Sporadic Mutations and Autism Spectrum Disorders

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DESCRIPTION (provided by applicant): Sporadic point mutations and large copy number variants (CNVs) contribute significantly to the etiology of autism but relatively few genes have been proven to be pathogenic. The goal of this project is to identify genes responsible for autism spectrum disorder (ASD) and developmental delay. We will apply an integrated approach combining exome sequence data and detailed ab initio CNV analysis to pinpoint likely candidate genes. We will test these candidates for an excess of de novo disruptive mutations in case versus control trios. There are three specific aims: 1) Expand our existing CNV morbidity map to include data from >40,000 cases of developmental delay versus 20,000 controls and integrate these data with emerging exome data to identify likely haploinsufficient genes; 2) Assess whether the burden of disruptive de novo mutations in these genes is significantly enriched in ASD families by molecular inversion probe (MIP) resequencing of approximately 6,200 cases and 6,200 controls; and 3) Select ten genes with the highest burden of de novo mutations for further clinical evaluation, phenotypic variability, and comprehensive genetic characterization. The end product of this analysis will be the identification and characterization of highly penetran genic mutations that contribute significantly to etiology of autism, providing targets for clinical diagnostics and future therapeutics.