Autism spectrum disorders (ASDs) are a highly heritable developmental nervous system disorders with varying degrees of impaired social interaction, defects in verbal and non-verbal communication and repetitive behavior. Symptoms typically begin before age 3 years and are accompanied by cognitive deficits. There is significant locus heterogeneity as evidenced by a number of Mendelian disorders with ASD as a feature. In addition, several large genomic sequencing studies have been undertaken in thousands of families with as ASD proband. The incomplete functional annotation of the majority of genes in the human genome leads to problems in interpreting the results of these studies as the functional impact of variants is usually not known. Studies in model organisms such as Drosophila have consistently contributed to our understanding of gene function including genes involved in neuronal development, neuronal function and maintenance. We are conducting a functional screen in Drosophila to analyze ASD candidate genes. We examined whole-exome sequencing data from 2,500 families with a proband with ASD from the Simon’s Simplex collection (SSC). Of these we focused on 2,437 human genes with de novo missense or in-frame indels in ASD cases. We focused on missense and in-frame alleles to study variants with unknown impact on gene function. Of these 1,931 genes (79.2%) are conserved in Drosophila. The ASD candidate genes are cross-referenced to independent genomic data from non-Autism cohorts in order to aid in prioritization. From a group of priority genes we have selected 62 Drosophila Mi[MIC] lines with insertions in introns between coding exons for functional screens. These lines are currently being converted to loss-of-function strains using the versatile artificial exonic element to generate a 2A-Gal4 line. These strains will be scored for viability, longevity, and a number of basic behavioral phenotypes. Strains with strong phenotypes will be studied for nervous system expression, knockdown and the human reference and ASD-related variant forms are being tested to determine the functional effect of the variants of interest. This synergy between human genomics and a versatile functional analysis pipeline in Drosophila should allow stronger links between the growing list of ASD candidate genes and the wealth of conserved neurobiology in model organisms.