This proposal will explore the hypothesis that autism is caused by highly-penetrant, rare mutations using emerging technologies that screen gene regions for autism-specific copy-number variation (CNV) mutations and DNA point mutations. The study will focus on 17 genomic regions (carrying 83 genes) and an additional 87 genes where copy-number changes and point mutations have been associated with autism. The screening and analysis will be applied to 1320 families with one or more children with autism using the Autism Genetic Resource Exchange (AGRE) and Simons Simplex Collection (SSC) for samples. A comprehensive assessment of 20 autism genomes will also be conducted. This proposal will develop a systematic strategy to identify mutations and genes associated with autism and will optimize new technology for the characterization of patient genomes for pathogenic copy-number variation and point mutations associated with complex genetic disease. This research could lead to early diagnosis in children as well as the genetic classification of different causes of autism. Such subcategorizations of autism could aid development of treatments and interventions for autism.