Low-level brain somatic mutations in exonic regions are collectively implicated in autism with germline mutations in autism risk genes

Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12–14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology. Autism Spectrum Disorder is a complex condition influenced by various genetic factors, including inherited traits and new changes in genes. This study investigates the role of low-level brain somatic mutations in ASD. The researchers analyzed brain tissues from deceased individuals, both with and without ASD, using high-depth whole-exome sequencing. The results showed that low-level brain somatic mutations, along with inherited genetic variations, contribute to ASD’s genetic makeup. These mutations were found in genes linked to brain development and function. The study emphasizes the need to consider both inherited and somatic mutations to understand ASD’s genetic complexity. Researchers conclude that the interaction between somatic and inherited mutations is crucial in ASD, providing new insights into its genetic basis. This study enhances our understanding of ASD’s genetic diversity and suggests a multifaceted genetic contribution to the disorder. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.