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https://ahro.austin.org.au/austinjspui/handle/1/25074| Title: | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders. | Austin Authors: | Wang, Tianyun;Hoekzema, Kendra;Vecchio, Davide;Wu, Huidan;Sulovari, Arvis;Coe, Bradley P;Gillentine, Madelyn A;Wilfert, Amy B;Perez-Jurado, Luis A;Kvarnung, Malin;Sleyp, Yoeri;Earl, Rachel K;Rosenfeld, Jill A;Geisheker, Madeleine R;Han, Lin;Du, Bing;Barnett, Chris;Thompson, Elizabeth;Shaw, Marie;Carroll, Renee;Friend, Kathryn;Catford, Rachael;Palmer, Elizabeth E;Zou, Xiaobing;Ou, Jianjun;Li, Honghui;Guo, Hui;Gerdts, Jennifer;Avola, Emanuela;Calabrese, Giuseppe;Elia, Maurizio;Greco, Donatella;Lindstrand, Anna;Nordgren, Ann;Anderlid, Britt-Marie;Vandeweyer, Geert;Van Dijck, Anke;Van der Aa, Nathalie;McKenna, Brooke;Hancarova, Miroslava;Bendova, Sarka;Havlovicova, Marketa;Malerba, Giovanni;Bernardina, Bernardo Dalla;Muglia, Pierandrea;van Haeringen, Arie;Hoffer, Mariette J V;Franke, Barbara;Cappuccio, Gerarda;Delatycki, Martin B ;Lockhart, Paul J;Manning, Melanie A;Liu, Pengfei;Scheffer, Ingrid E ;Brunetti-Pierri, Nicola;Rommelse, Nanda;Amaral, David G;Santen, Gijs W E;Trabetti, Elisabetta;Sedláček, Zdeněk;Michaelson, Jacob J;Pierce, Karen;Courchesne, Eric;Kooy, R Frank;Nordenskjöld, Magnus;Romano, Corrado;Peeters, Hilde;Bernier, Raphael A;Gecz, Jozef;Xia, Kun;Eichler, Evan E | Affiliation: | Department of Genome Sciences, University of Washington, Seattle, WA, USA Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, USA Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Rome, Italy Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, Australia South Australian Health and Medical Research Institute, Adelaide, SA, Australia Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, Spain Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA Baylor Genetics, Houston, TX, USA Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia Genetics of Learning Disability Service, Hunter New England Health Service, Waratah, NSW, Australia School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands Department of Translational Medicine, Federico II University, Naples, Italy Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy Murdoch Children's Research Institute, Melbourne, Australia Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, Australia Medicine (University of Melbourne) The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia Rare Disease and Medical Genetics, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, Italy Department of Pathology, Stanford University, Stanford, CA, USA Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands Karakter Child and Adolescent Psychiatry Center, Nijmegen, Netherlands Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, China Department of Genome Sciences, University of Washington, Seattle, WA, USA Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China Department of Genome Sciences, University of Washington, Seattle, WA, USA Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA Department of Genome Sciences, University of Washington, Seattle, WA, USA Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China Children Development Behavior Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, China Key Laboratory of Developmental Disorders in Children, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, China Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA Oasi Research Institute-IRCCS, Troina, Italy Department of Medical Genetics, University of Antwerp, Antwerp, Belgium Department of Psychology, Emory University, Atlanta, GA, USA Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy Child Neuropsychiatry Unit, AOUI, Verona, Italy UCB Pharma, Bruxelles, Belgium Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands Department of Psychiatry and Behavioral Sciences and the MIND Institute, University of California, Davis, Sacramento, CA, USA Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, CA, USA Department of Medical Genetics, University of Antwerp, Antwerp, Belgium Oasi Research Institute-IRCCS, Troina, Italy Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA |
Issue Date: | 1-Oct-2020 | Date: | 2020-10-01 | Publication information: | Nature Communications 2020; 11(1): 4932 | Abstract: | Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/25074 | DOI: | 10.1038/s41467-020-18723-y | ORCID: | 0000-0002-5179-087X 0000-0003-2907-3206 0000-0003-4354-9020 0000-0002-8989-2214 0000-0001-5664-7987 0000-0002-4166-3236 0000-0002-1570-2545 0000-0003-0806-5602 0000-0003-3285-4281 0000-0002-6713-2943 0000-0002-1812-7670 0000-0003-4375-6572 0000-0003-2531-8413 0000-0002-4177-709X 0000-0002-6895-8819 0000-0001-9713-0992 0000-0002-3772-5799 0000-0003-2024-0485 0000-0003-1049-0683 0000-0002-7884-6861 0000-0001-8090-6002 0000-0002-8246-4014 |
Journal: | Nature Communications | PubMed URL: | 33004838 | Type: | Journal Article |
| Appears in Collections: | Journal articles |
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