De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia

• De novo synonymous mutations likely affecting splicing regulation are enriched in ASD
• De novo synonymous mutations within frontal cortex-derived DHS are enriched in SCZ
• “Functional” synonymous mutations significantly contribute to disease liability
• “Functional” synonymous mutations support role of SETD1A and RAB2A in neuropsychiatry

SummaryWe analyze de novo synonymous mutations identified in autism spectrum disorders (ASDs) and schizophrenia (SCZ) with potential impact on regulatory elements using data from whole-exome sequencing (WESs) studies. Focusing on five types of genetic regulatory functions, we found that de novo near-splice site synonymous mutations changing exonic splicing regulators and those within frontal cortex-derived DNase I hypersensitivity sites are significantly enriched in ASD and SCZ, respectively. These results remained significant, albeit less so, after incorporating two additional ASD datasets. Among the genes identified, several are hit by multiple functional de novo mutations, with RAB2A and SETD1A showing the highest statistical significance in ASD and SCZ, respectively. The estimated contribution of these synonymous mutations to disease liability is comparable to de novo protein-truncating mutations. These findings expand the repertoire of functional de novo mutations to include “functional” synonymous ones and strengthen the role of rare variants in neuropsychiatric disease risk.