We have conducted a genome-wide analysis focusing primarily on the study of rare de novo CNVs in 4,457 individuals comprising 1,174 simplex ASD families from the Simons Simplex Collection (Fischbach and Lord, 2010), nearly three-fold larger than previously reported simplex cohorts. Each family is extensively phenotyped, with a single affected offspring, unaffected parents, and, in the majority of cases, at least one unaffected sibling. This ascertainment strategy is designed to enrich for rare de novo risk variants, the family-based case-control comparisons mitigate a wide range of technical and methodological confounders that have plagued association study designs (Altshuler et al., 2008), and we have developed a new rigorous approach to evaluating the genome-wide significance of recurrent rare de novo events. Consequently, the scale and design of this study provides an extraordinary opportunity to investigate the relative contributions of rare de novo and rare transmitted variants in simplex families, to identify novel ASD risk loci, to evaluate the relationship between rare structural variation and social and intellectual disability (ID), and to place these findings in the context of previous ASD data, particularly with regards rare de novo CNVs.
