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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

T. Wang, K. Hoekzema, D. Vecchio, H. Wu, A. Sulovari, BP. Coe, MA. Gillentine, AB. Wilfert, LA. Perez-Jurado, M. Kvarnung, Y. Sleyp, RK. Earl, JA. Rosenfeld, MR. Geisheker, L. Han, B. Du, C. Barnett, E. Thompson, M. Shaw, R. Carroll, K. Friend,...

. 2020 ; 11 (1) : 4932. [pub] 20201001

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, multicentrická studie, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20027790

Grantová podpora
R01 MH101221 NIMH NIH HHS - United States
R01 MH109912 NIMH NIH HHS - United States
T32 HG000035 NHGRI NIH HHS - United States
Howard Hughes Medical Institute - United States
NV17-29423A MZ0 CEP - Centrální evidence projektů

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.

Adelaide Medical School and the Robinson Research Institute the University of Adelaide Adelaide SA Australia

Center for Medical Genetics and Hunan Provincial Key Laboratory of Medical Genetics School of Life Sciences Central South University Changsha Hunan China

Center for Medical Genetics and 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 Chinese Academy of Sciences Shanghai China

Centre for Human Genetics KU Leuven and Leuven Autism Research Leuven Belgium

Child Neuropsychiatry Unit AOUI Verona Italy

Children Development Behavior Center The 3rd Affiliated Hospital Sun Yat Sen University Guangzhou Guangdong China

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Clinical Genetics Leiden University Medical Center Leiden Netherlands

Department of Genome Sciences University of Washington Seattle WA USA

Department of Genome Sciences University of Washington Seattle WA USA Howard Hughes Medical Institute University of Washington Seattle WA USA

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 Medical Genetics University of Antwerp Antwerp Belgium

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA Baylor Genetics Houston TX USA

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 Neurosciences Biomedicine and Movement Sciences University of Verona Verona Italy

Department of Neurosciences UC San Diego Autism Center School of Medicine University of California San Diego La Jolla CA USA

Department of Psychiatry and Behavioral Sciences and the MIND Institute University of California Davis Sacramento CA USA

Department of Psychiatry and Behavioral Sciences University of Washington Seattle WA 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

Department of Psychiatry University of Iowa Carver College of Medicine Iowa City IA USA

Department of Psychology Emory University Atlanta GA USA

Department of Translational Medicine Federico 2 University Naples Italy Telethon Institute of Genetics and Medicine Pozzuoli Naples Italy

Division of Medical Genetics Department of Pediatrics Stanford University Stanford CA USA Department of Pathology Stanford University Stanford CA USA

Genetics and Molecular Pathology SA Pathology 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

Key Laboratory of Developmental Disorders in Children Liuzhou Maternity and Child Healthcare Hospital Liuzhou China

Mental Health Institute of the 2nd Xiangya Hospital Central South University Changsha China

Murdoch Children's Research Institute Melbourne Australia

Murdoch Children's Research Institute Melbourne Australia Department of Paediatrics University of Melbourne Parkville VIC Australia

Murdoch Children's Research Institute Melbourne Australia Department of Paediatrics University of Melbourne Royal Children's Hospital Melbourne VIC Australia Department of Medicine University of Melbourne Austin Health Melbourne Australia The Florey Institute of Neuroscience and Mental Health Parkville VIC Australia

Oasi Research Institute IRCCS Troina Italy

Paediatric and Reproductive Genetics unit Women's and Children's Hospital Adelaide SA Australia

Paediatric and Reproductive Genetics unit Women's and Children's Hospital Adelaide SA Australia Adelaide Medical School and the Robinson Research Institute the University of Adelaide Adelaide SA Australia

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 and CIBERER Barcelona Spain

Rare Disease and Medical Genetics Academic Department of Pediatrics Bambino Gesù Children's Hospital Rome Italy Genetics and Rare Diseases Research Division Bambino Gesù Children's Hospital Rome Italy

South Australian Health and Medical Research Institute Adelaide SA Australia Adelaide Medical School and the Robinson Research Institute the University of Adelaide Adelaide SA Australia Genetics and Molecular Pathology SA Pathology Adelaide SA Australia

UCB Pharma Bruxelles Belgium

Citace poskytuje Crossref.org

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