@article{ee84ecfc8e4c4f9db16a7626b9cf870d,
title = "Excess of rare, inherited truncating mutations in autism",
abstract = "To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single-nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 families with autism. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio = 1.14, P = 0.0002) in comparison to unaffected siblings, an effect involving significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kb), maternally inherited events (P = 0.01) that are enriched in CHD8 target genes (P = 7.4 × 10 {\^a}'3). Using a logistic regression model, we show that private truncating SNVs and rare, inherited CNVs are statistically independent risk factors for autism, with odds ratios of 1.11 (P = 0.0002) and 1.23 (P = 0.01), respectively. This analysis identifies a second class of candidate genes (for example, RIMS1, CUL7 and LZTR1) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.",
author = "Niklas Krumm and Turner, {Tychele N.} and Carl Baker and Laura Vives and Kiana Mohajeri and Kali Witherspoon and Archana Raja and Coe, {Bradley P.} and Stessman, {Holly A.} and He, {Zong Xiao} and Leal, {Suzanne M.} and Raphael Bernier and Eichler, {Evan E.}",
note = "Funding Information: We thank D. Obenshain, D. Hall, B. Koser and S. Novikova for providing support for usage of the Amazon Cloud and for assistance in the deposition of SNV and CNV call sets into the National Database for Autism Research (NDAR). We are grateful to the laboratories of M. Wigler and M. State for providing early access to exome sequencing data as well as access to SNP microarray data. We also thank T. Brown for assistance in editing this manuscript. Funding for this study was provided, in part, by the US National Institutes of Health (1U01MH100233 to E.E.E.), by the National Institute for Mental Health (R01MH101221 to E.E.E. and R01MH100047 to R.B.) and by the Simons Foundation (SFARI 89368 to R.B. and SFARI 137578 to E.E.E.). E.E.E. is an investigator of the Howard Hughes Medical Institute. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). We appreciate obtaining access to phenotypic data on Simons Foundation Autism Research Initiative (SFARI) Base. Approved researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org/. Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",
year = "2015",
month = may,
day = "27",
doi = "10.1038/ng.3303",
language = "English",
volume = "47",
pages = "582--588",
journal = "Nature Genetics",
issn = "1061-4036",
number = "6",
}