There is ample evidence that rare genetic variants may contribute to a small subset of individualspresenting with Autism Spectrum Disorders (ASDs). The characterization of these unusual cases mayprovide important insights into pathophysiological mechanisms underlying disease. Our laboratory hasleveraged the comprehensive phenotyping capabilities of the Yale Autism Research Group to focus on thediscovery of rare variants contributing to developmental and social disability. Recently we have studied threeunrelated patients with ASD and/or Mental Retardation (MR) and chromosomal abnormalities, all of whowere found to have disruptions of genes in the Contactin (CNTN) or Contactin Association Protein(CNTNAP) families, including CNTN4, CNTNAP2 and CNTNAP4. These neuronal adhesion and recognitionmolecules are known to play key roles in axon pathfinding, fasciculation and neuronal-glial interactions. Wehave undertaken extensive re-sequencing efforts and, in our initial analysis of Contactin Associated Protein,we have identified a statistically significant increase in the burden of potentially damaging missensemutations among 218 cases and 449 controls regardless of whether we consider all non-synonymousvariants or only those predicted by bioinformatics approaches to be deleterious to protein function. This datais particularly compelling in light of two additional findings: a rare recessive mutation in this gene found inassociation with seizures, developmental delay and autistic features in Amish families; and, unpublisheddata from collaborators at UCLA showing a common haplotype of CNTNAP2 associated with language delayin individuals with Autism. Based on our recent findings we now propose to: 1) replicate the mutation burdenanalysis in CNTNAP2 and perform a similar preliminary study in patients with developmental delay but notsocial disability; 2) perform initial and, if warranted, replication studies of the other molecules disrupted bychromosomal abnormalities, Contactin 4 and Contactin Associated Protein 4 and 3) continue our genediscovery efforts using both conventional and array based cytogenetics on the well-characterized patientsrecruited under Projects 1-IV of this application focusing on the identification of rare, deleterious changes inchromosome structure.
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