Genome-wide characteristics of de novo mutations in autism

Abstract De novo mutations (DNMs) are important in autism spectrum disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole-genome sequencing (WGS) of 200 ASD parent–child trios and characterised germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only ( P =4.2×10 −10 ). However, when clustered DNMs (those within 20 kb) were found in ASD, not only did they mostly originate from the mother ( P =7.7×10 −13 ), but they could also be found adjacent to de novo copy number variations where the mutation rate was significantly elevated ( P =2.4×10 −24 ). By comparing with DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases ( P =8.0×10 −9 ; odds ratio=1.84), of which 15.6% ( P =4.3×10 −3 ) and 22.5% ( P =7.0×10 −5 ) were non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, regulatory sequences involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD-risk and epigenetic genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the aetiology of ASD.