Contributors: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School; Harvard Medical School Boston (HMS); Program in Medical and Population Genetics, Broad Institute of Harvard and MIT; Massachusetts Institute of Technology (MIT); Department of pharmacology and systems therapeutics Mount Sinai; Icahn School of Medicine at Mount Sinai New York (MSSM); Seaver Autism Center for Research and Treatment; Department of Statistics, Carnegie Mellon University; Carnegie Mellon University Pittsburgh (CMU); Human Genome Sequencing Center, Baylor College of Medicine; Baylor College of Medicine (BCM); Baylor University-Baylor University; Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania; University of Pennsylvania Philadelphia; Department of Psychiatry; Division of Genetics; Brigham and Women's Hospital Boston; Department of Molecular Physiology & Biophysics and Psychiatry; Vanderbilt University Nashville -Centers for Human Genetics Research and Molecular Neuroscience; Biostatistics Department and Computer Science Department, Johns Hopkins University; Johns Hopkins University (JHU); Departments of Psychiatry, Genetics and Genomic Sciences; Icahn School of Medicine at Mount Sinai New York (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute; Department of Pharmacology; University of Pennsylvania Philadelphia -Perelman School of Medicine; HudsonAlpha Institute for Biotechnology Huntsville, AL; Physiopathologie des Maladies du Système Nerveux Central; Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Human Genetics Center; The University of Texas Health Science Center at Houston (UTHealth); Friedman Brain Institute; Institute for Juvenile Research-University of Illinois Chicago (UIC); University of Illinois System-University of Illinois System; Department of Psychiatry Pittsburgh; University of Pittsburgh School of Medicine; Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE)
نبذة مختصرة : International audience ; Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
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