Autism is a neurodevelopmental disorder with characteristic impairments in social interaction and communication as well as restricted and repetitive patterns of behavior. It is typically diagnosed prior to the age of three and affects four times as many males as females. Twin studies have demonstrated a substantial genetic component in the development of autism; if one identical twin has autism, then the second twin has autism 60-90% of the time. In contrast, if one fraternal twin has autism, then the second twin has autism only 3-5% of the time, the same as observed between non-twin siblings. Therefore, our goal is to identify and functionally evaluate genes that underlie susceptibility to autism. Autism is a genetically complex disorder with many rare susceptibility variants rather than a few common ones, so we are using new technologies to identify genetic variants associated with autism. Recently, we have used microarrays to detect copy number variants ("medium" sized variants that either delete or duplicate a region of DNA sequence) in patients with autism. Our lab has identified several copy number variants that alter the DNA sequence of genes of interest in autism. One of these copy number variants deleted coding exons from the gene Neurexin1 (NRXN1) in two affected female siblings. Studies have shown that neurexins are located on the presynaptic terminus of both excitatory and inhibitory synapses in the brain and that they function as cell adhesion molecules, binding to neuroligins on the postsynaptic terminus. The neurexin/neuroligin complex has previously been implicated in autism and is hypothesized to have several functions including regulation of the ratio of excitatory to inhibitory synapses. The focus of my project is to further evaluate the role of NRXN1 in the development of autism by screening a large sample of individuals with autism for NRXN1 mutations. I will also use two animal models, the zebrafish and the mouse, to investigate the function of NRXN1.
