The Contribution of Mosaic Variants to Autism Spectrum Disorder

De novo mutation is highly implicated in autism spectrum disorder (asd). however,the contribution of post-zygotic mutation to asd is poorly characterized. we performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. while we find little evidence for tissue-specific mosaic mutation,multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent,with detectable mosaic variation comprising 5.4% of all de novo mutations. we identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in asd (kmt2c,nckap1,and myh10) in probands but none in siblings. we find a strong ascertainment bias for mosaic mutations in probands relative to their unaffected siblings (p = 0.003). we build a model of de novo variation incorporating mosaic variants and errors in classification of mosaic status and from this model we estimate that 33% of mosaic mutations in probands contribute to 5.1% of simplex asd diagnoses (95% credible interval 1.3% to 8.9%). our results indicate a contributory role for multi-tissue mosaic mutation in some individuals with an asd diagnosis. © 2016 freed,pevsner.