There is ample evidence that rare genetic variants may contribute to a small subset of individuals presenting with Autism Spectrum Disorders (ASDs). The characterization of these unusual cases may provide important insights into pathophysiological mechanisms underlying disease. Our laboratory has leveraged the comprehensive phenotyping capabilities of the Yale Autism Research Group to focus on the discovery of rare variants contributing to developmental and social disability. Recently we have studied three unrelated patients with ASD and/or Mental Retardation (MR) and chromosomal abnormalities, all of who were 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 recognition molecules are known to play key roles in axon pathfinding, fasciculation and neuronal-glial interactions. We have 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 missense mutations among 218 cases and 449 controls regardless of whether we consider all non-synonymous variants or only those predicted by bioinformatics approaches to be deleterious to protein function. This data is particularly compelling in light of two additional findings: a rare recessive mutation in this gene found in association with seizures, developmental delay and autistic features in Amish families;and, unpublished data from collaborators at UCLA showing a common haplotype of CNTNAP2 associated with language delay in individuals with Autism. Based on our recent findings we now propose to: 1) replicate the mutation burden analysis in CNTNAP2 and perform a similar preliminary study in patients with developmental delay but not social disability;2) perform initial and, if warranted, replication studies of the other molecules disrupted by chromosomal abnormalities, Contactin 4 and Contactin Associated Protein 4 and 3) continue our gene discovery efforts using both conventional and array based cytogenetics on the well-characterized patients recruited under Projects 1-IV of this application focusing on the identification of rare, deleterious changes in chromosome structure.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZHD1-MRG-C)
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Yale University
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Macari, Suzanne L; Koller, Judah; Campbell, Daniel J et al. (2017) Temperamental markers in toddlers with autism spectrum disorder. J Child Psychol Psychiatry 58:819-828
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