PMID- 28867142 OWN - NLM STAT- MEDLINE DCOM- 20171027 LR - 20200824 IS - 1537-6605 (Electronic) IS - 0002-9297 (Print) IS - 0002-9297 (Linking) VI - 101 IP - 3 DP - 2017 Sep 7 TI - Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder. PG - 369-390 LID - S0002-9297(17)30322-1 [pii] LID - 10.1016/j.ajhg.2017.07.016 [doi] AB - Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations. We developed a robust and sensitive SNV PMM calling approach integrating complementary callers, logistic regression modeling, and additional heuristics. In our high-confidence call set, we identified 470 PMMs in children, increasing the proportion of mosaic SNVs to 22%. Probands have a significant burden of synonymous PMMs and these mutations are enriched for computationally predicted impacts on splicing. Evidence of increased missense PMM burden was not seen in the full cohort. However, missense burden signal increased in subcohorts of families where probands lacked nonsynonymous germline mutations, especially in genes intolerant to mutations. Parental mosaic mutations that were transmitted account for 6.8% of the presumed de novo mutations in the children. PMMs were identified in previously implicated high-confidence neurodevelopmental disorder risk genes, such as CHD2, CTNNB1, SCN2A, and SYNGAP1, as well as candidate risk genes with predicted functions in chromatin remodeling or neurodevelopment, including ACTL6B, BAZ2B, COL5A3, SSRP1, and UNC79. We estimate that PMMs potentially contribute risk to 3%-4% of simplex ASD case subjects and future studies of PMMs in ASD and related disorders are warranted. CI - Copyright (c) 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. FAU - Krupp, Deidre R AU - Krupp DR AD - Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Barnard, Rebecca A AU - Barnard RA AD - Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Duffourd, Yannis AU - Duffourd Y AD - Equipe d'Accueil 4271, Genetique des Anomalies du Developpement, Universite Bourgogne Franche-Comte, 21000 Dijon, France. FAU - Evans, Sara A AU - Evans SA AD - Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Mulqueen, Ryan M AU - Mulqueen RM AD - Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. FAU - Bernier, Raphael AU - Bernier R AD - Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA. FAU - Riviere, Jean-Baptiste AU - Riviere JB AD - Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada. FAU - Fombonne, Eric AU - Fombonne E AD - Department of Psychiatry, Oregon Health & Science University, Portland, OR 97239, USA. FAU - O'Roak, Brian J AU - O'Roak BJ AD - Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: oroak@ohsu.edu. LA - eng GR - U54 HD083091/HD/NICHD NIH HHS/United States PT - Journal Article DEP - 20170831 PL - United States TA - Am J Hum Genet JT - American journal of human genetics JID - 0370475 SB - IM MH - Autism Spectrum Disorder/*genetics/pathology MH - Child MH - Cohort Studies MH - Databases, Genetic MH - Exons/*genetics MH - Female MH - *Genetic Predisposition to Disease MH - *Genetic Variation MH - Humans MH - Male MH - *Mosaicism MH - *Mutation MH - Zygote PMC - PMC5590950 OTO - NOTNLM OT - autism spectrum disorder OT - exome OT - mosaicism OT - mutation OT - neurodevelopment OT - postzygotic OT - somatic OT - splicing EDAT- 2017/09/05 06:00 MHDA- 2017/10/28 06:00 PMCR- 2018/03/07 CRDT- 2017/09/05 06:00 PHST- 2016/11/03 00:00 [received] PHST- 2017/07/24 00:00 [accepted] PHST- 2017/09/05 06:00 [pubmed] PHST- 2017/10/28 06:00 [medline] PHST- 2017/09/05 06:00 [entrez] PHST- 2018/03/07 00:00 [pmc-release] AID - S0002-9297(17)30322-1 [pii] AID - 10.1016/j.ajhg.2017.07.016 [doi] PST - ppublish SO - Am J Hum Genet. 2017 Sep 7;101(3):369-390. doi: 10.1016/j.ajhg.2017.07.016. Epub 2017 Aug 31.