Please use this identifier to cite or link to this item: 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
metadata.dc.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
PubMed URL: 33004838
Type: Journal Article
Appears in Collections:Journal articles

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