Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms

Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis. •More ASD brains had deleterious mutations in candidate ASD genes than controls•Recurrent deleterious mutations occurred in well-known ASD genes like SCN2A•Identified mutations and medical records suggest syndromic diagnoses in some cases•Two cases had deleterious somatic mutations which may contribute to ASD risk D’Gama et al. find more autism spectrum disorder brains have deleterious mutations in candidate ASD genes than control brains, including two ASD brains with deleterious somatic mutations. Results suggest combinations of germline and somatic mutations may contribute to ASD risk.