Modifiers of Genetics in ASD Etiology

Autism spectrum disorder (ASD) is a complex and heterogeneous neurodevelopmental condition with a multifactorial genetic architecture, with risk arising from the interplay between genetic and environmental factors. Although there is a strong heritable component, identified genetic variants explain only a proportion of its susceptibility. Mutations in individual genes or copy number variants (CNVs) each account for less than 1% of cases, while collectively, rare de novo mutations and CNVs are estimated to contribute to approximately 20% of ASD cases. This incomplete explanation of ASD risk through identified genetic variants suggests that additional mechanisms, including gene by environment (G×E) interactions, may contribute to ASD risk.Epigenetic mechanisms, including DNA methylation, provide an intermediate molecular phenotype through which genetic susceptibility and environmental exposures converge to influence neurodevelopment. Furthermore, consideration of sex by environment (S×E) interactions may help elucidate sex-related differences in ASD prevalence and molecular phenotypes. This chapter synthesizes current evidence for epigenetic mechanisms underlying ASD, with a focus on how genetic susceptibility, prenatal environmental exposures, and biological sex may interact to shape epigenomic patterns relevant to neurodevelopment and ASD risk.