Contributions of rare biallelic recessive mutations in autism

Autism spectrum disorder (ASD) exhibits complex genetic architecture with well-demonstrated contributions of both common and rare, especially de novo, variants. Biallelic, recessive mutations provide another powerful but comparatively underexplored avenue for illuminating disease-relevant biological processes. Published work by Timothy Yu and others has built the case for the contribution of biallelic mutations to ASD, but gene identification in this space has been slower, partially because biallelic mutations occur less frequently and require larger sample sizes to ascertain.

To address these issues, Yu will undertake a large-scale analysis of biallelic mutations in the Simons Simplex Collection (SSC), Simons Foundation Powering Autism Research for Knowledge (SPARK), the Autism Sequencing Consortium, the Google/Autism Speaks ASD genomic database MSSNG and the Autism BrainNet Biobank). Combined analyses of these cohorts will enable the largest survey to date of biallelic mutations in ASD, enabling a search for phenotypic signatures predictive of biallelic mutation. Yu will utilize these data to establish a catalog of human gene knockouts associated with disease risk and illuminate new neurobiological mechanisms in ASD. This work will be performed in conjunction with colleagues Christopher Walsh (Boston Children’s Hospital), Joseph Buxbaum (Icahn School of Medicine at Mt. Sinai) and Mark Daly and Daniel MacArthur (Massachusetts General Hospital).