Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Nature Communications, vol. 11, pp. 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.
Authors 92
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Affiliation as printed
Department of Genome Sciences, University of Washington, Seattle, WA, USA
University of Washington School of Medicine, Seattle, WA, USA
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Affiliation as printed
Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Bambino Gesù Children's Hospital
Affiliation as printed
Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, Rome, Italy
Rare Disease and Medical Genetics, Academic Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, Italy
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Affiliation as printed
Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
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Affiliation as printed
Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Affiliation as printed
Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Affiliation as printed
Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Affiliation as printed
Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Universitat Pompeu Fabra · Women's and Children's Hospital · Centre for Biomedical Network Research on Rare Diseases · South Australian Health and Medical Research Institute · Hospital del Mar Research Institute
Affiliation as printed
Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, Spain
Paediatric and Reproductive Genetics unit, Women's and Children's Hospital, Adelaide, SA, Australia
South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
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Baylor College of Medicine · Baylor Genetics
Affiliation as printed
Baylor Genetics, Houston, TX, USA
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Affiliation as printed
Department of Genome Sciences, University of Washington, Seattle, WA, USA
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Affiliation as printed
Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
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Affiliation as printed
Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia
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Affiliation as printed
Adelaide Medical School and the Robinson Research Institute, the University of Adelaide, Adelaide, SA, Australia
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Affiliation as printed
Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia
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Affiliation as printed
Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia
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UNSW Sydney · Hunter New England Local Health District
Affiliation as printed
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
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Sun Yat-sen University · Third Affiliated Hospital of Sun Yat-sen University
Affiliation as printed
Children Development Behavior Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
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Central South University · Second Xiangya Hospital of Central South University · Xiangya Hospital Central South University
Affiliation as printed
Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, China
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Liuzhou Maternal and Child Health Hospital
Affiliation as printed
Key Laboratory of Developmental Disorders in Children, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, China
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Affiliation as printed
Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
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Affiliation as printed
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
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Affiliation as printed
Oasi Research Institute-IRCCS, Troina, Italy
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Affiliation as printed
Oasi Research Institute-IRCCS, Troina, Italy
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Affiliation as printed
Oasi Research Institute-IRCCS, Troina, Italy
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Affiliation as printed
Oasi Research Institute-IRCCS, Troina, Italy
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Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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Affiliation as printed
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Department of Psychology, Emory University, Atlanta, GA, USA
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Charles University · University Hospital in Motol
Affiliation as printed
Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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Charles University · University Hospital in Motol
Affiliation as printed
Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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Charles University · University Hospital in Motol
Affiliation as printed
Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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Affiliation as printed
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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University of Verona · Azienda Ospedaliera Universitaria Integrata Verona
Affiliation as printed
Child Neuropsychiatry Unit, AOUI, Verona, Italy
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Affiliation as printed
UCB Pharma, Bruxelles, Belgium
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands
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Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
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
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Federico II University Hospital · Telethon Institute Of Genetics And Medicine · University of Naples Federico II
Affiliation as printed
Department of Translational Medicine, Federico II University, Naples, Italy
Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy
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Murdoch Children's Research Institute
Affiliation as printed
Murdoch Children's Research Institute, Melbourne, Australia
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The University of Melbourne · Murdoch Children's Research Institute
Affiliation as printed
Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
Murdoch Children's Research Institute, Melbourne, Australia
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Stanford Medicine · Stanford University
Affiliation as printed
Department of Pathology, Stanford University, Stanford, CA, USA
Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, USA
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Baylor College of Medicine · Baylor Genetics
Affiliation as printed
Baylor Genetics, Houston, TX, USA
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA
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Royal Children's Hospital · The University of Melbourne · Florey Institute of Neuroscience and Mental Health · Austin Hospital · Murdoch Children's Research Institute · Austin Health
Affiliation as printed
Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, Australia
Murdoch Children's Research Institute, Melbourne, Australia
The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
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Federico II University Hospital · Telethon Institute Of Genetics And Medicine · University of Naples Federico II
Affiliation as printed
Department of Translational Medicine, Federico II University, Naples, Italy
Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy
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Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
Karakter Child and Adolescent Psychiatry Center, Nijmegen, Netherlands
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University of California, Davis
Affiliation as printed
Department of Psychiatry and Behavioral Sciences and the MIND Institute, University of California, Davis, Sacramento, CA, USA
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, Netherlands
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Affiliation as printed
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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Charles University · University Hospital in Motol
Affiliation as printed
Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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Affiliation as printed
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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University of California San Diego
Affiliation as printed
Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, CA, USA
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University of California San Diego
Affiliation as printed
Department of Neurosciences, UC San Diego Autism Center, School of Medicine, University of California San Diego, La Jolla, CA, USA
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Affiliation as printed
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Simons Foundation, New York, NY, USA
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Simons Foundation, New York, NY, USA
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Simons Foundation, New York, NY, USA
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Simons Foundation, New York, NY, USA
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Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Simons Foundation · Columbia University
Affiliation as printed
Columbia University, New York, NY, USA
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Simons Foundation, New York, NY, USA
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Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Simons Foundation, New York, NY, USA
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Affiliation as printed
Columbia University, New York, NY, USA
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Affiliation as printed
Columbia University, New York, NY, USA
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Affiliation as printed
Columbia University, New York, NY, USA
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Washington University in St. Louis
Affiliation as printed
Washington University School of Medicine, St. Louis, MO, USA
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Affiliation as printed
University of Iowa Carver College of Medicine, Iowa City, IA, USA
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Affiliation as printed
University of Iowa Carver College of Medicine, Iowa City, IA, USA
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