Role of Rare Genetic Variants in Autism

Multiple lines of evidence support the contribution of rare genetic variation to the etiology of Autism Spectrum Disorders: it has long been recognized that cytogenetic abnormalities are over-represented in affected children, there are increased risks for ASD in a substantial number of rare genetic syndromes, rare mutations have been either linked or convincingly associated with non-syndromic autism in a small number of cases, and recent data suggests an increased rate of large de novo copy number variations in simplex autism families. In the last several years, the genomic technologies available to investigate rare variation have advanced dramatically, offering multiple new opportunities to pursue studies in this area while at the same time highlighting key challenges confronting efforts to confirm the relationship between ASD and individually rare genetic events. This presentation will present the "rare-variant common-disease hypothesis" of complex genetic disorders, review the evidence for the involvement of rare variants in ASD, discuss recent findings from our laboratory regarding rare structural and sequence variations in the neuronally-expressed molecules Contactin 4 (CNTN4), Contactin Associated Protein 2 (CNTNAP2) and Contactin Associated Protein 4 (CNTNAP4) and present the rationale and study design for a large-scale, multi-site investigation of rare variation currently underway in the Simons Simplex Collection.