Rare human knockouts in autism: patterns and mechanisms

The goal of these projects to identify human gene knockouts that cause autism and reveal critical neurobiological mechanisms of disease. We are analyzing sequencing data collected from tens of thousands of individuals with ASD, examine rates and patterns of biallelic gene knockouts, and compare these to matched controls and large reference databases (ExAC, gnomAD). We use this data to understand how variables like disease severity, comorbidity, and gender impact the likelihood of finding an underlying gene knockout. We also generate a catalog of specific genes that are knocked out more frequently in individuals with ASD than in the general population. The strongest candidates from this catalog are then subject to followup functional studies to provide insight into how dysfunction may alter brain development and plasticity in autistic individuals. For instance, a pilot screen of 2,300 individuals with ASD and >70,000 controls has led to the identification of 40 ASD-specific knockouts, including the first human knockout of FEV, a transcription factor required for differentiation of serotonergic nuclei in the human CNS. Two other strong candidate genes for which we are pursuing functional characterization are KIF22, a gene in the 16p11.2-critical region, and NCOA7, a brain-specific, estrogenregulated nuclear coregulator.