Greenup and S. Johnson); R. Smith and Z. Galfayan at Microangelo Associates for bioinformatics support; Prometheus Research; the Yale Center of Genomic Analysis staff, in particular S. Umlauf and C. Castaldi; T. Brooks-Boone and M. Wojciechowski for their help in administering the project at Yale; and J. Krystal, G.D. PF-01367338 clinical trial Fischbach, A. Packer, J. Spiro, and M. Benedetti for their suggestions throughout and very helpful comments during the preparation of this manuscript. Approved

researchers can obtain the SSC population data set described in this study by applying at https://base.sfari.org. D.H. Ledbetter acts as a consultant for Roche Diagnostics and BioReference Laboratories; M.W. State, R.P. Lifton, and B.J. O’Roak hold a patent relating to the gene CNTNAP2. “
“Autism spectrum disorders (ASDs) are among the most genetically determined of developmental and cognitive abnormalities, with concordance between identical twins reported at nearly 90% in some studies (Muhle et al., 2004 and Rosenberg et al., 2009). There is a strong gender VE-821 in vitro bias, with much higher incidence in males than in females, especially for higher-functioning children (Newschaffer et al., 2007). Previous studies found a higher incidence of new copy-number mutation in autistic children from simplex (only one affected child) ASD families than in typical children or in children from multiplex (multiple affected children) ASD families (Marshall et al.,

2008 and Sebat et al., 2007; see also Itsara et al., 2010). Based on these earlier findings, we proposed a role for new (or de novo) germline variation in simplex families, distinct from transmitted variation that might predominate in multiplex families. Similar findings have been reported for sporadic and inherited schizophrenia (Xu et al., 2008). Further analysis of the incidence of male probands in multiplex families led us to derive a risk function for the population and to propose that much of ASD arises from de novo variants of strong penetrance and that some de novo variants of high penetrance are transmitted

by relatively asymptomatic carriers in a dominant fashion (Zhao et al., 2007). In a continuing effort to explore ASDs and to reveal the targets of CTP synthase mutation, we have participated in a large study of simplex families: the Simons Simplex Collection (SSC), consisting of approximately 1000 families at the time of this analysis (Fischbach and Lord, 2010). Families with only a single child on the spectrum were recruited. In nearly all cases there was at least one unaffected sibling, and multiplex families were specifically excluded. We analyze copy-number variation (CNV) in SSC families by comparative genomic hybridization (Iafrate et al., 2004 and Sebat et al., 2004), using the NimbleGen HD2 2.1 million probe microarray platform (http://www.nimblegen.com/products/cgh/wgt/human/2.1m/index.html) with oligonucleotides optimized for both hybridization performance and uniform genome coverage.