RT Journal Article SR Electronic T1 Evolutionary Action of de novo Missense Variants across Pathways Prioritizes Genes Linked to Autism and Predicts Patient Phenotypic Severity JF bioRxiv FD Cold Spring Harbor Laboratory SP 158329 DO 10.1101/158329 A1 Amanda Koire A1 Christie Buchovecky A1 Panagiotis Katsonis A1 Young Won Kim A1 Stephen J. Wilson A1 Olivier Lichtarge YR 2017 UL http://biorxiv.org/content/early/2017/06/30/158329.abstract AB The pathogenicity of individual de novo missense mutations in autism spectrum disorder remains difficult to validate. Here we asked in 2,384 probands whether these variants exhibited collective functional impact biases across pathways. As measured with Evolutionary Action (EA) in 368 gene groupings, we found significant biases in axonogenesis, synaptic transmission, and other neurodevelopmental pathways. Strikingly, both de novo and inherited missense variants in prioritized genes correlated with patient IQ. This general integrative approach thus detects missense variants most likely to contribute to autism pathogenesis and is the first, to our knowledge, to link missense variant impact to autism phenotypic severity.