Drosophilafunctional screening ofde novovariants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

SummaryIndividuals with autism spectrum disorders (ASD) exhibit an increased burden ofde novovariants in a broadening range of genes. We functionally tested the effects of ASD missense variants usingDrosophilathrough ‘humanization’ rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identifiedGLRA2as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.