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 RSE Retention Harness 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 Accent Mug 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.