The contribution of de novo tandem repeat mutations to autism spectrum disorders

Autism Spectrum Disorder (ASD) is an early onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviors1,2. Family studies demonstrate that ASD has a significant genetic basis3 with contributions both from inherited and de novo variants. While the majority of variance in liability to ASD is estimated to arise from common genetic variation4, 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 family5. Tandem repeats (TRs), consisting of approximately 1-20bp motifs repeated in tandem, comprise one of the largest sources of de novo mutations in humans6. Yet, largely due to technical challenges they present, de novo TR mutations have not yet been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here, we develop novel bioinformatics tools for identifying and prioritizing de novo TR mutations from whole genome sequencing (WGS) data and use these to perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. Compared to recent work on TRs in ASD7, we explicitly infer mutation events and their precise changes in repeat copy number, and primarily focus on more prevalent stepwise copy number changes rather than large or complex expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. TR mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and predicted to be more evolutionarily deleterious compared to mutations observed in unaffected siblings. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations.