Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

• Type of Material: Article
• Authors: Stephan J. Sanders, Yale University; A. Gulhan Ercan-Sencicek, Yale University; Vanessa Hus, University of Michigan; Rui Luo, University of California Los Angeles; Michael T. Murtha, Yale University; Daniel Moreno-De-Luca, Emory University; Su H. Chu, Carnegie Mellon University; Michael P. Moreau, Rutgers State University; Abha R. Gupta, Yale University; Susanne A. Thomson, Vanderbilt University; Christopher E. Mason, Weill Cornell Medical College; Kaya Bilguvar, Yale University; Patricia B. S. Celestino-Soper, Baylor College of Medicine; Murim Choi, Yale University; Emily L. Crawford, Vanderbilt University; Lea Davis, University of Illinois; Nicole R. Davis Wright, Yale University; Rahul M. Dhodapkar, Yale University; Donna M Martin, Emory University; Christa Martin, Emory University
• Language: English
• Date: 2011-06-09
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuron.2011.05.002
• Title of Journal or Parent Work: Neuron
• Volume: 70
• Issue: 5
• Start Page: 863
• End Page: 885
• Grant/Funding Information: This work was supported by a grant from the Simons Foundation (SFARI 124827).
• Keywords: EARLY-ONSET; SNP GENOTYPING DATA; Neurosciences & Neurology; HIDDEN-MARKOV MODEL; Science & Technology; INCREASE RISK; RARE CHROMOSOMAL DELETIONS; SPECTRUM DISORDERS; COPY NUMBER VARIATION; GENOME; BEUREN-SYNDROME; Life Sciences & Biomedicine; GENETIC DISORDER; Neurosciences
• Research Categories: Psychology, Cognitive; Biology, Neuroscience; Biology, Genetics

Abstract

We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10 -7 ). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.