Abstract
Autism spectrum disorders (ASD) are a group of related neurodevelopmental diseases displaying significant genetic and phenotypic heterogeneity1-4. Despite recent progress in understanding ASD genetics, the nature of phenotypic heterogeneity across probands is currently unclear5,6. 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, suggesting that exons, rather than genes, often represent a unit of effective phenotypic impact for truncating mutations. We find that phenotypic effects are likely mediated by nonsense-mediated decay (NMD) of splicing isoforms and that autism phenotypes are usually triggered by relatively mild (15-30%) decreases in overall gene dosage. Notably, for genes with recurrent truncating mutations, predicted expression changes can be used to infer phenotypic consequences in individual ASD probands. As LGD mutations in the same exon lead to similar expression changes across human tissues, analogous phenotypic patterns may be also observed in other developmental disorders.