Rare Mutation Burden of the Contactin Pathway in Autism Spectrum Disorders

Background: Autism spectrum disorders (ASD) have a largely unknown complex genetic etiology. We have characterized patients de novo chromosomal abnormities to identify candidate genes that confer risk for idiopathic ASD. We identified patients with de novo abnormities disrupting CNTNAP2, CNTNAP4, and Contactin 4 and ASD and/or developmental delay (Fernandez et al. 2004, Bakkaloglu et al. 2008, and unpublished results). Additionally, frame-shift mutations have been identified in CNTNAP2 in a recessive syndrome characterized by intractable seizures, mental retardation, and ASD (Strauss et al. 2006). We have also identified putatively functional variants at CNTNAP2 in ASD patients (Bakkaloglu et al. 2008). These data suggest that defects in a contactin pathway may confer risk for ASD. Objectives: I. To determine the burden of rare deleterious variants in the contactin pathway among ASD cases and controls. II. To test the functionality of identified variants. Methods: I. Using homologies and known interactions, a contactin pathway was determined (~40 genes). Next-generation sequencing and copy number analysis will be used to analyze mutation burden in a large case-control study. The rate of rare unique variants will be compared. II. CNTNAP2 variants were cloned into expression vectors. Vectors were then injected into chick spinal cords, electroporated, and examined for defects in neuron morphology. Results: Sequencing and copy number analysis are currently being performed on the contactin pathway. Variants have been cloned and are now being tested in our functional assay. Conclusions: Rare likely functional variants are present at CNTNAP2 in ASD cases. Our results indicate that this risk is likely moderate and will require large sample sizes to confirm these findings. Results on additional members of the contacin pathway are forthcoming. Analysis of the contactin pathway may provide valuable insights into the pathophysiology of ASD.