@article{3aa09b9c915841269b71546536886c19,
title = "Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder",
abstract = "We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.",
author = "Lim, {Elaine T.} and Mohammed Uddin and {De Rubeis}, Silvia and Yingleong Chan and Kamumbu, {Anne S.} and Xiaochang Zhang and D'Gama, {Alissa M.} and Kim, {Sonia N.} and Hill, {Robert Sean} and Goldberg, {Arthur P.} and Christopher Poultney and Minshew, {Nancy J.} and Itaru Kushima and Branko Aleksic and Norio Ozaki and Mara Parellada and Celso Arango and Penzol, {Maria J.} and Angel Carracedo and Alexander Kolevzon and Hultman, {Christina M.} and Weiss, {Lauren A.} and Menachem Fromer and Chiocchetti, {Andreas G.} and Freitag, {Christine M.} and Church, {George M.} and Scherer, {Stephen W.} and Buxbaum, {Joseph D.} and Walsh, {Christopher A.}",
note = "Funding Information: We are grateful to all the families who participated in the research, including the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC), the Autism Sequencing Consortium (ASC) and Autism Speaks. We acknowledge the clinicians and organizations that contributed to samples used in this study, including the ASC and SSC principal investigators; the coordinators and staff at the ASC and SSC sites for the recruitment and comprehensive assessment of simplex families; and the ASC, SFARI and NDAR staff for facilitating access to the data sets. This work was supported by a grant from the Simons Foundation (178093, C.A.W.); the National Institutes of Health (NIH) grants R01MH083565, RC2MH089952 and U01MH106883 to C.A.W.; grants R01MH097849, U01MH100233, U01MH100209, U01MH100229, U01MH100239, U01MH111661, U01MH111660, U01MH111658, U01MH111662 and R01MH097849 to the Autism Sequencing Consortium; grants from the Centre for Applied Genomics, the University of Toronto McLaughlin Centre, Genome Canada and Autism Speaks (S.W.S.); Simons Foundation grant (368485, G.M.C.); SRPBS and Brain/ MINDS grants from AMED (I.K., B.A., N.O.); grants from the Spanish Ministry of Economy and Competitiveness (M.P.), Instituto de Salud Carlos III (M.P.), PI10/02989 (M.P.), CIBERSAM (M.P.) and ERA-NET NEURON (M.P., C.M.F.), Network of European Funding for Neuroscience Research (M.P.), and Fundaci{\'o}n Mar{\'i}a Jos{\'e} Jove and The Institute of Health Carlos III-Fondo de Investigaciones Sanitarias grant project PI13/01136 (A.C.) and the Seaver Foundation. We thank A. Hossain and N. Hatem for their help with sample preparation; F. Zhao and C. Stevens for their help with reprocessing the BAM files; and M. Daly, S. McCarroll, G. Genovese and J. Hirschhorn for comments and suggestions. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. Additional computing support was provided by the Harvard Medical School{\textquoteright}s Orchestra High-Performance Computing Group, which is partially supported by NIH grant NCRR 1S10RR028832-01. The NHLBI GO Exome Sequencing Project and its ongoing studies produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). C.A.W. is an Investigator of the Howard Hughes Medical Institute; S.W.S. is funded by the GlaxoSmithKline-Canadian Institutes of Heath Research Chair in Genome Sciences at the Hospital for Sick Children and University of Toronto; A.M.D. is supported by the NIGMS (T32GM007753) and NRSA (5T32 GM007226-39); S.D.R. is supported by the Seaver Foundation.",
year = "2017",
month = sep,
day = "1",
doi = "10.1038/nn.4598",
language = "English",
volume = "20",
pages = "1217--1224",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "9",
}