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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  Kdm5a  as a candidate ASD gene. To validate our discovery, we generated a  Kdm5a  knockout mouse model ( Kdm5a  -/- ) and confirmed that inactivating  Kdm5a  disrupts vocalization. In addition,  Kdm5a  -/-  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  KDM5A  mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic  KDM5A  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.

KDM5A mutations identified in autism spectrum disorder using forward genetics