Genotype to phenotype relationships in autism spectrum disorders

Abstract

Autism spectrum disorders (ASD) are characterized by both phenotypic and genetic heterogeneity. Our analysis of functional networks perturbed in ASD suggests that both truncating and non-truncating de novo mutations contribute to autism, although there is a strong bias against truncating mutations in early embryonic development. We find that functional mutations are preferentially observed in genes likely to be haploinsufficient. Multiple cell types and brain areas are affected, but the impact of ASD mutations appears to be strongest in the cortical neurons and the medium spiny neurons of the striatum, implicating corticostriatal brain circuits. In females, truncating ASD mutations on average impact genes with 50–100% higher brain expression levels compared to males. Our study also suggests that truncating de novo mutations play a smaller role in the etiology of high-functioning ASD cases. Overall, we find that stronger functional insults usually lead to more severe intellectual, social and behavioral ASD phenotypes.