<i>KDM5A</i> mutations identified in autism spectrum disorder using forward genetics.

Abstract

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified <i>Kdm5a</i> as a candidate ASD gene. To validate our discovery, we generated a <i>Kdm5a</i> knockout mouse model (<i>Kdm5a</i>^-/-) and confirmed that inactivating <i>Kdm5a</i> disrupts vocalization. In addition, <i>Kdm5a</i>^-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome. To determine if <i>KDM5A</i> mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic <i>KDM5A</i> variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function.