Advancing precision diagnosis in autism: Insights from large-scale genomic studies

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex genetic basis. Large-scale whole-exome sequencing and whole-genome sequencing studies, with increasing sample sizes and improved ancestral diversity, have significantly advanced the discovery of ASD-associated genes. In addition to identifying coding variants, whole-genome sequencing has facilitated the detection of risk noncoding variants in regulatory elements such as enhancers, promoters, and untranslated regions, prompting experimental validation of their functional impact on neurodevelopment. A deeper understanding of ASD genetic liability has revealed the interplay between rare and common variants. Moreover, genetic liability varies by sex and phenotype profile, underscoring the complexity of ASD's genetic architecture. While the clinical application of these genomic insights remains in early stages, progress has been made in gene-based therapeutic development, the interpretation of noncoding risk variants, and the use of polygenic score for risk stratification. In this review, we summarize key findings from large-scale genomic studies, explore the role of coding and noncoding variants in ASD, and discuss emerging opportunities for translating these discoveries into clinical practice.