Patterns of de novo tandem repeat mutations and their role in autism

Autism Spectrum Disorder (ASD) is an early onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviors(1,2). Family studies demonstrate that ASD has a significant genetic basis with contributions both from inherited and de novo variants(3,4). It has been estimated that de novo mutations may contribute to 30% of all simplex cases, in which only a single child is affected per family(5). Tandem repeats (TRs), defined here as 1-20bp sequences repeated consecutively, comprise one of the largest sources of de novo mutations in humans(6). TR expansions are implicated in dozens of neurological and psychiatric disorders(7). Yet, de novo TR mutations have not been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. We develop novel bioinformatics methods for identifying and prioritizing de novo TR mutations from sequencing data and then perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. Compared to recent work on TRs in ASD(8), we explicitly infer mutation events and their precise changes in repeat number, and primarily focus on more prevalent stepwise copy number changes rather than large expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. Mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and predicted to be more evolutionarily deleterious. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations.