Towards a gene-level map of resilience to genetic variants associated with autism

While over 100 genes are now significantly associated with autism spectrum disorders (ASD), the penetrance of the variants affecting these genes remains poorly understood. Here, we quantified the prevalence of rare loss-of-function (LoF) mutations affecting 156 genes robustly associated with ASD (SPARK genes) using genetic data from more than 10,000 individuals with ASD and 100,000 undiagnosed individuals. We then investigated the clinical, brain imaging and genetic profiles of individuals heterozygous for these rare deleterious variants who were not diagnosed with ASD. These "resilient" individuals, observed in less than 1% of the general population, were equally distributed among males and females, but displayed low polygenic scores for ASD compared to LoF heterozygotes diagnosed with ASD. The interplay between rare and common variants may therefore contribute to the clinical profiles of the individuals carrying LoF in genes associated with ASD.