Abstract
Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. We systematically evaluated PMMs by leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection. We found evidence that 11% of published single nucleotide variant (SNV) de novo mutations are potentially PMMs. We then developed a robust SNV PMM calling approach that leverages complementary callers, logistic regression modeling, and additional heuristics. Using this approach, we recalled SNVs and found that 22% of de novo mutations likely occur as PMMs in children. Unexpectedly, we found a significant burden of synonymous PMMs in probands that are predicted to alter splicing. We found no evidence of missense PMM burden in the full cohort. However, we did observe increased signal for missense PMMs in families without germline mutations in probands, which strengthens in genes intolerant to mutations. We also determined that 7-11% of parental mosaics are transmitted to children. Parental mosaic mutations make up 6.8% of all mutations newly germline in children, which has important implications for recurrence risk. PMMs intersect previously implicated high confidence and other ASD candidate risk genes, further suggesting that this class of mutations contribute to ASD risk. We also identified PMMs in novel candidate risk genes involved with chromatin remodeling or neurodevelopment. We estimate that PMMs contribute risk to 4-8% of simplex ASD cases. Overall, these findings argue for future studies of PMMs in ASD and related-disorders.
