Intellectual phenotypes in autism strongly correlate with gene dosage changes and exon locations of truncating mutations

Autism spectrum disorders (ASD) are a group of related neurodevelopmental diseases displaying significant genetic and phenotypic heterogeneity. Despite recent progress in understanding ASD genetics, the nature of phenotypic heterogeneity across probands is currently unclear. It is also unknown how autism-associated mutations affect specific disorder phenotypes or whether similar genetic insults lead to similar phenotypic consequences. Likely gene-disrupting (LGD) de novo mutations affecting the same gene often result in substantially different intellectual quotient (IQ) phenotypes. Nevertheless, we find that truncating mutations affecting the same exon frequently lead to strikingly similar intellectual phenotypes in unrelated simplex ASD probands. Analogous patterns are observed for several other important ASD phenotypes. These findings suggest that exons, rather than genes, often represent a unit of effective phenotypic impact for truncating mutations. Our analysis shows that similar phenotypic effects are likely mediated by similar perturbations to the expression of splicing isoforms and corresponding gene dosage changes. For genes with recurrent truncating mutations, predicted changes in expression dosage strongly correlate with relative phenotypic consequences. Further analysis demonstrates that LGD mutations in the same exon often lead to similar perturbations of gene and isoform expression across human tissues. Therefore, analogous phenotypic patterns may be also observed in other developmental disorders triggered by highly penetrant genetic insults.