Tarailo-Graovac, Maja and van Karnebeek, Clara D M and Lupski, James R and Ren, Dejian and Yoon, Grace} } @article {30, title = {Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Aug 04}, pages = {318-36}, abstract = {

Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5\%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture.

}, keywords = {Adolescent, Adult, Alleles, Animals, Bardet-Biedl Syndrome, Child, Child, Preschool, Chromosome Breakpoints, Cytoskeletal Proteins, DNA Copy Number Variations, Exons, Female, Gastrulation, Genes, Recessive, Humans, Infant, Male, Mutation, Pedigree, Young Adult, Zebrafish, Zebrafish Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.04.023}, author = {Lindstrand, Anna and Frangakis, Stephan and Carvalho, Claudia M B and Richardson, Ellen B and McFadden, Kelsey A and Willer, Jason R and Pehlivan, Davut and Liu, Pengfei and Pediaditakis, Igor L and Sabo, Aniko and Lewis, Richard Alan and Banin, Eyal and Lupski, James R and Davis, Erica E and Katsanis, Nicholas} } @article {414, title = {De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 12}, pages = {1399-1409}, abstract = {

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Exome, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heart Defects, Congenital, Humans, Intellectual Disability, Male, Mutation, Missense, Phosphorylation, Protein Phosphatase 1}, issn = {1432-1203}, doi = {10.1007/s00439-016-1731-1}, author = {Ma, Lijiang and Bayram, Yavuz and McLaughlin, Heather M and Cho, Megan T and Krokosky, Alyson and Turner, Clesson E and Lindstrom, Kristin and Bupp, Caleb P and Mayberry, Katey and Mu, Weiyi and Bodurtha, Joann and Weinstein, Veronique and Zadeh, Neda and Alcaraz, Wendy and Powis, Z{\"o}e and Shao, Yunru and Scott, Daryl A and Lewis, Andrea M and White, Janson J and Jhangiani, Shalani N and Gulec, Elif Yilmaz and Lalani, Seema R and Lupski, James R and Retterer, Kyle and Schnur, Rhonda E and Wentzensen, Ingrid M and Bale, Sherri and Chung, Wendy K} } @article {94, title = {Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.}, journal = {Clin Genet}, volume = {90}, year = {2016}, month = {2016 10}, pages = {351-60}, abstract = {

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.

}, keywords = {Adolescent, Adult, Animals, Child, Child, Preschool, Cohort Studies, Esophageal Achalasia, Female, Humans, Hypertension, Infant, Male, Middle Aged, Moyamoya Disease, Mutation, Nitric Oxide, Nonlinear Dynamics, Regression Analysis, Sf9 Cells, Signal Transduction, Soluble Guanylyl Cyclase}, issn = {1399-0004}, doi = {10.1111/cge.12739}, author = {Wallace, S and Guo, D-C and Regalado, E and Mellor-Crummey, L and Bamshad, M and Nickerson, D A and Dauser, R and Hanchard, N and Marom, R and Martin, E and Berka, V and Sharina, I and Ganesan, V and Saunders, D and Morris, S A and Milewicz, D M} } @article {114, title = {Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Jan 15}, pages = {348-57}, abstract = {

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.

}, keywords = {Amino Acid Sequence, Cardiomyopathies, Child, Child, Preschool, Connexin 43, Desmoplakins, Desmosomes, Female, Humans, Infant, Male, Molecular Sequence Data, Mutation, Missense, Myocardium, Protein Transport, Sequence Alignment, Skin, Skin Diseases, Genetic, Syndrome}, issn = {1460-2083}, doi = {10.1093/hmg/ddv481}, author = {Boyden, Lynn M and Kam, Chen Y and Hern{\'a}ndez-Mart{\'\i}n, Angela and Zhou, Jing and Craiglow, Brittany G and Sidbury, Robert and Mathes, Erin F and Maguiness, Sheilagh M and Crumrine, Debra A and Williams, Mary L and Hu, Ronghua and Lifton, Richard P and Elias, Peter M and Green, Kathleen J and Choate, Keith A} } @article {100, title = {Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability.}, journal = {Eur J Hum Genet}, volume = {24}, year = {2016}, month = {2016 08}, pages = {1223-7}, abstract = {

Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the β-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.

}, keywords = {Adolescent, Adult, Alopecia, Child, Female, Humans, Integrin beta Chains, Intellectual Disability, Male, Mutation, Missense, Pedigree, Phenotype, Protein Domains, Syndrome, Tooth Abnormalities}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.260}, author = {Ansar, Muhammad and Jan, Abid and Santos-Cortez, Regie Lyn P and Wang, Xin and Suliman, Muhammad and Acharya, Anushree and Habib, Rabia and Abbe, Izoduwa and Ali, Ghazanfar and Lee, Kwanghyuk and Smith, Joshua D and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Ahmad, Wasim and Leal, Suzanne M} } @article {105, title = {Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 08}, pages = {788-95}, abstract = {

PURPOSE: The pace of Mendelian gene discovery is slowed by the "n-of-1 problem"-the difficulty of establishing the causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier, but it is often impeded by lack of a convenient or widely available way to share data on candidate variants/genes among families, clinicians, and researchers.

METHODS: Social networking among families, clinicians, and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.

RESULTS: De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.

CONCLUSION: Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with nonspecific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP; http://uwcmg.org/$\#$/family). Design and development of MyGene2 (http://www.mygene2.org), a Web-based tool that enables families, clinicians, and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP, is under way.Genet Med 18 8, 788-795.

}, keywords = {Child, Child, Preschool, Databases, Factual, Developmental Disabilities, Female, Genetic Association Studies, Histone Demethylases, Humans, Information Dissemination, Male, Mutation, Missense, Phenotype, Social Networking, Web Browser}, issn = {1530-0366}, doi = {10.1038/gim.2015.161}, author = {Chong, Jessica X and Yu, Joon-Ho and Lorentzen, Peter and Park, Karen M and Jamal, Seema M and Tabor, Holly K and Rauch, Anita and Saenz, Margarita Sifuentes and Boltshauser, Eugen and Patterson, Karynne E and Nickerson, Deborah A and Bamshad, Michael J} } @article {71, title = {Genome-Wide Association and Exome Sequencing Study of Language Disorder in an Isolated Population.}, journal = {Pediatrics}, volume = {137}, year = {2016}, month = {2016 04}, abstract = {

BACKGROUND AND OBJECTIVE: Developmental language disorder (DLD) is a highly prevalent neurodevelopmental disorder associated with negative outcomes in different domains; the etiology of DLD is unknown. To investigate the genetic underpinnings of DLD, we performed genome-wide association and whole exome sequencing studies in a geographically isolated population with a substantially elevated prevalence of the disorder (ie, the AZ sample).

METHODS: DNA samples were collected from 359 individuals for the genome-wide association study and from 12 severely affected individuals for whole exome sequencing. Multifaceted phenotypes, representing major domains of expressive language functioning, were derived from collected speech samples.

RESULTS: Gene-based analyses revealed a significant association between SETBP1 and complexity of linguistic output (P = 5.47 {\texttimes} 10(-7)). The analysis of exome variants revealed coding sequence variants in 14 genes, most of which play a role in neural development. Targeted enrichment analysis implicated myocyte enhancer factor-2 (MEF2)-regulated genes in DLD in the AZ population. The main findings were successfully replicated in an independent cohort of children at risk for related disorders (n = 372).

CONCLUSIONS: MEF2-regulated pathways were identified as potential candidate pathways in the etiology of DLD. Several genes (including the candidate SETBP1 and other MEF2-related genes) seem to jointly influence certain, but not all, facets of the DLD phenotype. Even when genetic and environmental diversity is reduced, DLD is best conceptualized as etiologically complex. Future research should establish whether the signals detected in the AZ population can be replicated in other samples and languages and provide further characterization of the identified pathway.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Exome, Genome-Wide Association Study, Humans, Language Disorders, Middle Aged, Polymorphism, Single Nucleotide, Russia, Sequence Analysis, DNA, Young Adult}, issn = {1098-4275}, doi = {10.1542/peds.2015-2469}, author = {Kornilov, Sergey A and Rakhlin, Natalia and Koposov, Roman and Lee, Maria and Yrigollen, Carolyn and {\c C}a{\u g}layan, Ahmet Okay and Magnuson, James S and Mane, Shrikant and Chang, Joseph T and Grigorenko, Elena L} } @article {65, title = {Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 05 05}, pages = {1001-1010}, abstract = {

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein~subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p~=~7.1~{\texttimes} 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Germ-Line Mutation, GTP-Binding Protein beta Subunits, Humans, Infant, Intellectual Disability, Male, Muscle Hypotonia, Phenotype, Protein Conformation, Seizures, Signal Transduction, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.011}, author = {Petrovski, Slav{\'e} and K{\"u}ry, S{\'e}bastien and Myers, Candace T and Anyane-Yeboa, Kwame and Cogn{\'e}, Benjamin and Bialer, Martin and Xia, Fan and Hemati, Parisa and Riviello, James and Mehaffey, Michele and Besnard, Thomas and Becraft, Emily and Wadley, Alexandrea and Politi, Anya Revah and Colombo, Sophie and Zhu, Xiaolin and Ren, Zhong and Andrews, Ian and Dudding-Byth, Tracy and Schneider, Amy L and Wallace, Geoffrey and Rosen, Aaron B I and Schelley, Susan and Enns, Gregory M and Corre, Pierre and Dalton, Joline and Mercier, Sandra and Latypova, X{\'e}nia and Schmitt, S{\'e}bastien and Guzman, Edwin and Moore, Christine and Bier, Louise and Heinzen, Erin L and Karachunski, Peter and Shur, Natasha and Grebe, Theresa and Basinger, Alice and Nguyen, Joanne M and B{\'e}zieau, St{\'e}phane and Wierenga, Klaas and Bernstein, Jonathan A and Scheffer, Ingrid E and Rosenfeld, Jill A and Mefford, Heather C and Isidor, Bertrand and Goldstein, David B} } @article {50, title = {Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.}, journal = {Acta Neuropathol Commun}, volume = {4}, year = {2016}, month = {2016 06 01}, pages = {56}, abstract = {

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8~\%) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101\&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial~acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Female, Gene Duplication, Germ-Line Mutation, Gigantism, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Pituitary Neoplasms, Receptors, G-Protein-Coupled, Treatment Outcome, Young Adult}, issn = {2051-5960}, doi = {10.1186/s40478-016-0328-1}, author = {Iacovazzo, Donato and Caswell, Richard and Bunce, Benjamin and Jose, Sian and Yuan, Bo and Hern{\'a}ndez-Ram{\'\i}rez, Laura C and Kapur, Sonal and Caimari, Francisca and Evanson, Jane and Ferra{\`u}, Francesco and Dang, Mary N and Gabrovska, Plamena and Larkin, Sarah J and Ansorge, Olaf and Rodd, Celia and Vance, Mary L and Ram{\'\i}rez-Renteria, Claudia and Mercado, Mois{\'e}s and Goldstone, Anthony P and Buchfelder, Michael and Burren, Christine P and Gurlek, Alper and Dutta, Pinaki and Choong, Catherine S and Cheetham, Timothy and Trivellin, Giampaolo and Stratakis, Constantine A and Lopes, Maria-Beatriz and Grossman, Ashley B and Trouillas, Jacqueline and Lupski, James R and Ellard, Sian and Sampson, Julian R and Roncaroli, Federico and Korbonits, M{\'a}rta} } @article {126, title = {Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 Jan}, pages = {156-61}, abstract = {

The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, DNA-Binding Proteins, Exome, Face, Female, Hand Deformities, Congenital, Heterozygote, Humans, Intellectual Disability, Male, Micrognathism, Mosaicism, Mutation, Neck, Pedigree, Siblings, Transcription Factors}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37405}, author = {Ben-Salem, Salma and Sobreira, Nara and Akawi, Nadia A and Al-Shamsi, Aisha M and John, Anne and Pramathan, Thachillath and Valle, David and Ali, Bassam R and Al-Gazali, Lihadh} } @article {117, title = {Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population.}, journal = {Pigment Cell Melanoma Res}, volume = {29}, year = {2016}, month = {2016 Mar}, pages = {231-5}, keywords = {Adolescent, Adult, Alleles, Child, Child, Preschool, Female, Hermanski-Pudlak Syndrome, Humans, Infant, Male, Membrane Proteins, Middle Aged, Pakistan, Pedigree}, issn = {1755-148X}, doi = {10.1111/pcmr.12438}, author = {Yousaf, Sairah and Shahzad, Mohsin and Kausar, Tasleem and Sheikh, Shakeel A and Tariq, Nabeela and Shabbir, Asra S and Ali, Muhammad and Waryah, Ali M and Shaikh, Rehan S and Riazuddin, Saima and Ahmed, Zubair M} } @article {72, title = {Loss of B Cells in Patients with Heterozygous Mutations in IKAROS.}, journal = {N Engl J Med}, volume = {374}, year = {2016}, month = {2016 Mar 17}, pages = {1032-1043}, abstract = {

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late-onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10\% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells.

METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates.

RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7-Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients.

CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.).

}, keywords = {Adolescent, Adult, Antigens, CD, B-Lymphocytes, Bone Marrow, Bone Marrow Examination, Child, Child, Preschool, Chromosomes, Human, Pair 7, Common Variable Immunodeficiency, Exome, Female, Heterozygote, Humans, Ikaros Transcription Factor, Immunoglobulin G, Lymphocyte Count, Male, Mutation, Pedigree, Sequence Analysis, DNA}, issn = {1533-4406}, doi = {10.1056/NEJMoa1512234}, author = {Kuehn, H S and Boisson, B and Cunningham-Rundles, C and Reichenbach, J and Stray-Pedersen, A and Gelfand, E W and Maffucci, P and Pierce, K R and Abbott, J K and Voelkerding, K V and South, S T and Augustine, N H and Bush, J S and Dolen, W K and Wray, B B and Itan, Y and Cobat, A and Sorte, H S and Ganesan, S and Prader, S and Martins, T B and Lawrence, M G and Orange, J S and Calvo, K R and Niemela, J E and Casanova, J-L and Fleisher, T A and Hill, H R and Kum{\'a}novics, A and Conley, M E and Rosenzweig, S D} } @article {354, title = {Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 05 15}, pages = {1923-1933}, abstract = {

Elevated sweat chloride levels, failure to thrive (FTT), and lung disease are characteristic features of cystic fibrosis (CF, OMIM $\#$219700). Here we describe variants in CA12 encoding carbonic anhydrase XII in two pedigrees exhibiting CF-like phenotypes. Exome sequencing of a white American adult diagnosed with CF due to elevated sweat chloride, recurrent hyponatremia, infantile FTT and lung disease identified deleterious variants in each CA12 gene: c.908-1 G>A in a splice acceptor and a novel frameshift insertion c.859_860insACCT. In an unrelated consanguineous Omani family, two children with elevated sweat chloride, infantile FTT, and recurrent hyponatremia were homozygous for a novel missense variant (p.His121Gln). Deleterious CFTR variants were absent in both pedigrees. CA XII protein was localized apically in human bronchiolar epithelia and basolaterally in the reabsorptive duct of human sweat glands. Respiratory epithelial cell RNA from the adult proband revealed only aberrant CA12 transcripts and in vitro analysis showed greatly reduced CA XII protein. Studies of ion transport across respiratory epithelial cells in vivo and in culture revealed intact CFTR-mediated chloride transport in the adult proband. CA XII protein bearing either p.His121Gln or a previously identified p.Glu143Lys missense variant localized to the basolateral membranes of polarized Madin-Darby canine kidney (MDCK) cells, but enzyme activity was severely diminished when assayed at physiologic concentrations of extracellular chloride. Our findings indicate that loss of CA XII function should be considered in individuals without CFTR mutations who exhibit CF-like features in the sweat gland and lung.

}, keywords = {Adolescent, Adult, Animals, Carbonic Anhydrases, Child, Child, Preschool, Chlorides, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Dogs, Female, Gene Expression Regulation, Enzymologic, Homozygote, Humans, Lung, Lung Diseases, Madin Darby Canine Kidney Cells, Male, Mutation, Pedigree, Phenotype, Sweat}, issn = {1460-2083}, doi = {10.1093/hmg/ddw065}, author = {Lee, Melissa and Vecchio-Pag{\'a}n, Briana and Sharma, Neeraj and Waheed, Abdul and Li, Xiaopeng and Raraigh, Karen S and Robbins, Sarah and Han, Sangwoo T and Franca, Arianna L and Pellicore, Matthew J and Evans, Taylor A and Arcara, Kristin M and Nguyen, Hien and Luan, Shan and Belchis, Deborah and Hertecant, Jozef and Zabner, Joseph and Sly, William S and Cutting, Garry R} } @article {342, title = {MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Dec 01}, pages = {1229-1244}, abstract = {

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285), c.247_250del (p.Asn83Hisfs4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

}, keywords = {Basal Ganglia, Cells, Cultured, Child, Child, Preschool, Dystonic Disorders, Fatty Acids, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Mitochondria, Mitochondrial Diseases, Models, Molecular, Mutation, Mutation, Missense, Optic Atrophy, Oxidoreductases Acting on CH-CH Group Donors, Pedigree, RNA Splice Sites, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.021}, author = {Heimer, Gali and Ker{\"a}t{\"a}r, Juha M and Riley, Lisa G and Balasubramaniam, Shanti and Eyal, Eran and Pietik{\"a}inen, Laura P and Hiltunen, J Kalervo and Marek-Yagel, Dina and Hamada, Jeffrey and Gregory, Allison and Rogers, Caleb and Hogarth, Penelope and Nance, Martha A and Shalva, Nechama and Veber, Alvit and Tzadok, Michal and Nissenkorn, Andreea and Tonduti, Davide and Renaldo, Florence and Kraoua, Ichraf and Panteghini, Celeste and Valletta, Lorella and Garavaglia, Barbara and Cowley, Mark J and Gayevskiy, Velimir and Roscioli, Tony and Silberstein, Jonathon M and Hoffmann, Chen and Raas-Rothschild, Annick and Tiranti, Valeria and Anikster, Yair and Christodoulou, John and Kastaniotis, Alexander J and Ben-Zeev, Bruria and Hayflick, Susan J} } @article {83, title = {Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP.}, journal = {BMC Med Genet}, volume = {17}, year = {2016}, month = {2016 Feb 16}, pages = {13}, abstract = {

BACKGROUND: Nonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity.

METHODS: We identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression.

RESULTS: Affected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old.

CONCLUSION: This study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, Alleles, Asian Continental Ancestry Group, Child, Cloning, Molecular, Exome, Female, Genetic Linkage, Haplotypes, HEK293 Cells, Homozygote, Humans, Introns, Male, Mitral Valve Insufficiency, Pakistan, Pedigree, Phenotype, Polymorphism, Single Nucleotide, RNA Splicing, Sequence Analysis, DNA, Trichothiodystrophy Syndromes, Young Adult}, issn = {1471-2350}, doi = {10.1186/s12881-016-0275-5}, author = {Shah, Khadim and Ali, Raja Hussain and Ansar, Muhammad and Lee, Kwanghyuk and Chishti, Muhammad Salman and Abbe, Izoduwa and Li, Biao and Smith, Joshua D and Nickerson, Deborah A and Shendure, Jay and Coucke, Paul J and Steyaert, Wouter and Bamshad, Michael J and Santos-Cortez, Regie Lyn P and Leal, Suzanne M and Ahmad, Wasim} } @article {75, title = {Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Mar 03}, pages = {562-570}, abstract = {

The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.

}, keywords = {Adolescent, Alleles, Amino Acid Sequence, Atrophy, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Endoplasmic Reticulum-Associated Degradation, Female, Genetic Association Studies, Genetic Variation, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Muscle Hypotonia, Mutation, Pedigree, Protein Folding, Proteins, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.01.011}, author = {Harel, Tamar and Yesil, G{\"o}zde and Bayram, Yavuz and Coban-Akdemir, Zeynep and Charng, Wu-Lin and Karaca, Ender and Al Asmari, Ali and Eldomery, Mohammad K and Hunter, Jill V and Jhangiani, Shalini N and Rosenfeld, Jill A and Pehlivan, Davut and El-Hattab, Ayman W and Saleh, Mohammed A and LeDuc, Charles A and Muzny, Donna and Boerwinkle, Eric and Gibbs, Richard A and Chung, Wendy K and Yang, Yaping and Belmont, John W and Lupski, James R} } @article {55, title = {Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 09}, pages = {608-15}, abstract = {

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene.

METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes.

RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype.

CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1\% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Cell Cycle Proteins, Cerebellar Diseases, Cerebellum, Child, Ciliopathies, Encephalocele, Eye Abnormalities, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Kidney Diseases, Cystic, Male, Mutation, Mutation Rate, Orofaciodigital Syndromes, Pedigree, Phenotype, Retina, Sequence Alignment}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103832}, author = {Roosing, Susanne and Romani, Marta and Isrie, Mala and Rosti, Rasim Ozgur and Micalizzi, Alessia and Musaev, Damir and Mazza, Tommaso and Al-Gazali, Lihadh and Altunoglu, Umut and Boltshauser, Eugen and D{\textquoteright}Arrigo, Stefano and De Keersmaecker, Bart and Kayserili, H{\"u}lya and Brandenberger, Sarah and Kraoua, Ichraf and Mark, Paul R and McKanna, Trudy and Van Keirsbilck, Joachim and Moerman, Philippe and Poretti, Andrea and Puri, Ratna and Van Esch, Hilde and Gleeson, Joseph G and Valente, Enza Maria} } @article {23, title = {Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {912-916}, abstract = {

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.

}, keywords = {Acyltransferases, Arachidonic Acid, Autistic Disorder, Child, Child, Preschool, Consanguinity, Epilepsy, Female, Homozygote, Humans, Infant, Intellectual Disability, Lysophospholipids, Male, Membrane Proteins, Mutation, Pedigree, Phosphatidylinositols}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.07.019}, author = {Johansen, Anide and Rosti, Rasim O and Musaev, Damir and Sticca, Evan and Harripaul, Ricardo and Zaki, Maha and {\c C}a{\u g}layan, Ahmet Okay and Azam, Matloob and Sultan, Tipu and Froukh, Tawfiq and Reis, Andr{\'e} and Popp, Bernt and Ahmed, Iltaf and John, Peter and Ayub, Muhammad and Ben-Omran, Tawfeg and Vincent, John B and Gleeson, Joseph G and Abou Jamra, Rami} } @article {84, title = {Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Apr}, pages = {457-65}, abstract = {

Nucleoporins are essential components of the nuclear pore complex (NPC). Only a few diseases have been attributed to NPC dysfunction. Steroid-resistant nephrotic syndrome (SRNS), a frequent cause of chronic kidney disease, is caused by dysfunction of glomerular podocytes. Here we identify in eight families with SRNS mutations in NUP93, its interaction partner NUP205 or XPO5 (encoding exportin 5) as hitherto unrecognized monogenic causes of SRNS. NUP93 mutations caused disrupted NPC assembly. NUP93 knockdown reduced the presence of NUP205 in the NPC, and, reciprocally, a NUP205 alteration abrogated NUP93 interaction. We demonstrate that NUP93 and exportin 5 interact with the signaling protein SMAD4 and that NUP93 mutations abrogated interaction with SMAD4. Notably, NUP93 mutations interfered with BMP7-induced SMAD transcriptional reporter activity. We hereby demonstrate that mutations of NUP genes cause a distinct renal disease and identify aberrant SMAD signaling as a new disease mechanism of SRNS, opening a potential new avenue for treatment.

}, keywords = {Age of Onset, Amino Acid Sequence, Animals, Cell Movement, Cell Proliferation, Cells, Cultured, Child, Child, Preschool, Drug Resistance, Female, Genes, Recessive, Genetic Association Studies, Genetic Linkage, HEK293 Cells, Humans, Infant, Karyopherins, Male, Mice, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Nuclear Pore Complex Proteins, Oxidative Stress, Podocytes, Sequence Analysis, DNA, Steroids, Xenopus laevis}, issn = {1546-1718}, doi = {10.1038/ng.3512}, author = {Braun, Daniela A and Sadowski, Carolin E and Kohl, Stefan and Lovric, Svjetlana and Astrinidis, Susanne A and Pabst, Werner L and Gee, Heon Yung and Ashraf, Shazia and Lawson, Jennifer A and Shril, Shirlee and Airik, Merlin and Tan, Weizhen and Schapiro, David and Rao, Jia and Choi, Won-Il and Hermle, Tobias and Kemper, Markus J and Pohl, Martin and Ozaltin, Fatih and Konrad, Martin and Bogdanovic, Radovan and B{\"u}scher, Rainer and Helmchen, Udo and Serdaroglu, Erkin and Lifton, Richard P and Antonin, Wolfram and Hildebrandt, Friedhelm} } @article {41, title = {Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 Oct}, pages = {1161-74}, abstract = {

Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosomes, Human, Pair 17, DNA Copy Number Variations, DNA Replication, Female, Gene Deletion, Haploinsufficiency, Homologous Recombination, Humans, Intellectual Disability, Male, Mutation, Myelin Proteins, Smith-Magenis Syndrome, Trans-Activators, Transcription Factors}, issn = {1432-1203}, doi = {10.1007/s00439-016-1703-5}, author = {Yuan, Bo and Neira, Juanita and Gu, Shen and Harel, Tamar and Liu, Pengfei and Brice{\~n}o, Ignacio and Elsea, Sarah H and G{\'o}mez, Alberto and Potocki, Lorraine and Lupski, James R} } @article {127, title = {Novel genetic causes for cerebral visual impairment.}, journal = {Eur J Hum Genet}, volume = {24}, year = {2016}, month = {2016 May}, pages = {660-5}, abstract = {

Cerebral visual impairment (CVI) is a major cause of low vision in children due to impairment in projection and/or interpretation of the visual input in the brain. Although acquired causes for CVI are well known, genetic causes underlying CVI are largely unidentified. DNAs of 25 patients with CVI and intellectual disability, but without acquired (eg, perinatal) damage, were investigated by whole-exome sequencing. The data were analyzed for de novo, autosomal-recessive, and X-linked variants, and subsequently classified into known, candidate, or unlikely to be associated with CVI. This classification was based on the Online Mendelian Inheritance in Man database, literature reports, variant characteristics, and functional relevance of the gene. After classification, variants in four genes known to be associated with CVI (AHDC1, NGLY1, NR2F1, PGAP1) in 5 patients (20\%) were identified, establishing a conclusive genetic diagnosis for CVI. In addition, in 11 patients (44\%) with CVI, variants in one or more candidate genes were identified (ACP6, AMOT, ARHGEF10L, ATP6V1A, DCAF6, DLG4, GABRB2, GRIN1, GRIN2B, KCNQ3, KCTD19, RERE, SLC1A1, SLC25A16, SLC35A2, SOX5, UFSP2, UHMK1, ZFP30). Our findings show that diverse genetic causes underlie CVI, some of which will provide insight into the biology underlying this disease process.

}, keywords = {Adolescent, Blindness, Cortical, Child, Child, Preschool, Female, Genetic Loci, Humans, Male, Polymorphism, Single Nucleotide, Young Adult}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.186}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and de Leeuw, Nicole and Pfundt, Rolph and Nillesen, Willy M and de Ligt, Joep and Gilissen, Christian and Jhangiani, Shalini and Lupski, James R and Cremers, Frans P M and de Vries, Bert B A} } @article {12, title = {Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 11}, pages = {1158-1162}, abstract = {

PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.

METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.

RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.

CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.

}, keywords = {Adolescent, Anodontia, Child, Exome, Female, Frameshift Mutation, Genetic Predisposition to Disease, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Male, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Wnt Signaling Pathway}, issn = {1530-0366}, doi = {10.1038/gim.2016.10}, author = {Ockeloen, Charlotte W and Khandelwal, Kriti D and Dreesen, Karoline and Ludwig, Kerstin U and Sullivan, Robert and van Rooij, Iris A L M and Thonissen, Michelle and Swinnen, Steven and Phan, Milien and Conte, Federica and Ishorst, Nina and Gilissen, Christian and RoaFuentes, Laury and van de Vorst, Maartje and Henkes, Arjen and Steehouwer, Marloes and van Beusekom, Ellen and Bloemen, Marjon and Vankeirsbilck, Bruno and Berg{\'e}, Stefaan and Hens, Greet and Schoenaers, Joseph and Poorten, Vincent Vander and Roosenboom, Jasmien and Verdonck, An and Devriendt, Koen and Roeleveldt, Nel and Jhangiani, Shalini N and Vissers, Lisenka E L M and Lupski, James R and de Ligt, Joep and Von den Hoff, Johannes W and Pfundt, Rolph and Brunner, Han G and Zhou, Huiqing and Dixon, Jill and Mangold, Elisabeth and van Bokhoven, Hans and Dixon, Michael J and Kleefstra, Tjitske and Hoischen, Alexander and Carels, Carine E L} } @article {82, title = {Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 May}, pages = {1165-73}, abstract = {

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

}, keywords = {Autistic Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Developmental Disabilities, DNA Copy Number Variations, Female, Genetic Association Studies, Humans, Male, Psychotic Disorders, Schizophrenia, Signal Transduction}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37595}, author = {Brownstein, Catherine A and Kleiman, Robin J and Engle, Elizabeth C and Towne, Meghan C and D{\textquoteright}Angelo, Eugene J and Yu, Timothy W and Beggs, Alan H and Picker, Jonathan and Fogler, Jason M and Carroll, Devon and Schmitt, Rachel C O and Wolff, Robert R and Shen, Yiping and Lip, Va and Bilguvar, Kaya and Kim, April and Tembulkar, Sahil and O{\textquoteright}Donnell, Kyle and Gonzalez-Heydrich, Joseph} } @article {44, title = {PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies.}, journal = {Pediatr Neurol}, volume = {60}, year = {2016}, month = {2016 Jul}, pages = {83-7}, abstract = {

BACKGROUND: Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research.

METHODS: We enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome. All four individuals subsequently underwent whole-exome sequencing and comprehensive genomic analysis.

RESULTS: We identified disease-causing mutations in known genes associated with neurodevelopmental disorders including GNAO1 and CDKL5 in two of four individuals. One patient with PEHO syndrome and a de novoGNAO1 mutation was found to have an additional de novo mutation in HESX1 that is associated with optic atrophy.

CONCLUSIONS: We hypothesize that PEHO and PEHO-like syndrome may represent a severe end of the spectrum of the early-onset encephalopathies and, in some instances, its complex phenotype may result from an aggregated effect of mutations at two loci.

}, keywords = {Brain Edema, Child, Child, Preschool, Female, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Infant, Male, Mutation, Neurodegenerative Diseases, Optic Atrophy, Phenotype, Protein Serine-Threonine Kinases, Spasms, Infantile}, issn = {1873-5150}, doi = {10.1016/j.pediatrneurol.2016.03.011}, author = {Gawlinski, Pawel and Posmyk, Renata and Gambin, Tomasz and Sielicka, Danuta and Chorazy, Monika and Nowakowska, Beata and Jhangiani, Shalini N and Muzny, Donna M and Bekiesinska-Figatowska, Monika and Bal, Jerzy and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Wiszniewski, Wojciech} } @article {16, title = {Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Nov 03}, pages = {1005-1014}, abstract = {

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 12, Complement C1r, Complement C1s, Ehlers-Danlos Syndrome, Endoplasmic Reticulum, Exome, Female, Gene Deletion, Genetic Loci, Humans, Male, Mutation, Missense, Pedigree, Periodontitis, Protein Conformation, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.019}, author = {Kapferer-Seebacher, Ines and Pepin, Melanie and Werner, Roland and Aitman, Timothy J and Nordgren, Ann and Stoiber, Heribert and Thielens, Nicole and Gaboriaud, Christine and Amberger, Albert and Schossig, Anna and Gruber, Robert and Giunta, Cecilia and Bamshad, Michael and Bj{\"o}rck, Erik and Chen, Christina and Chitayat, David and Dorschner, Michael and Schmitt-Egenolf, Marcus and Hale, Christopher J and Hanna, David and Hennies, Hans Christian and Heiss-Kisielewsky, Irene and Lindstrand, Anna and Lundberg, Pernilla and Mitchell, Anna L and Nickerson, Deborah A and Reinstein, Eyal and Rohrbach, Marianne and Romani, Nikolaus and Schmuth, Matthias and Silver, Rachel and Taylan, Fulya and Vandersteen, Anthony and Vandrovcova, Jana and Weerakkody, Ruwan and Yang, Margaret and Pope, F Michael and Byers, Peter H and Zschocke, Johannes} } @article {63, title = {PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.}, journal = {Ann Neurol}, volume = {80}, year = {2016}, month = {2016 07}, pages = {59-70}, abstract = {

OBJECTIVE: A study was undertaken to characterize the clinical features of the newly described hypomyelinating leukodystrophy type 10 with microcephaly. This is an autosomal recessive disorder mapped to chromosome 1q42.12 due to mutations in the PYCR2 gene, encoding an enzyme involved in proline synthesis in mitochondria.

METHODS: From several international clinics, 11 consanguineous families were identified with PYCR2 mutations by whole exome or targeted sequencing, with detailed clinical and radiological phenotyping. Selective mutations from patients were tested for effect on protein function.

RESULTS: The characteristic clinical presentation of patients with PYCR2 mutations included failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Patients did not survive beyond the first decade of life. Brain magnetic resonance imaging showed global brain atrophy and white matter T2 hyperintensities. Routine serum metabolic profiles were unremarkable. Both nonsense and missense mutations were identified, which impaired protein multimerization.

INTERPRETATION: PYCR2-related syndrome represents a clinically recognizable condition in which PYCR2 mutations lead to protein dysfunction, not detectable on routine biochemical assessments. Mutations predict a poor outcome, probably as a result of impaired mitochondrial function. Ann Neurol 2016;80:59-70.

}, keywords = {Adolescent, Child, Child, Preschool, Codon, Nonsense, Exome, Failure to Thrive, Female, Fibroblasts, Gene Expression, Genetic Predisposition to Disease, Genotype, Humans, Infant, Male, Microcephaly, Mutation, Missense, Phenotype, Primary Cell Culture, Pyrroline Carboxylate Reductases, Syndrome, Transfection, Young Adult}, issn = {1531-8249}, doi = {10.1002/ana.24678}, author = {Zaki, Maha S and Bhat, Gifty and Sultan, Tipu and Issa, Mahmoud and Jung, Hea-Jin and Dikoglu, Esra and Selim, Laila and G Mahmoud, Imam and Abdel-Hamid, Mohamed S and Abdel-Salam, Ghada and Marin-Valencia, Isaac and Gleeson, Joseph G} } @article {532, title = {Rapid molecular diagnostics of severe primary immunodeficiency determined by using targeted next-generation sequencing.}, journal = {J Allergy Clin Immunol}, volume = {138}, year = {2016}, month = {2016 10}, pages = {1142-1151.e2}, abstract = {

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are inherited disorders of the immune system. The most severe form, severe combined immunodeficiency (SCID), presents with profound deficiencies of T~cells, B~cells, or both at birth. If not treated promptly, affected patients usually do not live beyond infancy because of infections. Genetic heterogeneity of SCID frequently delays the diagnosis; a specific diagnosis is crucial for life-saving treatment and optimal management.

OBJECTIVE: We developed a next-generation sequencing (NGS)-based multigene-targeted panel for SCID and other severe PIDDs requiring rapid therapeutic actions in a clinical laboratory setting.

METHODS: The target gene capture/NGS assay provides an average read depth of approximately 1000{\texttimes}. The deep coverage facilitates simultaneous detection of single nucleotide variants and exonic copy number variants in one comprehensive assessment. Exons with insufficient coverage (<20{\texttimes} read depth) or high sequence homology (pseudogenes) are complemented by amplicon-based sequencing with specific primers to ensure 100\% coverage of all targeted regions.

RESULTS: Analysis of 20 patient samples with low T-cell receptor excision circle numbers on newborn screening or a positive family history or clinical suspicion of SCID or other severe PIDD identified deleterious mutations in 14 of them. Identified pathogenic variants included both single nucleotide variants and exonic copy number variants, such as hemizygous nonsense, frameshift, and missense changes in IL2RG; compound heterozygous changes in ATM, RAG1, and CIITA; homozygous changes in DCLRE1C and IL7R; and a heterozygous nonsense mutation in CHD7.

CONCLUSION: High-throughput deep sequencing analysis with complete clinical validation greatly increases the diagnostic yield of severe primary immunodeficiency. Establishing a molecular diagnosis enables early immune reconstitution through prompt therapeutic intervention and guides management for improved long-term quality of life.

}, keywords = {Adolescent, Child, Female, Genetic Variation, Humans, Male, Pathology, Molecular, Sequence Analysis, DNA, Severe Combined Immunodeficiency}, issn = {1097-6825}, doi = {10.1016/j.jaci.2016.05.035}, author = {Yu, Hui and Zhang, Victor Wei and Stray-Pedersen, Asbj{\o}rg and Hanson, Imelda Celine and Forbes, Lisa R and de la Morena, M Teresa and Chinn, Ivan K and Gorman, Elizabeth and Mendelsohn, Nancy J and Pozos, Tamara and Wiszniewski, Wojciech and Nicholas, Sarah K and Yates, Anne B and Moore, Lindsey E and Berge, Knut Erik and Sorte, Hanne and Bayer, Diana K and ALZahrani, Daifulah and Geha, Raif S and Feng, Yanming and Wang, Guoli and Orange, Jordan S and Lupski, James R and Wang, Jing and Wong, Lee-Jun} } @article {70, title = {Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Apr 07}, pages = {772-81}, abstract = {

Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, dysgenesis of the corpus callosum, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1-domain-containing kinase) were independently identified by whole-exome sequencing as the cause of this condition in four unrelated families. Matching these families was facilitated by the sharing of phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin-cytoskeleton dynamics, and mTOR signaling. Two of the three mutations (c.376C>T [p.Arg126(*)] and c.1363A>T [p.Lys455(*)]) are predicted to truncate the protein, and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A (p.Arg511His), alters a conserved residue within the TBC1 domain. Structural analysis implicated Arg511 as a required residue for Rab-GAP function, and in~silico homology modeling predicted impaired GAP function in the corresponding mutant. These results suggest that loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume.

}, keywords = {Adolescent, Alleles, Amino Acid Sequence, Brain Diseases, Child, Child, Preschool, Corpus Callosum, Female, GTPase-Activating Proteins, Humans, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Protein-Serine-Threonine Kinases, Signal Transduction, TOR Serine-Threonine Kinases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.01.016}, author = {Chong, Jessica X and Caputo, Viviana and Phelps, Ian G and Stella, Lorenzo and Worgan, Lisa and Dempsey, Jennifer C and Nguyen, Alina and Leuzzi, Vincenzo and Webster, Richard and Pizzuti, Antonio and Marvin, Colby T and Ishak, Gisele E and Ardern-Holmes, Simone and Richmond, Zara and Bamshad, Michael J and Ortiz-Gonzalez, Xilma R and Tartaglia, Marco and Chopra, Maya and Doherty, Dan} } @article {21, title = {Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {831-845}, abstract = {

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

}, keywords = {Adenosine Triphosphatases, Adult, Alleles, Animals, ATPases Associated with Diverse Cellular Activities, Axons, Cardiomyopathies, Child, Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Drosophila melanogaster, Female, Fibroblasts, Homozygote, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Muscle Hypotonia, Muscles, Mutation, Nervous System Diseases, Neurons, Optic Atrophy, Phenotype, Polymorphism, Single Nucleotide, Syndrome, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.007}, author = {Harel, Tamar and Yoon, Wan Hee and Garone, Caterina and Gu, Shen and Coban-Akdemir, Zeynep and Eldomery, Mohammad K and Posey, Jennifer E and Jhangiani, Shalini N and Rosenfeld, Jill A and Cho, Megan T and Fox, Stephanie and Withers, Marjorie and Brooks, Stephanie M and Chiang, Theodore and Duraine, Lita and Erdin, Serkan and Yuan, Bo and Shao, Yunru and Moussallem, Elie and Lamperti, Costanza and Donati, Maria A and Smith, Joshua D and McLaughlin, Heather M and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Pippucci, Tommaso and Magini, Pamela and Seri, Marco and Zeviani, Massimo and Hirano, Michio and Hunter, Jill V and Srour, Myriam and Zanigni, Stefano and Lewis, Richard Alan and Muzny, Donna M and Lotze, Timothy E and Boerwinkle, Eric and Gibbs, Richard A and Hickey, Scott E and Graham, Brett H and Yang, Yaping and Buhas, Daniela and Martin, Donna M and Potocki, Lorraine and Graziano, Claudio and Bellen, Hugo J and Lupski, James R} } @article {90, title = {Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Feb 04}, pages = {347-57}, abstract = {

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous \~{}34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

}, keywords = {Alleles, Arabs, Arrhythmias, Cardiac, Base Sequence, Child, Child, Preschool, Endoplasmic Reticulum Stress, European Continental Ancestry Group, Exome, Exons, Female, Gene Deletion, Golgi Apparatus, Hispanic Americans, Homozygote, Humans, Infant, Male, Molecular Sequence Data, Muscle Weakness, Pedigree, Rhabdomyolysis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.12.008}, author = {Lalani, Seema R and Liu, Pengfei and Rosenfeld, Jill A and Watkin, Levi B and Chiang, Theodore and Leduc, Magalie S and Zhu, Wenmiao and Ding, Yan and Pan, Shujuan and Vetrini, Francesco and Miyake, Christina Y and Shinawi, Marwan and Gambin, Tomasz and Eldomery, Mohammad K and Akdemir, Zeynep Hande Coban and Emrick, Lisa and Wilnai, Yael and Schelley, Susan and Koenig, Mary Kay and Memon, Nada and Farach, Laura S and Coe, Bradley P and Azamian, Mahshid and Hernandez, Patricia and Zapata, Gladys and Jhangiani, Shalini N and Muzny, Donna M and Lotze, Timothy and Clark, Gary and Wilfong, Angus and Northrup, Hope and Adesina, Adekunle and Bacino, Carlos A and Scaglia, Fernando and Bonnen, Penelope E and Crosson, Jane and Duis, Jessica and Maegawa, Gustavo H B and Coman, David and Inwood, Anita and McGill, Jim and Boerwinkle, Eric and Graham, Brett and Beaudet, Art and Eng, Christine M and Hanchard, Neil A and Xia, Fan and Orange, Jordan S and Gibbs, Richard A and Lupski, James R and Yang, Yaping} } @article {85, title = {Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.}, journal = {Hepatology}, volume = {63}, year = {2016}, month = {2016 06}, pages = {1977-86}, abstract = {

UNLABELLED: Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism.

CONCLUSION: Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (Hepatology 2016;63:1977-1986).

}, keywords = {Adolescent, Amino Acid Sequence, Animals, Cattle, Child, Child, Preschool, DNA Mutational Analysis, Dogs, Female, Genes, Recessive, Homozygote, Humans, Hypertension, Portal, Infant, Liver Failure, Male, Molecular Sequence Data, Pedigree, Phosphotransferases (Alcohol Group Acceptor), Principal Component Analysis, Rats, Young Adult}, issn = {1527-3350}, doi = {10.1002/hep.28499}, author = {Vilarinho, S{\'\i}lvia and Sari, Sinan and Yilmaz, G{\"u}ldal and Stiegler, Amy L and Boggon, Titus J and Jain, Dhanpat and Akyol, G{\"u}len and Dalgi{\c c}, Buket and G{\"u}nel, Murat and Lifton, Richard P} } @article {61, title = {Somatic Mutations in NEK9 Cause Nevus Comedonicus.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 May 05}, pages = {1030-1037}, abstract = {

Acne vulgaris (AV) affects most adolescents, and of those affected, moderate to severe disease occurs in 20\%. Comedones, follicular plugs consisting of desquamated keratinocytes and sebum, are central to its pathogenesis. Despite high heritability in first-degree relatives, AV genetic determinants remain incompletely understood. We therefore employed whole-exome sequencing (WES) in nevus comedonicus (NC), a rare disorder that features comedones and inflammatory acne cysts in localized, linear configurations. WES identified somatic NEK9 mutations, each affecting highly conserved residues within its kinase or RCC1 domains, in affected tissue of three out of three NC-affected subjects. All mutations are gain of function, resulting in increased phosphorylation at Thr210, a hallmark of NEK9 kinase activation. We found that comedo formation in NC is marked by loss of follicular differentiation markers, expansion of keratin-15-positive cells from localization within the bulge to the entire sub-bulge follicle and cyst, and ectopic expression of keratin 10, a marker of interfollicular differentiation not present in normal follicles. These findings suggest that NEK9 mutations in NC disrupt normal follicular differentiation and identify NEK9 as a potential regulator of follicular homeostasis.

}, keywords = {Adolescent, Adult, Child, Female, Fluorescent Antibody Technique, High-Throughput Nucleotide Sequencing, Humans, Male, Mutation, Nevus, NIMA-Related Kinases, Prognosis, Skin Neoplasms, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.019}, author = {Levinsohn, Jonathan L and Sugarman, Jeffrey L and McNiff, Jennifer M and Antaya, Richard J and Choate, Keith A} } @article {31, title = {SRD5A3-CDG: Expanding the phenotype of a congenital disorder of glycosylation with emphasis on adult onset features.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 Dec}, pages = {3165-3171}, abstract = {

Increasing numbers of congenital disorders of glycosylation (CDG) have been reported recently resulting in an expansion of the phenotypes associated with this group of disorders. SRD5A3 codes for polyprenol reductase which converts polyprenol to dolichol. This is a major pathway for dolichol biosynthesis for N-glycosylation, O-mannosylation, C-mannosylation, and GPI anchor synthesis. We present the features of five individuals (three children and two adults) with mutations in SRD5A3 focusing on the variable eye and skin involvement. We compare that to 13 affected individuals from the literature including five adults allowing us to delineate the features that may develop over time with this disorder including kyphosis, retinitis pigmentosa, and cataracts. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Adult, Child, Congenital Disorders of Glycosylation, Dolichols, Eye, Female, Glycosylation, Homozygote, Humans, Male, Membrane Proteins, Mutation, Phenotype, Skin, Tretinoin}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37875}, author = {Wheeler, Patricia G and Ng, Bobby G and Sanford, Laura and Sutton, V Reid and Bartholomew, Dennis W and Pastore, Matthew T and Bamshad, Michael J and Kircher, Martin and Buckingham, Kati J and Nickerson, Deborah A and Shendure, Jay and Freeze, Hudson H} } @article {62, title = {A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 05 05}, pages = {909-918}, abstract = {

The proteins encoded by TELO2, TTI1, and TTI2 interact to form the TTT complex, a co-chaperone for maturation of the phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Here we report six affected individuals from four families with intellectual disability (ID) and neurological and other congenital abnormalities associated with compound heterozygous variants in TELO2. Although their fibroblasts showed reduced steady-state levels of TELO2 and the other components of the TTT complex, PIKK functions were normal in cellular assays. Our results suggest that these TELO2 missense variants result in loss of function, perturb TTT complex stability, and cause an autosomal-recessive syndromic form of ID.

}, keywords = {Adolescent, Carrier Proteins, Child, Female, Humans, Intellectual Disability, Male, Molecular Chaperones, Pedigree, Phosphatidylinositol 3-Kinases, Protein-Serine-Threonine Kinases, Telomere-Binding Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.014}, author = {You, Jing and Sobreira, Nara L and Gable, Dustin L and Jurgens, Julie and Grange, Dorothy K and Belnap, Newell and Siniard, Ashley and Szelinger, Szabolcs and Schrauwen, Isabelle and Richholt, Ryan F and Vallee, Stephanie E and Dinulos, Mary Beth P and Valle, David and Armanios, Mary and Hoover-Fong, Julie} } @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 {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 {641, title = {An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Jan}, pages = {159-63}, abstract = {

We describe a boy who has an anadysplasia-like spondylometaphyseal dysplasia. By whole exome sequencing he was shown to have compound heterozygous mutations of LBR that codes for the lamin B receptor. He shares many similarities with a case previously described, but in whom the early natural history could not be established [Borovik et al., 2013]. Thus, in addition to Greenberg dysplasia (a perinatal lethal disorder), homozygosity or compound heterozygosity of mutations in LBR can result in a mild, spontaneously regressing bone dysplasia.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phenotype, Pregnancy, Radiography, Receptors, Cytoplasmic and Nuclear, Spine}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36808}, author = {Sobreira, Nara and Modaff, Peggy and Steel, Gary and You, Jing and Nanda, Sonia and Hoover-Fong, Julie and Valle, David and Pauli, Richard M} } @article {184, title = {Cerebral visual impairment and intellectual disability caused by PGAP1 variants.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Dec}, pages = {1689-93}, abstract = {

Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI.

}, keywords = {Animals, Cell Line, Tumor, Child, CHO Cells, Cricetinae, Cricetulus, Humans, Intellectual Disability, Male, Membrane Proteins, Mutation, Phosphoinositide Phospholipase C, Phosphoric Monoester Hydrolases, Syndrome, Vision Disorders, Visual Perception}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.42}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and Kinoshita, Taroh and Jhangiani, Shalini and de Ligt, Joep and Cremers, Frans P M and Lupski, James R and Murakami, Yoshiko and de Vries, Bert B A} } @article {640, title = {Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Jun 05}, pages = {1011-9}, abstract = {

BACKGROUND AND OBJECTIVES: Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.

RESULTS: Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A>G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.

CONCLUSIONS: This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process next-generation sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases.

}, keywords = {Adolescent, Atypical Hemolytic Uremic Syndrome, Base Sequence, Blotting, Western, Child, Diacylglycerol Kinase, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Infant, Introns, Male, Molecular Sequence Data, Mutation, Phenotype, Predictive Value of Tests, Risk Factors}, issn = {1555-905X}, doi = {10.2215/CJN.08520814}, author = {Mele, Caterina and Lemaire, Mathieu and Iatropoulos, Paraskevas and Piras, Rossella and Bresin, Elena and Bettoni, Serena and Bick, David and Helbling, Daniel and Veith, Regan and Valoti, Elisabetta and Donadelli, Roberta and Murer, Luisa and Neunh{\"a}userer, Maria and Breno, Matteo and Fremeaux-Bacchi, Veronique and Lifton, Richard and Remuzzi, Giuseppe and Noris, Marina} } @article {129, title = {CRB1-Related Maculopathy With Cystoid Macular Edema.}, journal = {JAMA Ophthalmol}, volume = {133}, year = {2015}, month = {2015 Nov}, pages = {1357-60}, keywords = {Administration, Topical, Carbonic Anhydrase Inhibitors, Child, Diseases in Twins, DNA Mutational Analysis, Electroretinography, Eye Proteins, Female, Fluorescein Angiography, Humans, Macular Edema, Membrane Proteins, Mutation, Nerve Tissue Proteins, Ophthalmic Solutions, Retinal Dystrophies, Sulfonamides, Thiophenes, Tomography, Optical Coherence, Twins, Monozygotic, Visual Acuity}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2015.2814}, author = {Wolfson, Yulia and Applegate, Carolyn D and Strauss, Rupert W and Han, Ian C and Scholl, Hendrik P} } @article {213, title = {Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.}, journal = {J Invest Dermatol}, volume = {135}, year = {2015}, month = {2015 Jun}, pages = {1540-1547}, abstract = {

Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.

}, keywords = {Amino Acid Sequence, Cell Membrane, Child, Child, Preschool, Connexin 43, Connexins, Craniofacial Abnormalities, Disease Progression, Erythrokeratodermia Variabilis, Exome, Eye Abnormalities, Female, Foot Deformities, Congenital, Golgi Apparatus, HeLa Cells, Humans, Immunohistochemistry, Male, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Phenotype, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Skin Diseases, Syndactyly, Tooth Abnormalities}, issn = {1523-1747}, doi = {10.1038/jid.2014.485}, author = {Boyden, Lynn M and Craiglow, Brittany G and Zhou, Jing and Hu, Ronghua and Loring, Erin C and Morel, Kimberly D and Lauren, Christine T and Lifton, Richard P and Bilguvar, Kaya and Paller, Amy S and Choate, Keith A} } @article {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 {181, title = {Exome sequencing identifies a homozygous C5orf42 variant in a Turkish kindred with oral-facial-digital syndrome type VI.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Sep}, pages = {2132-7}, abstract = {

Oral-facial-digital syndrome type VI (OFDVI) is a rare ciliopathy in the spectrum of Joubert syndrome (JS) and distinguished from other oral-facial-digital syndromes by metacarpal abnormalities with central polydactyly and by a molar tooth sign on cranial MRI. Additional characteristic features include short stature, micrognathia, posteriorly rotated low-set ears, hypertelorism, epicanthal folds, broad nasal tip, tongue hamartoma, upper lip notch, intraoral frenula, cleft lip/palate, and renal anomalies. Recently, novel mutations in C5orf42 were identified in 9 out of 11 OFDVI families. In a subsequent study C5orf42 was found to be mutated in only 2 out of 17 OFDVI probands while 28 patients with a pure JS phenotype also had pathogenic mutations of C5orf42. We report on two affected cousins diagnosed with OFDVI who were born from first degree cousin marriages. Whole exome sequencing (WES) identified a homozygous predicted damaging missense mutation (c.4034A > G; p.Gln1345Arg) in the C5orf42 gene. Our data contribute to the evidence that C5orf42 is one of the causative genes for OFDVI.

}, keywords = {Abnormalities, Multiple, Cerebellar Diseases, Cerebellum, Child, Cleft Palate, Exome, Eye Abnormalities, Female, Genetic Predisposition to Disease, Hamartoma, Homozygote, Humans, Kidney Diseases, Cystic, Magnetic Resonance Imaging, Male, Membrane Proteins, Middle Aged, Mutation, Orofaciodigital Syndromes, Phenotype, Retina, Turkey}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37092}, author = {Bayram, Yavuz and Aydin, Hatip and Gambin, Tomasz and Akdemir, Zeynep Coban and Atik, Mehmed M and Karaca, Ender and Karaman, Ali and Pehlivan, Davut and Jhangiani, Shalini N and Gibbs, Richard A and Lupski, James R} } @article {202, title = {Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas.}, journal = {Int J Cancer}, volume = {137}, year = {2015}, month = {2015 Jul 15}, pages = {320-31}, abstract = {

In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5\% (4/266) of all patients, 4\% (3/77) of all familial cases and 7\% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes.

}, keywords = {Adenoma, Adolescent, Adult, Aged, Aged, 80 and over, Child, Colorectal Neoplasms, DNA Polymerase II, DNA-Directed DNA Polymerase, Family Health, Female, Gene Frequency, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Isoenzymes, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Phospholipase D, Poly-ADP-Ribose Binding Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Young Adult}, issn = {1097-0215}, doi = {10.1002/ijc.29396}, author = {Spier, Isabel and Holzapfel, Stefanie and Altm{\"u}ller, Janine and Zhao, Bixiao and Horpaopan, Sukanya and Vogt, Stefanie and Chen, Sophia and Morak, Monika and Raeder, Susanne and Kayser, Katrin and Stienen, Dietlinde and Adam, Ronja and N{\"u}rnberg, Peter and Plotz, Guido and Holinski-Feder, Elke and Lifton, Richard P and Thiele, Holger and Hoffmann, Per and Steinke, Verena and Aretz, Stefan} } @article {187, title = {Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.}, journal = {J Clin Invest}, volume = {125}, year = {2015}, month = {2015 Apr}, pages = {1703-7}, abstract = {

Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.

}, keywords = {Adult, Age of Onset, Amino Acid Sequence, Cell Line, Tumor, Cell Nucleus, Child, Child, Preschool, Chromosomes, Human, Pair 12, Cytoskeleton, Frameshift Mutation, Humans, Ichthyosis, Intermediate Filaments, Keratin-1, Keratinocytes, Loss of Heterozygosity, Male, Molecular Sequence Data, Mosaicism, Phenotype, Polymorphism, Single Nucleotide, Protein Transport, Transfection}, issn = {1558-8238}, doi = {10.1172/JCI64415}, author = {Choate, Keith A and Lu, Yin and Zhou, Jing and Elias, Peter M and Zaidi, Samir and Paller, Amy S and Farhi, Anita and Nelson-Williams, Carol and Crumrine, Debra and Milstone, Leonard M and Lifton, Richard P} } @article {146, title = {GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {1009-1014}, abstract = {

We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, Craniofacial Abnormalities, Databases, Genetic, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein K, Humans, Information Dissemination, Intellectual Disability, Male, Muscular Atrophy, Phenotype, Polymorphism, Single Nucleotide, Ribonucleoproteins, Software, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22837}, author = {Au, P Y Billie and You, Jing and Caluseriu, Oana and Schwartzentruber, Jeremy and Majewski, Jacek and Bernier, Francois P and Ferguson, Marcia and Valle, David and Parboosingh, Jillian S and Sobreira, Nara and Innes, A Micheil and Kline, Antonie D} } @article {167, title = {Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.}, journal = {Eur J Endocrinol}, volume = {172}, year = {2015}, month = {2015 06}, pages = {803-11}, abstract = {

OBJECTIVE: We have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing{\textquoteright}s syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype-phenotype correlation of their PRKACA amplification.

DESIGN: This study is a case series.

METHODS: Molecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.

RESULTS: Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entire PRKACA gene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype.

CONCLUSIONS: Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

}, keywords = {Adrenal Glands, Adrenalectomy, Adult, Child, Child, Preschool, Cushing Syndrome, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, DNA Copy Number Variations, Female, Gene Amplification, Humans, Hyperplasia, Male, Phenotype, Young Adult}, issn = {1479-683X}, doi = {10.1530/EJE-14-1154}, author = {Lodish, Maya B and Yuan, Bo and Levy, Isaac and Braunstein, Glenn D and Lyssikatos, Charalampos and Salpea, Paraskevi and Szarek, Eva and Karageorgiadis, Alexander S and Belyavskaya, Elena and Raygada, Margarita and Faucz, Fabio Rueda and Izzat, Louise and Brain, Caroline and Gardner, James and Quezado, Martha and Carney, J Aidan and Lupski, James R and Stratakis, Constantine A} } @article {198, title = {Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.}, journal = {J Clin Invest}, volume = {125}, year = {2015}, month = {2015 Feb}, pages = {636-51}, abstract = {

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65\% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.

}, keywords = {Adolescent, Adult, Cell Cycle Proteins, Child, Child, Preschool, Chondroitin Sulfate Proteoglycans, Chromosomal Proteins, Non-Histone, Codon, Nonsense, De Lange Syndrome, Exome, Exonucleases, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Heterozygote, Histone Deacetylases, Histone-Lysine N-Methyltransferase, Humans, Infant, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Proteins, Repressor Proteins, Transcriptome}, issn = {1558-8238}, doi = {10.1172/JCI77435}, author = {Yuan, Bo and Pehlivan, Davut and Karaca, Ender and Patel, Nisha and Charng, Wu-Lin and Gambin, Tomasz and Gonzaga-Jauregui, Claudia and Sutton, V Reid and Yesil, G{\"o}zde and Bozdogan, Sevcan Tug and Tos, Tulay and Koparir, Asuman and Koparir, Erkan and Beck, Christine R and Gu, Shen and Aslan, Huseyin and Yuregir, Ozge Ozalp and Al Rubeaan, Khalid and Alnaqeb, Dhekra and Alshammari, Muneera J and Bayram, Yavuz and Atik, Mehmed M and Aydin, Hatip and Geckinli, B Bilge and Seven, Mehmet and Ulucan, Hakan and Fenercioglu, Elif and Ozen, Mustafa and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Tuysuz, Beyhan and Alkuraya, Fowzan S and Gibbs, Richard A and Lupski, James R} } @article {186, title = {Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism.}, journal = {J Clin Endocrinol Metab}, volume = {100}, year = {2015}, month = {2015 May}, pages = {E808-14}, abstract = {

CONTEXT: Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hypergonadotropic hypogonadism. Responsible genes include those with roles in gonadal development or maintenance, sex steroid synthesis, or end-organ resistance to gonadotropins. Identification of novel causative genes in this disorder will contribute to our understanding of the regulation of human reproductive function.

OBJECTIVES: The aim of this study was to identify and report the gene responsible for autosomal-recessive hypergonadotropic hypogonadism in two unrelated families.

DESIGN AND PARTICIPANTS: Clinical evaluation and whole-exome sequencing were performed in two pairs of sisters with nonsyndromic hypergonadotropic hypogonadism from two unrelated families.

RESULTS: Exome sequencing analysis revealed two different truncating mutations in the same gene: SOHLH1 c.705delT (p.Pro235fs*4) and SOHLH1 c.27C>G (p.Tyr9stop). Both mutations were unique to the families and segregation was consistent with Mendelian expectations for an autosomal-recessive mode of inheritance.

CONCLUSIONS: Sohlh1 was known from previous mouse studies to be a transcriptional regulator that functions in the maintenance and survival of primordial ovarian follicles, but loss-of-function mutations in human females have not been reported. Our results provide evidence that homozygous-truncating mutations in SOHLH1 cause female nonsyndromic hypergonadotropic hypogonadism.

}, keywords = {Adolescent, Basic Helix-Loop-Helix Transcription Factors, Child, Exome, Female, Homozygote, Humans, Hypogonadism, Mutation}, issn = {1945-7197}, doi = {10.1210/jc.2015-1150}, author = {Bayram, Yavuz and Gulsuner, Suleyman and Guran, Tulay and Abaci, Ayhan and Yesil, G{\"o}zde and Gulsuner, Hilal Unal and Atay, Zeynep and Pierce, Sarah B and Gambin, Tomasz and Lee, Ming and Turan, Serap and Bober, Ece and Atik, Mehmed M and Walsh, Tom and Karaca, Ender and Pehlivan, Davut and Jhangiani, Shalini N and Muzny, Donna and Bereket, Abdullah and Buyukgebiz, Atilla and Boerwinkle, Eric and Gibbs, Richard A and King, Mary-Claire and Lupski, James R} } @article {150, title = {A homozygous missense variant in type I keratin KRT25 causes autosomal recessive woolly hair.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Oct}, pages = {676-80}, abstract = {

BACKGROUND: Woolly hair (WH) is a hair abnormality that is primarily characterised by tightly curled hair with abnormal growth.

METHODS: In two unrelated consanguineous Pakistani families with non-syndromic autosomal recessive (AR) WH, homozygosity mapping and linkage analysis identified a locus within 17q21.1-q22, which contains the type I keratin gene cluster. A DNA sample from an affected individual from each family underwent exome sequencing.

RESULTS: A homozygous missense variant c.950T>C (p.(Leu317Pro)) within KRT25 segregated with ARWH in both families, and has a combined maximum two-point LOD score of 7.9 at ϴ=0. The KRT25 variant is predicted to result in disruption of the second α-helical rod domain and the entire protein structure, thus possibly interfering with heterodimerisation of K25 with type II keratins within the inner root sheath (IRS) of the hair follicle and the medulla of the hair shaft.

CONCLUSIONS: Our findings implicate a novel gene involved in human hair abnormality, and are consistent with the curled, fragile hair found in mice with Krt25 mutations, and further support the role of IRS-specific type I keratins in hair follicle development and maintenance of hair texture.

}, keywords = {Child, Child, Preschool, Consanguinity, Hair, Hair Diseases, Humans, Keratins, Type I, Male, Mutation, Missense, Pakistan, Pedigree, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103255}, author = {Ansar, Muhammad and Raza, Syed Irfan and Lee, Kwanghyuk and Shahi, Shamim and Acharya, Anushree and Dai, Hang and Smith, Joshua D and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Santos-Cortez, Regie Lyn P and Ahmad, Wasim and Leal, Suzanne M} } @article {161, title = {Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jul}, pages = {809-13}, abstract = {

Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.

}, keywords = {Adolescent, Animals, Biological Transport, Blood-Brain Barrier, Brain, Case-Control Studies, Child, Child, Preschool, Consanguinity, Fatty Acids, Omega-3, Female, Genes, Lethal, Genetic Association Studies, HEK293 Cells, Humans, Infant, Male, Mice, Knockout, Microcephaly, Mutation, Missense, Syndrome, Tumor Suppressor Proteins, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3311}, author = {Guemez-Gamboa, Alicia and Nguyen, Long N and Yang, Hongbo and Zaki, Maha S and Kara, Majdi and Ben-Omran, Tawfeg and Akizu, Naiara and Rosti, Rasim Ozgur and Rosti, Basak and Scott, Eric and Schroth, Jana and Copeland, Brett and Vaux, Keith K and Cazenave-Gassiot, Amaury and Quek, Debra Q Y and Wong, Bernice H and Tan, Bryan C and Wenk, Markus R and G{\"u}nel, Murat and Gabriel, Stacey and Chi, Neil C and Silver, David L and Gleeson, Joseph G} } @article {154, title = {KIAA0586 is Mutated in Joubert Syndrome.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Sep}, pages = {831-5}, abstract = {

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62\% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5\% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Alternative Splicing, Brain, Cell Cycle Proteins, Cerebellum, Child, Child, Preschool, DNA Mutational Analysis, Eye Abnormalities, Gene Order, Genetic Association Studies, Humans, Kidney Diseases, Cystic, Magnetic Resonance Imaging, Mutation, Phenotype, Retina, Young Adult}, issn = {1098-1004}, doi = {10.1002/humu.22821}, author = {Bachmann-Gagescu, Ruxandra and Phelps, Ian G and Dempsey, Jennifer C and Sharma, Vivek A and Ishak, Gisele E and Boyle, Evan A and Wilson, Meredith and Marques Louren{\c c}o, Charles and Arslan, Mutluay and Shendure, Jay and Doherty, Dan} } @article {109, title = {Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Dec 03}, pages = {790-800}, abstract = {

Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.

}, keywords = {Adolescent, Animals, Brain, Child, Cutis Laxa, Female, Gene Dosage, Gene Expression Regulation, Developmental, Genes, Recessive, Hamartoma, Haploinsufficiency, Humans, Infant, Inheritance Patterns, Male, Microtubule-Associated Proteins, Microtubules, Mutation, Protein Folding, Protein Multimerization, Skin, Skin Abnormalities, Tubulin, Young Adult, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.10.014}, author = {Isrie, Mala and Breuss, Martin and Tian, Guoling and Hansen, Andi Harley and Cristofoli, Francesca and Morandell, Jasmin and Kupchinsky, Zachari A and Sifrim, Alejandro and Rodriguez-Rodriguez, Celia Maria and Dapena, Elena Porta and Doonanco, Kurston and Leonard, Norma and Tinsa, Faten and Moortgat, St{\'e}phanie and Ulucan, Hakan and Koparir, Erkan and Karaca, Ender and Katsanis, Nicholas and Marton, Valeria and Vermeesch, Joris Robert and Davis, Erica E and Cowan, Nicholas J and Keays, David Anthony and Van Esch, Hilde} } @article {216, title = {New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.}, journal = {JAMA Ophthalmol}, volume = {133}, year = {2015}, month = {2015 Feb}, pages = {133-9}, abstract = {

IMPORTANCE: The families evaluated in this study represent the second report of cone-rod dystrophy (CRD) cases caused by mutations in RAB28, a recently discovered gene associated with CRD.

OBJECTIVE: To determine the disease-causing gene in 2 families of Spanish descent presenting with CRD who do not have ABCA4 mutations.

DESIGN, SETTING, AND PARTICIPANTS: Molecular genetics and observational case studies of 2 families, each with 1 affected proband with CRD and 3 or 5 unaffected family members. The affected individual from each family received a complete ophthalmic examination including assessment of refractive errors and best-corrected visual acuity, biomicroscopy, color fundus photography, electroretinography analysis, and visual-evoked potential analysis. After complete sequencing of the ABCA4 gene with negative results, the screening for disease-causing mutations was performed by whole-exome sequencing. Possible disease-associated variants were determined by filtering based on minor allele frequency, predicted pathogenicity, and segregation analysis in all family members.

MAIN OUTCOMES AND MEASURES: The appearance of the macula was evaluated by clinical examination, fundus photography, and fundus autofluorescence imaging, and visual function was assessed by electroretinography. Disease-causing mutations were assessed by sequence analyses.

RESULTS: Ophthalmologic findings included markedly reduced visual acuity, bull{\textquoteright}s eye maculopathy, foveal hyperpigmentation, peripapillary atrophy, dyschromatopsia, extinguished photopic responses, and reduced scotopic responses observed on electroretinography consistent with the CRD phenotype often associated with ABCA4 mutations. Although no ABCA4 mutations were detected in either patient, whole-exome sequencing analysis identified 2 new homozygous mutations in the recently described RAB28 gene, the c.172 + 1G>C splice site variant in IVS2 and the missense c.T651G:p.C217W substitution. Both variants were determined as deleterious by predictive programs and were segregated with the disease in both families. Sequencing of 107 additional patients of Spanish descent with CRD did not reveal other cases with RAB28 mutations.

CONCLUSIONS AND RELEVANCE: Deleterious mutations in RAB28 result in a classic CRD phenotype and are an infrequent cause of CRD in the Spanish population.

}, keywords = {Adolescent, Adult, Child, Diagnosis, Differential, DNA Mutational Analysis, Female, Follow-Up Studies, Genetic Predisposition to Disease, Hispanic Americans, Humans, Male, Microscopy, Acoustic, Mutation, Pedigree, Phenotype, rab GTP-Binding Proteins, Retinitis Pigmentosa, Retrospective Studies, Young Adult}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2014.4266}, author = {Riveiro-{\'A}lvarez, Rosa and Xie, Yajing Angela and L{\'o}pez-Mart{\'\i}nez, Miguel-{\'A}ngel and Gambin, Tomasz and P{\'e}rez-Carro, Raquel and {\'A}vila-Fern{\'a}ndez, Almudena and L{\'o}pez-Molina, Mar{\'\i}a-Isabel and Zernant, Jana and Jhangiani, Shalini and Muzny, Donna and Yuan, Bo and Boerwinkle, Eric and Gibbs, Richard and Lupski, James R and Ayuso, Carmen and Allikmets, Rando} } @article {223, title = {NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy.}, journal = {Eur J Med Genet}, volume = {58}, year = {2015}, month = {2015 Jan}, pages = {39-43}, abstract = {

N-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteasome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson{\textquoteright}s disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA, p.Asn511LysfsX51). We hypothesize that this mutation likely limits the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, Corneal Opacity, Developmental Disabilities, Female, Frameshift Mutation, Genotype, Humans, Intellectual Disability, Male, Movement Disorders, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, Peripheral Nervous System Diseases}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2014.08.008}, author = {{\c C}a{\u g}layan, Ahmet Okay and Comu, Sinan and Baranoski, Jacob F and Parman, Yesim and Kaymak{\c c}alan, Hande and Akg{\"u}m{\"u}{\c s}, G{\"o}zde Tu{\u g}ce and Caglar, Caner and D{\"o}len, Duygu and Erson-Omay, Emine Zeynep and Harmanci, Akdes Serin and Mishra-Gorur, Ketu and Freeze, Hudson H and Yasuno, Katsuhito and Bilguvar, Kaya and G{\"u}nel, Murat} } @article {120, title = {Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {691-707}, abstract = {

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.

}, keywords = {Abnormalities, Multiple, Charcot-Marie-Tooth Disease, Child, Child, Preschool, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 17, Comparative Genomic Hybridization, Female, Follow-Up Studies, Gene Duplication, Gene Rearrangement, Genome, Human, Genomics, Humans, Infant, Male, Models, Genetic, Myelin Proteins, Phenotype, Prognosis, Recombination, Genetic, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.10.003}, author = {Yuan, Bo and Harel, Tamar and Gu, Shen and Liu, Pengfei and Burglen, Lydie and Chantot-Bastaraud, Sandra and Gelowani, Violet and Beck, Christine R and Carvalho, Claudia M B and Cheung, Sau Wai and Coe, Andrew and Malan, Val{\'e}rie and Munnich, Arnold and Magoulas, Pilar L and Potocki, Lorraine and Lupski, James R} } @article {144, title = {Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {1004-8}, abstract = {

Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.

}, keywords = {Adolescent, Adult, Child, Collagen Type II, Exome, Female, Humans, Joint Diseases, Male, Osteochondrodysplasias, Pedigree, Polymorphism, Single Nucleotide, Radiography, Sequence Analysis, DNA}, issn = {1098-1004}, doi = {10.1002/humu.22839}, author = {Jurgens, Julie and Sobreira, Nara and Modaff, Peggy and Reiser, Catherine A and Seo, Soo Hyun and Seong, Moon-Woo and Park, Sung Sup and Kim, Ok Hwa and Cho, Tae-Joon and Pauli, Richard M} } @article {152, title = {Rare A2ML1 variants confer susceptibility to otitis media.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Aug}, pages = {917-20}, abstract = {

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

}, keywords = {alpha-Macroglobulins, Animals, Base Sequence, Child, Cochlea, Exome, Family Health, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Otitis Media, Pedigree, Principal Component Analysis, Protein Conformation, Sequence Analysis, DNA}, issn = {1546-1718}, doi = {10.1038/ng.3347}, author = {Santos-Cortez, Regie Lyn P and Chiong, Charlotte M and Reyes-Quintos, Ma Rina T and Tantoco, Ma Leah C and Wang, Xin and Acharya, Anushree and Abbe, Izoduwa and Giese, Arnaud P and Smith, Joshua D and Allen, E Kaitlynn and Li, Biao and Cutiongco-de la Paz, Eva Maria and Garcia, Marieflor Cristy and Llanes, Erasmo Gonzalo D V and Labra, Patrick John and Gloria-Cruz, Teresa Luisa I and Chan, Abner L and Wang, Gao T and Daly, Kathleen A and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Patel, Janak A and Riazuddin, Saima and Sale, Michele M and Chonmaitree, Tasnee and Ahmed, Zubair M and Abes, Generoso T and Leal, Suzanne M} } @article {171, title = {Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.}, journal = {Elife}, volume = {4}, year = {2015}, month = {2015 Apr 24}, pages = {e06315}, abstract = {

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5\%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

}, keywords = {Adolescent, Adult, Age of Onset, Aldosterone, Amino Acid Sequence, Calcium, Calcium Channels, T-Type, Calcium Signaling, Child, Child, Preschool, Female, Gene Expression, Genotype, Heterozygote, Humans, Hyperaldosteronism, Hypertension, Infant, Male, Membrane Potentials, Middle Aged, Molecular Sequence Data, Mutation, Phenotype, Recurrence, Sequence Alignment, Zona Glomerulosa}, issn = {2050-084X}, doi = {10.7554/eLife.06315}, author = {Scholl, Ute I and St{\"o}lting, Gabriel and Nelson-Williams, Carol and Vichot, Alfred A and Choi, Murim and Loring, Erin and Prasad, Manju L and Goh, Gerald and Carling, Tobias and Juhlin, C Christofer and Quack, Ivo and Rump, Lars C and Thiel, Anne and Lande, Marc and Frazier, Britney G and Rasoulpour, Majid and Bowlin, David L and Sethna, Christine B and Trachtman, Howard and Fahlke, Christoph and Lifton, Richard P} } @article {106, title = {Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT).}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0143846}, abstract = {

UNLABELLED: Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18 patients with RPE65- or LRAT-related retinitis pigmentosa. Eight of 18 patients (44\%) showed a >=20\% increase and 4 of 18 (22\%) showed a >=40\% increase in functional retinal area determined from Goldmann visual fields; 12 (67\%) and 5 (28\%) of 18 patients showed a >=5 and >=10 ETDRS letter score increase of visual acuity, respectively, in one or both eyes at two or more visits within 2 months of treatment. In two patients who underwent fMRI, a significant positive response was measured to stimuli of medium contrast, moving, pattern targets in both left and right hemispheres of the occipital cortex. There were no serious adverse events. Treatment-related adverse events were transient and the most common included headache, photophobia, nausea, vomiting, and minor biochemical abnormalities. Measuring the outer segment length of the photoreceptor layer with high-definition optical coherence tomography was highly predictive of treatment responses with responders having a significantly larger baseline outer segment thickness (11.7 {\textpm} 4.8 μm, mean {\textpm} 95\% CI) than non-responders (3.5 {\textpm} 1.2 μm). This structure-function relationship suggests that treatment with QLT091001 is more likely to be efficacious if there is sufficient photoreceptor integrity.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01014052.

}, keywords = {Acyltransferases, Administration, Oral, Adult, Anticarcinogenic Agents, Cerebral Cortex, Child, cis-trans-Isomerases, Drug Dosage Calculations, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Radiography, Retinal Ganglion Cells, Retinal Neurons, Retinitis Pigmentosa, Treatment Outcome, Visual Acuity, Visual Fields, Vitamin A, Young Adult}, issn = {1932-6203}, doi = {10.1371/journal.pone.0143846}, author = {Scholl, Hendrik P N and Moore, Anthony T and Koenekoop, Robert K and Wen, Yuquan and Fishman, Gerald A and van den Born, L Ingeborgh and Bittner, Ava and Bowles, Kristen and Fletcher, Emily C and Collison, Frederick T and Dagnelie, Gislin and Degli Eposti, Simona and Michaelides, Michel and Saperstein, David A and Schuchard, Ronald A and Barnes, Claire and Zein, Wadih and Zobor, Ditta and Birch, David G and Mendola, Janine D and Zrenner, Eberhart} } @article {190, title = {Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma.}, journal = {J Invest Dermatol}, volume = {135}, year = {2015}, month = {2015 Jun}, pages = {1698-1700}, keywords = {Adolescent, Cell Proliferation, Child, Child, Preschool, Female, Gene Expression Regulation, Neoplastic, Granuloma, Pyogenic, Humans, Infant, Infant, Newborn, Male, Mutation, ras Proteins, Vascular Neoplasms}, issn = {1523-1747}, doi = {10.1038/jid.2015.55}, author = {Lim, Young H and Douglas, Stephanie R and Ko, Christine J and Antaya, Richard J and McNiff, Jennifer M and Zhou, Jing and Choate, Keith A and Narayan, Deepak} } @article {166, title = {Somatic V600E BRAF Mutation in Linear and Sporadic Syringocystadenoma Papilliferum.}, journal = {J Invest Dermatol}, volume = {135}, year = {2015}, month = {2015 Oct}, pages = {2536-2538}, keywords = {Biopsy, Needle, Child, Cystadenoma, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Mutation, Proto-Oncogene Proteins B-raf, Sweat Gland Neoplasms, Syringoma}, issn = {1523-1747}, doi = {10.1038/jid.2015.180}, author = {Levinsohn, Jonathan L and Sugarman, Jeffrey L and Bilguvar, Kaya and McNiff, Jennifer M and Choate, Keith A} } @article {158, title = {Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh{\textquoteright}s disease.}, journal = {Mol Genet Metab}, volume = {115}, year = {2015}, month = {2015 Aug}, pages = {161-7}, abstract = {

PURPOSE: 3-Hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine metabolism. We present a family with the oldest reported subjects with HIBCH deficiency and provide support that HIBCH deficiency should be included in the differential for elevated hydroxy-C4-carnitine in newborn screening (NBS).

METHODS: Whole exome sequencing (WES) was performed on one affected sibling. HIBCH enzymatic activity was measured in patient fibroblasts. Acylcarnitines were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Disease incidence was estimated using a cohort of 61,434 individuals.

RESULTS: Two siblings presented with infantile-onset, progressive neurodegenerative disease. WES identified a novel homozygous variant in HIBCH c.196C>T; p.Arg66Trp. HIBCH enzymatic activity was significantly reduced in patients{\textquoteright} fibroblasts. Acylcarnitine analysis showed elevated hydroxy-C4-carnitine in blood spots of both affected siblings, including in their NBS cards, while plasma acylcarnitines were normal. Estimates show HIBCH deficiency incidence as high as 1 in ~130,000 individuals.

CONCLUSION: We describe a novel family with HIBCH deficiency at the biochemical, enzymatic and molecular level. Disease incidence estimates indicate HIBCH deficiency may be under-diagnosed. This together with the elevated hydroxy-C4-carnitine found in the retrospective analysis of our patient{\textquoteright}s NBS cards suggests that this disorder could be screened for by NBS programs and should be added to the differential diagnosis for elevated hydroxy-C4-carnitine which is already measured in most NBS programs using MS/MS.

}, keywords = {Abnormalities, Multiple, Adolescent, Amino Acid Metabolism, Inborn Errors, Carnitine, Child, Child, Preschool, Cohort Studies, Exome, Female, Fibroblasts, Humans, Infant, Infant, Newborn, Leigh Disease, Male, Mass Spectrometry, Neonatal Screening, Prognosis, Retrospective Studies, Sequence Analysis, DNA, Siblings, Thiolester Hydrolases}, issn = {1096-7206}, doi = {10.1016/j.ymgme.2015.05.008}, author = {Stiles, Ashlee R and Ferdinandusse, Sacha and Besse, Arnaud and Appadurai, Vivek and Leydiker, Karen B and Cambray-Forker, E J and Bonnen, Penelope E and Abdenur, Jose E} } @article {201, title = {TBX6 null variants and a common hypomorphic allele in congenital scoliosis.}, journal = {N Engl J Med}, volume = {372}, year = {2015}, month = {2015 Jan 22}, pages = {341-50}, abstract = {

BACKGROUND: Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.

METHODS: We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions.

RESULTS: We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11\%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8{\texttimes}10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1{\texttimes}10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis.

CONCLUSIONS: Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11\% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.).

}, keywords = {Adolescent, Asian Continental Ancestry Group, Child, Child, Preschool, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Mutation, Pedigree, Phenotype, Radiography, Scoliosis, Sequence Deletion, Spine, T-Box Domain Proteins}, issn = {1533-4406}, doi = {10.1056/NEJMoa1406829}, author = {Wu, N and Ming, X and Xiao, J and Wu, Z and Chen, X and Shinawi, M and Shen, Y and Yu, G and Liu, J and Xie, H and Gucev, Z S and Liu, S and Yang, N and Al-Kateb, H and Chen, J and Zhang, J and Hauser, N and Zhang, T and Tasic, V and Liu, P and Su, X and Pan, X and Liu, C and Wang, L and Shen, J and Shen, J and Chen, Y and Zhang, T and Zhang, J and Choy, K W and Wang, J and Wang, Q and Li, S and Zhou, W and Guo, J and Wang, Y and Zhang, C and Zhao, Hong and An, Yu and Zhao, Yu and Wang, J and Liu, Z and Zuo, Y and Tian, Y and Weng, X and Sutton, V R and Wang, H and Ming, Y and Kulkarni, S and Zhong, T P and Giampietro, P F and Dunwoodie, S L and Cheung, S W and Zhang, X and Jin, L and Lupski, J R and Qiu, G and Zhang, F} } @article {214, title = {Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Feb}, pages = {271-81}, abstract = {

Lateral meningocele syndrome (LMS, OMIM\%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL.

}, keywords = {Abnormalities, Multiple, Child, Child, Preschool, DNA Mutational Analysis, Exome, Exons, Facies, High-Throughput Nucleotide Sequencing, Humans, Magnetic Resonance Imaging, Male, Meningocele, Mutation, Phenotype, Receptor, Notch3, Receptors, Notch, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36863}, author = {Gripp, Karen W and Robbins, Katherine M and Sobreira, Nara L and Witmer, P Dane and Bird, Lynne M and Avela, Kristiina and M{\"a}kitie, Outi and Alves, Daniela and Hogue, Jacob S and Zackai, Elaine H and Doheny, Kimberly F and Stabley, Deborah L and Sol-Church, Katia} } @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 {238, title = {Attitudes of genetics professionals toward the return of incidental results from exome and whole-genome sequencing.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Jul 03}, pages = {77-84}, abstract = {

Professional recommendations for the return of results from exome and whole-genome sequencing (ES/WGS) have been controversial. The lack of clear guidance about whether and, if so, how to return ES/WGS incidental results limits the extent to which individuals and families might benefit from ES/WGS. The perspectives of genetics professionals, particularly those at the forefront of using ES/WGS in clinics, are largely unknown. Data on stakeholder perspectives could help clarify how to weigh expert positions and recommendations. We conducted an online survey of 9,857 genetics professionals to learn their attitudes on the return of incidental results from ES/WGS and the recent American College of Medical Genetic and Genomics Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. Of the 847 respondents, 760 completed the survey. The overwhelming majority of respondents thought that incidental ES/WGS results should be offered to adult patients (85\%), healthy adults (75\%), and the parents of a child with a medical condition (74\%). The majority thought that incidental results about adult-onset conditions (62\%) and carrier status (62\%) should be offered to the parents of a child with a medical condition. About half thought that offered results should not be limited to those deemed clinically actionable. The vast majority (81\%) thought that individual preferences should guide return. Genetics professionals{\textquoteright} perspectives on the return of ES/WGS results differed substantially from current recommendations, underscoring the need to establish clear purpose for recommendations on the return of incidental ES/WGS results as professional societies grapple with developing and updating recommendations.

}, keywords = {Adult, Attitude of Health Personnel, Child, Exome, Genetics, Medical, Genome, Human, Humans, Incidental Findings, Workforce}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.06.004}, author = {Yu, Joon-Ho and Harrell, Tanya M and Jamal, Seema M and Tabor, Holly K and Bamshad, Michael J} } @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 {248, title = {De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {784-9}, abstract = {

Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25\% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.

}, keywords = {Child, Child, Preschool, DNA-Binding Proteins, Exome, Female, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Muscle Hypotonia, Mutation, Sleep Apnea Syndromes, Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.04.006}, author = {Xia, Fan and Bainbridge, Matthew N and Tan, Tiong Yang and Wangler, Michael F and Scheuerle, Angela E and Zackai, Elaine H and Harr, Margaret H and Sutton, V Reid and Nalam, Roopa L and Zhu, Wenmiao and Nash, Margot and Ryan, Monique M and Yaplito-Lee, Joy and Hunter, Jill V and Deardorff, Matthew A and Penney, Samantha J and Beaudet, Arthur L and Plon, Sharon E and Boerwinkle, Eric A and Lupski, James R and Eng, Christine M and Muzny, Donna M and Yang, Yaping and Gibbs, Richard A} } @article {281, title = {The genetic basis of DOORS syndrome: an exome-sequencing study.}, journal = {Lancet Neurol}, volume = {13}, year = {2014}, month = {2014 Jan}, pages = {44-58}, abstract = {

BACKGROUND: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.

METHODS: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.

FINDINGS: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.

INTERPRETATION: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.

FUNDING: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

}, keywords = {Adolescent, Carrier Proteins, Child, Child, Preschool, Craniofacial Abnormalities, Exome, Female, Hand Deformities, Congenital, Hearing Loss, Sensorineural, Humans, Infant, Intellectual Disability, Internationality, Male, Nails, Malformed, Phenotype, Sequence Analysis, DNA, Young Adult}, issn = {1474-4465}, doi = {10.1016/S1474-4422(13)70265-5}, author = {Campeau, Philippe M and Kasperaviciute, Dalia and Lu, James T and Burrage, Lindsay C and Kim, Choel and Hori, Mutsuki and Powell, Berkley R and Stewart, Fiona and F{\'e}lix, T{\^e}mis Maria and van den Ende, Jenneke and Wisniewska, Marzena and Kayserili, H{\"u}lya and Rump, Patrick and Nampoothiri, Sheela and Aftimos, Salim and Mey, Antje and Nair, Lal D V and Begleiter, Michael L and De Bie, Isabelle and Meenakshi, Girish and Murray, Mitzi L and Repetto, Gabriela M and Golabi, Mahin and Blair, Edward and Male, Alison and Giuliano, Fabienne and Kariminejad, Ariana and Newman, William G and Bhaskar, Sanjeev S and Dickerson, Jonathan E and Kerr, Bronwyn and Banka, Siddharth and Giltay, Jacques C and Wieczorek, Dagmar and Tostevin, Anna and Wiszniewska, Joanna and Cheung, Sau Wai and Hennekam, Raoul C and Gibbs, Richard A and Lee, Brendan H and Sisodiya, Sanjay M} } @article {234, title = {Germ-line and somatic DICER1 mutations in pineoblastoma.}, journal = {Acta Neuropathol}, volume = {128}, year = {2014}, month = {2014 Oct}, pages = {583-95}, abstract = {

Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.

}, keywords = {Adolescent, Brain Neoplasms, Child, Child, Preschool, DEAD-box RNA Helicases, DNA Mutational Analysis, Family Health, Female, Germ-Line Mutation, Humans, Infant, Male, Pineal Gland, Pinealoma, Ribonuclease III, Young Adult}, issn = {1432-0533}, doi = {10.1007/s00401-014-1318-7}, author = {de Kock, Leanne and Sabbaghian, Nelly and Druker, Harriet and Weber, Evan and Hamel, Nancy and Miller, Suzanne and Choong, Catherine S and Gottardo, Nicholas G and Kees, Ursula R and Rednam, Surya P and van Hest, Liselotte P and Jongmans, Marjolijn C and Jhangiani, Shalini and Lupski, James R and Zacharin, Margaret and Bouron-Dal Soglio, Doroth{\'e}e and Huang, Annie and Priest, John R and Perry, Arie and Mueller, Sabine and Albrecht, Steffen and Malkin, David and Grundy, Richard G and Foulkes, William D} } @article {207, title = {Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Dec 18}, pages = {2363-74}, abstract = {

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.

METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.

RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients{\textquoteright} pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.

CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

}, keywords = {Acromegaly, Adolescent, Adult, Age of Onset, Child, Child, Preschool, Chromosome Duplication, Chromosomes, Human, X, Female, Gigantism, Human Growth Hormone, Humans, Infant, Male, Mutation, Phenotype, Protein Conformation, Receptors, G-Protein-Coupled}, issn = {1533-4406}, doi = {10.1056/NEJMoa1408028}, author = {Trivellin, Giampaolo and Daly, Adrian F and Faucz, Fabio R and Yuan, Bo and Rostomyan, Liliya and Larco, Darwin O and Schernthaner-Reiter, Marie Helene and Szarek, Eva and Leal, Let{\'\i}cia F and Caberg, Jean-Hubert and Castermans, Emilie and Villa, Chiara and Dimopoulos, Aggeliki and Chittiboina, Prashant and Xekouki, Paraskevi and Shah, Nalini and Metzger, Daniel and Lysy, Philippe A and Ferrante, Emanuele and Strebkova, Natalia and Mazerkina, Nadia and Zatelli, Maria Chiara and Lodish, Maya and Horvath, Anelia and de Alexandre, Rodrigo Bertollo and Manning, Allison D and Levy, Isaac and Keil, Margaret F and Sierra, Maria de la Luz and Palmeira, Leonor and Coppieters, Wouter and Georges, Michel and Naves, Luciana A and Jamar, Mauricette and Bours, Vincent and Wu, T John and Choong, Catherine S and Bertherat, Jerome and Chanson, Philippe and Kamenick{\'y}, Peter and Farrell, William E and Barlier, Anne and Quezado, Martha and Bjelobaba, Ivana and Stojilkovic, Stanko S and Wess, Jurgen and Costanzi, Stefano and Liu, Pengfei and Lupski, James R and Beckers, Albert and Stratakis, Constantine A} } @article {257, title = {Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Mar}, pages = {e1004258}, abstract = {

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon{\textquoteright}s initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.

}, keywords = {Abnormalities, Multiple, Actins, Adolescent, Adult, Child, Child, Preschool, Colon, Exome, Female, Heterozygote, Humans, Intestinal Pseudo-Obstruction, Male, Muscle, Smooth, Mutation, Urinary Bladder}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004258}, author = {Wangler, Michael F and Gonzaga-Jauregui, Claudia and Gambin, Tomasz and Penney, Samantha and Moss, Timothy and Chopra, Atul and Probst, Frank J and Xia, Fan and Yang, Yaping and Werlin, Steven and Eglite, Ieva and Kornejeva, Liene and Bacino, Carlos A and Baldridge, Dustin and Neul, Jeff and Lehman, Efrat Lev and Larson, Austin and Beuten, Joke and Muzny, Donna M and Jhangiani, Shalini and Gibbs, Richard A and Lupski, James R and Beaudet, Arthur} } @article {236, title = {Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.}, journal = {J Hepatol}, volume = {61}, year = {2014}, month = {2014 Nov}, pages = {1056-63}, abstract = {

BACKGROUND \& AIMS: In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology.

METHODS: Patient 1 was a 10 year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2 day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown aetiology since age 3 months.

RESULTS: Unbiased whole-exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations.

CONCLUSIONS: Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.

}, keywords = {Amino Acid Sequence, Base Sequence, Carboxylic Ester Hydrolases, Child, Cholestasis, DNA Mutational Analysis, End Stage Liver Disease, Exome, Fatal Outcome, Female, Genes, Recessive, Hepatolenticular Degeneration, Heterozygote, Homozygote, Humans, Infant, Newborn, Liver Failure, Liver Failure, Acute, Male, Membrane Proteins, Mitochondrial Proteins, Molecular Sequence Data, Pedigree, Receptor, Notch2, RNA Splice Sites, Sequence Homology, Amino Acid}, issn = {1600-0641}, doi = {10.1016/j.jhep.2014.06.038}, author = {Vilarinho, S{\'\i}lvia and Choi, Murim and Jain, Dhanpat and Malhotra, Ajay and Kulkarni, Sanjay and Pashankar, Dinesh and Phatak, Uma and Patel, Mohini and Bale, Allen and Mane, Shrikant and Lifton, Richard P and Mistry, Pramod K} } @article {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 {273, title = {Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jun 01}, pages = {2888-900}, abstract = {

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80\% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for \~{}5\% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

}, keywords = {Amino Acid Sequence, Child, Child, Preschool, Cohort Studies, Cranial Fontanelles, De Lange Syndrome, Eye Abnormalities, Female, Genes, X-Linked, Histone Deacetylases, Humans, Hypertelorism, Infant, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Repressor Proteins, Sequence Alignment}, issn = {1460-2083}, doi = {10.1093/hmg/ddu002}, author = {Kaiser, Frank J and Ansari, Morad and Braunholz, Diana and Concepci{\'o}n Gil-Rodr{\'\i}guez, Mar{\'\i}a and Decroos, Christophe and Wilde, Jonathan J and Fincher, Christopher T and Kaur, Maninder and Bando, Masashige and Amor, David J and Atwal, Paldeep S and Bahlo, Melanie and Bowman, Christine M and Bradley, Jacquelyn J and Brunner, Han G and Clark, Dinah and Del Campo, Miguel and Di Donato, Nataliya and Diakumis, Peter and Dubbs, Holly and Dyment, David A and Eckhold, Juliane and Ernst, Sarah and Ferreira, Jose C and Francey, Lauren J and Gehlken, Ulrike and Guill{\'e}n-Navarro, Encarna and Gyftodimou, Yolanda and Hall, Bryan D and Hennekam, Raoul and Hudgins, Louanne and Hullings, Melanie and Hunter, Jennifer M and Yntema, Helger and Innes, A Micheil and Kline, Antonie D and Krumina, Zita and Lee, Hane and Leppig, Kathleen and Lynch, Sally Ann and Mallozzi, Mark B and Mannini, Linda and McKee, Shane and Mehta, Sarju G and Micule, Ieva and Mohammed, Shehla and Moran, Ellen and Mortier, Geert R and Moser, Joe-Ann S and Noon, Sarah E and Nozaki, Naohito and Nunes, Luis and Pappas, John G and Penney, Lynette S and P{\'e}rez-Ayt{\'e}s, Antonio and Petersen, Michael B and Puisac, Beatriz and Revencu, Nicole and Roeder, Elizabeth and Saitta, Sulagna and Scheuerle, Angela E and Schindeler, Karen L and Siu, Victoria M and Stark, Zornitza and Strom, Samuel P and Thiese, Heidi and Vater, Inga and Willems, Patrick and Williamson, Kathleen and Wilson, Louise C and Hakonarson, Hakon and Quintero-Rivera, Fabiola and Wierzba, Jolanta and Musio, Antonio and Gillessen-Kaesbach, Gabriele and Ramos, Feliciano J and Jackson, Laird G and Shirahige, Katsuhiko and Pi{\'e}, Juan and Christianson, David W and Krantz, Ian D and FitzPatrick, David R and Deardorff, Matthew A} } @article {217, title = {Molecular findings among patients referred for clinical whole-exome sequencing.}, journal = {JAMA}, volume = {312}, year = {2014}, month = {2014 Nov 12}, pages = {1870-9}, abstract = {

IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.

OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.

DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient{\textquoteright}s physician. The patients were primarily pediatric (1756 [88\%]; mean age, 6 years; 888 females [44\%], 1101 males [55\%], and 11 fetuses [1\% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.

RESULTS: A molecular diagnosis was reported for 504 patients (25.2\%) with 58\% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2\%; 95\% CI, 23.5\%-31.2\%) for the neurological group, 282/1147 (24.6\%; 95\% CI, 22.1\%-27.2\%) for the neurological plus other organ systems group, 30/83 (36.1\%; 95\% CI, 26.1\%-47.5\%) for the specific neurological group, and 49/244 (20.1\%; 95\% CI, 15.6\%-25.8\%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1\%) autosomal dominant, 181 (34.3\%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3\%) X-linked, and 1 (0.2\%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6\%) had blended phenotypes resulting from 2 single gene defects. About 30\% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6\%), including 59 patients (3\%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.

CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25\% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Exome, Female, Fetus, Genetic Diseases, Inborn, Genetic Testing, Genomics, Humans, Incidental Findings, Infant, Infant, Newborn, Male, Molecular Diagnostic Techniques, Mutation, Phenotype, Referral and Consultation, Sequence Analysis, DNA}, issn = {1538-3598}, doi = {10.1001/jama.2014.14601}, author = {Yang, Yaping and Muzny, Donna M and Xia, Fan and Niu, Zhiyv and Person, Richard and Ding, Yan and Ward, Patricia and Braxton, Alicia and Wang, Min and Buhay, Christian and Veeraraghavan, Narayanan and Hawes, Alicia and Chiang, Theodore and Leduc, Magalie and Beuten, Joke and Zhang, Jing and He, Weimin and Scull, Jennifer and Willis, Alecia and Landsverk, Megan and Craigen, William J and Bekheirnia, Mir Reza and Stray-Pedersen, Asbjorg and Liu, Pengfei and Wen, Shu and Alcaraz, Wendy and Cui, Hong and Walkiewicz, Magdalena and Reid, Jeffrey and Bainbridge, Matthew and Patel, Ankita and Boerwinkle, Eric and Beaudet, Arthur L and Lupski, James R and Plon, Sharon E and Gibbs, Richard A and Eng, Christine M} } @article {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 {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 {256, title = {Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {734-44}, abstract = {

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83\%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82\%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher{\textquoteright}s exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.

}, keywords = {Abnormalities, Multiple, Arachnodactyly, Arthrogryposis, Blepharophimosis, Child, Child, Preschool, Cleft Palate, Clubfoot, Connective Tissue Diseases, Contracture, Exome, Female, Hand Deformities, Congenital, Humans, Ion Channels, Male, Mutation, Ophthalmoplegia, Pedigree, Retinal Diseases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.03.015}, author = {McMillin, Margaret J and Beck, Anita E and Chong, Jessica X and Shively, Kathryn M and Buckingham, Kati J and Gildersleeve, Heidi I S and Aracena, Mariana I and Aylsworth, Arthur S and Bitoun, Pierre and Carey, John C and Clericuzio, Carol L and Crow, Yanick J and Curry, Cynthia J and Devriendt, Koenraad and Everman, David B and Fryer, Alan and Gibson, Kate and Giovannucci Uzielli, Maria Luisa and Graham, John M and Hall, Judith G and Hecht, Jacqueline T and Heidenreich, Randall A and Hurst, Jane A and Irani, Sarosh and Krapels, Ingrid P C and Leroy, Jules G and Mowat, David and Plant, Gordon T and Robertson, Stephen P and Schorry, Elizabeth K and Scott, Richard H and Seaver, Laurie H and Sherr, Elliott and Splitt, Miranda and Stewart, Helen and Stumpel, Constance and Temel, Sehime G and Weaver, David D and Whiteford, Margo and Williams, Marc S and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {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 {242, title = {New syndrome with retinitis pigmentosa is caused by nonsense mutations in retinol dehydrogenase RDH11.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Nov 01}, pages = {5774-80}, abstract = {

Retinitis pigmentosa (RP), a genetically heterogeneous group of retinopathies that occur in both non-syndromic and syndromic forms, is caused by mutations in \~{}100 genes. Although recent advances in next-generation sequencing have aided in the discovery of novel RP genes, a number of the underlying contributing genes and loci remain to be identified. We investigated three siblings, born to asymptomatic parents of Italian-American descent, who each presented with atypical RP with systemic features, including facial dysmorphologies, psychomotor developmental delays recognized since early childhood, learning disabilities and short stature. RP-associated ophthalmological findings included salt-and-pepper retinopathy, attenuation of the arterioles and generalized rod-cone dysfunction as determined by almost extinguished electroretinogram in 2 of 3 siblings. Atypical for RP features included mottled macula at an early age and peripapillary sparing of the retinal pigment epithelium. Whole-exome sequencing data, queried under a recessive model of inheritance, identified compound heterozygous stop mutations, c.C199T:p.R67* and c.C322T:p.R108*, in the retinol dehydrogenase 11 (RDH11) gene, resulting in a non-functional protein, in all affected children. In summary, deleterious mutations in RDH11, an important enzyme for vision-related and systemic retinoic acid metabolism, cause a new syndrome with RP.

}, keywords = {Adolescent, Child, Codon, Nonsense, Female, Humans, Male, Oxidoreductases, Pedigree, Phenotype, Retinitis Pigmentosa, Syndrome, Vision Tests, Visual Acuity, Young Adult}, issn = {1460-2083}, doi = {10.1093/hmg/ddu291}, author = {Xie, Yajing Angela and Lee, Winston and Cai, Carolyn and Gambin, Tomasz and N{\~o}upuu, Kalev and Sujirakul, Tharikarn and Ayuso, Carmen and Jhangiani, Shalini and Muzny, Donna and Boerwinkle, Eric and Gibbs, Richard and Greenstein, Vivienne C and Lupski, James R and Tsang, Stephen H and Allikmets, Rando} } @article {271, title = {NR2F1 mutations cause optic atrophy with intellectual disability.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {303-9}, abstract = {

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Child, Child, Preschool, COUP Transcription Factor I, DNA-Binding Proteins, Female, Genotype, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Optic Atrophy, Phenotype, Young Adult, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.002}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and Gonzaga-Jauregui, Claudia and Xu, Mafei and de Ligt, Joep and Jhangiani, Shalini and Wiszniewski, Wojciech and Muzny, Donna M and Yntema, Helger G and Pfundt, Rolph and Vissers, Lisenka E L M and Spruijt, Liesbeth and Blokland, Ellen A W and Chen, Chun-An and Lewis, Richard A and Tsai, Sophia Y and Gibbs, Richard A and Tsai, Ming-Jer and Lupski, James R and Zoghbi, Huda Y and Cremers, Frans P M and de Vries, Bert B A and Schaaf, Christian P} } @article {239, title = {Opsismodysplasia resulting from an insertion mutation in the SH2 domain, which destabilizes INPPL1.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2407-11}, keywords = {Adolescent, Amino Acid Sequence, Base Sequence, Child, Child, Preschool, Female, Humans, Infant, Molecular Sequence Data, Mutagenesis, Insertional, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Protein Stability, Radiography, RNA Splice Sites, src Homology Domains}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36640}, author = {Li, Bing and Krakow, Deborah and Nickerson, Deborah A and Bamshad, Michael J and Chang, Yong and Lachman, Ralph S and Yilmaz, Alev and Kayserili, H{\"u}lya and Cohn, Daniel H} } @article {219, title = {RNF213 rare variants in an ethnically diverse population with Moyamoya disease.}, journal = {Stroke}, volume = {45}, year = {2014}, month = {2014 Nov}, pages = {3200-7}, abstract = {

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States.

METHODS: We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families.

RESULTS: RNF213 p.R4810K was identified in 56\% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6\% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29\% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant.

CONCLUSIONS: These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD.

}, keywords = {Adenosine Triphosphatases, Adolescent, Adult, Child, Cohort Studies, Ethnic Groups, Female, Genetic Variation, Humans, Male, Moyamoya Disease, Population Surveillance, Ubiquitin-Protein Ligases, Young Adult}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.114.006244}, author = {Cecchi, Alana C and Guo, Dongchuan and Ren, Zhao and Flynn, Kelly and Santos-Cortez, Regie Lyn P and Leal, Suzanne M and Wang, Gao T and Regalado, Ellen S and Steinberg, Gary K and Shendure, Jay and Bamshad, Michael J and Grotta, James C and Nickerson, Deborah A and Pannu, Hariyadarshi and Milewicz, Dianna M} } @article {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 {233, title = {Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2328-34}, abstract = {

GAPO syndrome (OMIM$\#$230740) is the acronym for growth retardation, alopecia, pseudoanodontia, and optic atrophy. About 35 cases have been reported, making it among one of the rarest recessive conditions. Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype. While this genomic study was in progress mutations in ANTXR1 were reported to cause GAPO syndrome. In our study we performed whole exome sequencing (WES) for five affected individuals from three Turkish kindreds segregating the GAPO trait. Exome sequencing analysis identified three novel homozygous mutations including; one frame-shift (c.1220_1221insT; p.Ala408Cysfs*2), one splice site (c.411A>G; p.Gln137Gln), and one non-synonymous (c.1150G>A; p.Gly384Ser) mutation in the ANTXR1 gene. Our studies expand the allelic spectrum in this rare condition and potentially provide insight into the role of ANTXR1 in the regulation of the extracellular matrix.

}, keywords = {Adolescent, Adult, Alopecia, Anodontia, Base Sequence, Child, Chromosome Segregation, DNA Mutational Analysis, Exome, Facies, Family, Female, Growth Disorders, Humans, Male, Molecular Sequence Data, Mutation, Neoplasm Proteins, Optic Atrophies, Hereditary, Pedigree, Protein Structure, Tertiary, Receptors, Cell Surface}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36678}, author = {Bayram, Yavuz and Pehlivan, Davut and Karaca, Ender and Gambin, Tomasz and Jhangiani, Shalini N and Erdin, Serkan and Gonzaga-Jauregui, Claudia and Wiszniewski, Wojciech and Muzny, Donna and Elcioglu, Nursel H and Yildirim, M Selman and Bozkurt, Banu and Zamani, Ayse Gul and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R} } @article {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 {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 {290, title = {Evidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome.}, journal = {Am J Med Genet A}, volume = {161A}, year = {2013}, month = {2013 Dec}, pages = {3182-6}, abstract = {

Haploinsufficiency of CHD7 (OMIM$\#$ 608892) is known to cause CHARGE syndrome (OMIM$\#$ 214800). Molecular testing supports a definitive diagnosis in approximately 65-70\% of cases. Most CHD7 mutations arise de novo, and no mutations affecting exon-7 have been reported to date. We report on an 8-year-old girl diagnosed with CHARGE syndrome that was referred to our laboratory for comprehensive CHD7 gene screening. Genomic DNA from the subject with a suspected diagnosis of CHARGE was isolated from peripheral blood lymphocytes and comprehensive Sanger sequencing, along with deletion/duplication analysis of the CHD7 gene using multiplex ligation-dependent probe amplification (MLPA), was performed. MLPA analysis identified a reduced single probe signal for exon-7 of the CHD7 gene consistent with potential heterozygous deletion. Long-range PCR breakpoint analysis identified a complex genomic rearrangement (CGR) leading to the deletion of exon-7 and breakpoints consistent with a replicative mechanism such as fork stalling and template switching (FoSTeS) or microhomology-mediated break-induced replication (MMBIR). Taken together this represents the first evidence for a CHD7 intragenic CGR in a patient with CHARGE syndrome leading to what appears to be also the first report of a mutation specifically disrupting exon-7. Although likely rare, CGR may represent an overlooked mechanism in subjects with CHARGE syndrome that can be missed by current sequencing and dosage assays.

}, keywords = {Abnormalities, Multiple, CHARGE Syndrome, Child, DNA Helicases, DNA Replication, DNA-Binding Proteins, Exons, Female, Gene Deletion, Haploinsufficiency, Humans, Mutation}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36178}, author = {Vatta, Matteo and Niu, Zhiyv and Lupski, James R and Putnam, Philip and Spoonamore, Katherine G and Fang, Ping and Eng, Christine M and Willis, Alecia S} } @article {305, title = {Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Apr 04}, pages = {632-6}, abstract = {

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.

}, keywords = {Biological Transport, Case-Control Studies, Child, Child, Preschool, Congenital Disorders of Glycosylation, Exome, Female, Glycosylation, Humans, Male, Monosaccharide Transport Proteins, Mosaicism, Mutation, Spectrometry, Mass, Electrospray Ionization, Transferrin, Uridine Diphosphate Galactose}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.03.012}, author = {Ng, Bobby G and Buckingham, Kati J and Raymond, Kimiyo and Kircher, Martin and Turner, Emily H and He, Miao and Smith, Joshua D and Eroshkin, Alexey and Szybowska, Marta and Losfeld, Marie E and Chong, Jessica X and Kozenko, Mariya and Li, Chumei and Patterson, Marc C and Gilbert, Rodney D and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Freeze, Hudson H} } @article {295, title = {Mutations in DSTYK and dominant urinary tract malformations.}, journal = {N Engl J Med}, volume = {369}, year = {2013}, month = {2013 Aug 15}, pages = {621-9}, abstract = {

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.

METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.

RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.

CONCLUSIONS: We detected independent DSTYK mutations in 2.3\% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

}, keywords = {Adult, Animals, Base Sequence, Child, Exome, Female, Gene Knockdown Techniques, Genetic Linkage, Genome-Wide Association Study, Heterozygote, Humans, Infant, Kidney, Male, Mice, Molecular Sequence Data, Mutation, Pedigree, Receptor-Interacting Protein Serine-Threonine Kinases, RNA, Small Interfering, Urinary Tract, Urogenital Abnormalities, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa1214479}, author = {Sanna-Cherchi, Simone and Sampogna, Rosemary V and Papeta, Natalia and Burgess, Katelyn E and Nees, Shannon N and Perry, Brittany J and Choi, Murim and Bodria, Monica and Liu, Yan and Weng, Patricia L and Lozanovski, Vladimir J and Verbitsky, Miguel and Lugani, Francesca and Sterken, Roel and Paragas, Neal and Caridi, Gianluca and Carrea, Alba and Dagnino, Monica and Materna-Kiryluk, Anna and Santamaria, Giuseppe and Murtas, Corrado and Ristoska-Bojkovska, Nadica and Izzi, Claudia and Kacak, Nilgun and Bianco, Beatrice and Giberti, Stefania and Gigante, Maddalena and Piaggio, Giorgio and Gesualdo, Loreto and Vukic, Durdica Kosuljandic and Vukojevic, Katarina and Saraga-Babic, Mirna and Saraga, Marijan and Gucev, Zoran and Allegri, Landino and Latos-Bielenska, Anna and Casu, Domenica and State, Matthew and Scolari, Francesco and Ravazzolo, Roberto and Kiryluk, Krzysztof and Al-Awqati, Qais and D{\textquoteright}Agati, Vivette D and Drummond, Iain A and Tasic, Velibor and Lifton, Richard P and Ghiggeri, Gian Marco and Gharavi, Ali G} } @article {287, title = {Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly.}, journal = {JAMA Neurol}, volume = {70}, year = {2013}, month = {2013 Dec}, pages = {1491-8}, abstract = {

IMPORTANCE: Patients with rare diseases and complex clinical presentations represent a challenge for clinical diagnostics. Genomic approaches are allowing the identification of novel variants in genes for very rare disorders, enabling a molecular diagnosis. Genomics is also revealing a phenotypic expansion whereby the full spectrum of clinical expression conveyed by mutant alleles at a locus can be better appreciated.

OBJECTIVE: To elucidate the molecular cause of a complex neuropathy phenotype in 3 patients by applying genomic sequencing strategies.

DESIGN, SETTING, AND PARTICIPANTS: Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly. They were recruited into the Centers for Mendelian Genomics research program to identify the molecular cause of their phenotype. Whole-genome, targeted whole-exome sequencing, and high-resolution single-nucleotide polymorphism arrays were performed in genetics clinics of tertiary care pediatric hospitals and biomedical research institutions.

MAIN OUTCOMES AND MEASURES: Whole-genome and whole-exome sequencing identified the variants responsible for the patients{\textquoteright} clinical phenotype.

RESULTS: We identified compound heterozygous alleles in 2 affected siblings from 1 family and a homozygous nonsense variant in the third unrelated patient in the vaccinia-related kinase 1 gene (VRK1). In the latter subject, we found a common haplotype on which the nonsense mutation occurred and that segregates in the Ashkenazi Jewish population.

CONCLUSIONS AND RELEVANCE: We report the identification of disease-causing alleles in 3 children from 2 unrelated families with a previously uncharacterized complex axonal motor and sensory neuropathy accompanied by severe nonprogressive microcephaly and cerebral dysgenesis. Our data raise the question of whether VRK1 mutations disturb cell cycle progression and may result in apoptosis of cells in the nervous system. The application of unbiased genomic approaches allows the identification of potentially pathogenic mutations in unsuspected genes in highly genetically heterogeneous and uncharacterized neurological diseases.

}, keywords = {Child, Child, Preschool, DNA Mutational Analysis, Female, Genotype, Hereditary Sensory and Motor Neuropathy, Humans, Infant, Intracellular Signaling Peptides and Proteins, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Neural Conduction, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2013.4598}, author = {Gonzaga-Jauregui, Claudia and Lotze, Timothy and Jamal, Leila and Penney, Samantha and Campbell, Ian M and Pehlivan, Davut and Hunter, Jill V and Woodbury, Suzanne L and Raymond, Gerald and Adesina, Adekunle M and Jhangiani, Shalini N and Reid, Jeffrey G and Muzny, Donna M and Boerwinkle, Eric and Lupski, James R and Gibbs, Richard A and Wiszniewski, Wojciech} } @article {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 {293, title = {Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Sep}, pages = {1050-4}, abstract = {

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause \~{}40\% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.

}, keywords = {Adrenal Cortex Neoplasms, Adrenocortical Adenoma, Aldosterone, Amino Acid Sequence, Calcium Channels, L-Type, Cell Line, Child, Child, Preschool, Female, Germ-Line Mutation, Humans, Hyperaldosteronism, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Sequence Alignment}, issn = {1546-1718}, doi = {10.1038/ng.2695}, author = {Scholl, Ute I and Goh, Gerald and St{\"o}lting, Gabriel and de Oliveira, Regina Campos and Choi, Murim and Overton, John D and Fonseca, Annabelle L and Korah, Reju and Starker, Lee F and Kunstman, John W and Prasad, Manju L and Hartung, Erum A and Mauras, Nelly and Benson, Matthew R and Brady, Tammy and Shapiro, Jay R and Loring, Erin and Nelson-Williams, Carol and Libutti, Steven K and Mane, Shrikant and Hellman, Per and Westin, Gunnar and Akerstr{\"o}m, G{\"o}ran and Bj{\"o}rklund, Peyman and Carling, Tobias and Fahlke, Christoph and Hidalgo, Patricia and Lifton, Richard P} } @article {297, title = {TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Aug 08}, pages = {197-210}, abstract = {

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70\% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1\%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

}, keywords = {Age of Onset, Aging, Premature, Asian Continental Ancestry Group, Base Sequence, Brain, Child, Child, Preschool, Chromosomes, Human, Pair 2, Exons, Female, Genetic Predisposition to Disease, Humans, Language Development Disorders, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Pedigree, Sequence Analysis, DNA, Sequence Deletion, Tetraspanins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.05.027}, author = {Wiszniewski, Wojciech and Hunter, Jill V and Hanchard, Neil A and Willer, Jason R and Shaw, Chad and Tian, Qi and Illner, Anna and Wang, Xueqing and Cheung, Sau W and Patel, Ankita and Campbell, Ian M and Gelowani, Violet and Hixson, Patricia and Ester, Audrey R and Azamian, Mahshid S and Potocki, Lorraine and Zapata, Gladys and Hernandez, Patricia P and Ramocki, Melissa B and Santos-Cortez, Regie L P and Wang, Gao and York, Michele K and Justice, Monica J and Chu, Zili D and Bader, Patricia I and Omo-Griffith, Lisa and Madduri, Nirupama S and Scharer, Gunter and Crawford, Heather P and Yanatatsaneejit, Pattamawadee and Eifert, Anna and Kerr, Jeffery and Bacino, Carlos A and Franklin, Adiaha I A and Goin-Kochel, Robin P and Simpson, Gayle and Immken, LaDonna and Haque, Muhammad E and Stosic, Marija and Williams, Misti D and Morgan, Thomas M and Pruthi, Sumit and Omary, Reed and Boyadjiev, Simeon A and Win, Kay K and Thida, Aye and Hurles, Matthew and Hibberd, Martin Lloyd and Khor, Chiea Chuen and Van Vinh Chau, Nguyen and Gallagher, Thomas E and Mutirangura, Apiwat and Stankiewicz, Pawel and Beaudet, Arthur L and Maletic-Savatic, Mirjana and Rosenfeld, Jill A and Shaffer, Lisa G and Davis, Erica E and Belmont, John W and Dunstan, Sarah and Simmons, Cameron P and Bonnen, Penelope E and Leal, Suzanne M and Katsanis, Nicholas and Lupski, James R and Lalani, Seema R} } @article {312, title = {Whole-exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum.}, journal = {Clin Genet}, volume = {84}, year = {2013}, month = {2013 Oct}, pages = {394-5}, keywords = {Abnormalities, Multiple, Base Sequence, Child, Consanguinity, Exome, Humans, Male, Membrane Proteins, Pedigree, Phenotype, Sequence Analysis, DNA, Syndrome}, issn = {1399-0004}, doi = {10.1111/cge.12088}, author = {Caglayan, A O and Per, H and Akgumus, G and Gumus, H and Baranoski, J and Canpolat, M and Calik, M and Yikilmaz, A and Bilguvar, K and Kumandas, S and Gunel, M} } @article {318, title = {Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.}, journal = {J Invest Dermatol}, volume = {133}, year = {2013}, month = {2013 Mar}, pages = {827-830}, keywords = {Adolescent, Adult, Amino Acid Sequence, Biopsy, Child, Child, Preschool, Cohort Studies, Epidermis, Exome, Humans, Infant, Middle Aged, Molecular Sequence Data, Mutation, Nevus, Sebaceous of Jadassohn, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Sequence Analysis, DNA, Young Adult}, issn = {1523-1747}, doi = {10.1038/jid.2012.379}, author = {Levinsohn, Jonathan L and Tian, Li C and Boyden, Lynn M and McNiff, Jennifer M and Narayan, Deepak and Loring, Erin S and Yun, Duri and Sugarman, Jeffrey L and Overton, John D and Mane, Shrikant M and Lifton, Richard P and Paller, Amy S and Wagner, Annette M and Antaya, Richard J and Choate, Keith A} } @article {313, title = {Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jan 10}, pages = {137-43}, abstract = {

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60\% of cases overall, including both of the families in our cohort with more than one affected child and 50\% of the simplex cases.

}, keywords = {Child, Child, Preschool, Female, Genome, Human, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.11.011}, author = {Below, Jennifer E and Earl, Dawn L and Shively, Kathryn M and McMillin, Margaret J and Smith, Joshua D and Turner, Emily H and Stephan, Mark J and Al-Gazali, Lihadh I and Hertecant, Jozef L and Chitayat, David and Unger, Sheila and Cohn, Daniel H and Krakow, Deborah and Swanson, James M and Faustman, Elaine M and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {327, title = {Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome.}, journal = {Am J Hum Genet}, volume = {90}, year = {2012}, month = {2012 May 04}, pages = {925-33}, abstract = {

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57\%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings add Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

}, keywords = {Adult, Child, Child, Preschool, Cohort Studies, Exome, Female, Haploinsufficiency, Humans, Limb Deformities, Congenital, Male, Mandibulofacial Dysostosis, Mutation, Reproducibility of Results, RNA Precursors, RNA Splicing Factors, RNA-Binding Proteins, Spliceosomes, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.04.004}, author = {Bernier, Francois P and Caluseriu, Oana and Ng, Sarah and Schwartzentruber, Jeremy and Buckingham, Kati J and Innes, A Micheil and Jabs, Ethylin Wang and Innis, Jeffrey W and Schuette, Jane L and Gorski, Jerome L and Byers, Peter H and Andelfinger, Gregor and Siu, Victoria and Lauzon, Julie and Fernandez, Bridget A and McMillin, Margaret and Scott, Richard H and Racher, Hilary and Majewski, Jacek and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael J and Parboosingh, Jillian S} } @article {328, title = {Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis.}, journal = {Blood}, volume = {119}, year = {2012}, month = {2012 May 17}, pages = {4731-40}, abstract = {

Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole-exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.

}, keywords = {Adult, beta-Glucosidase, Child, Child, Preschool, Female, Gaucher Disease, Genome, Human, Hematologic Neoplasms, Humans, Individuality, Male, Pedigree, Phenotype, Sequence Analysis, DNA, Siblings}, issn = {1528-0020}, doi = {10.1182/blood-2011-10-386862}, author = {Lo, Sarah M and Choi, Murim and Liu, Jun and Jain, Dhanpat and Boot, Rolf G and Kallemeijn, Wouter W and Aerts, Johannes M F G and Pashankar, Farzana and Kupfer, Gary M and Mane, Shrikant and Lifton, Richard P and Mistry, Pramod K} }