Alternative splicing in autism spectrum disorder: Recent insights from mechanisms to therapy

Alternative splicing (AS) is a vital and highly dynamic RNA regulatory mechanism that allows a single gene to generate multiple mRNA and protein isoforms. Dysregulation of AS has been identified as a key contributor to the pathogenesis of autism spectrum disorders (ASD). A comprehensive understanding of aberrant splicing mechanisms and their functional consequences in ASD can help uncover the molecular basis of the disorder and facilitate the development of therapeutic strategies. This review focuses on the major aberrant splicing events and key splicing regulators associated with ASD, highlighting their roles in linking defective splicing to ASD pathogenesis. In addition, a discussion of how emerging technologies, such as long-read sequencing, single-cell sequencing, spatial transcriptomics and CRISPR-Cas systems are offering novel insights into the role and mechanisms of AS in ASD is presented. Finally, the RNA splicing-based therapeutic strategies are evaluated, emphasizing their potential to address unmet clinical needs in ASD treatment. • Dysregulation of alternative splicing is a critical factor in the pathogenesis of autism. • Understanding of aberrant splicing in autism helps reveal its pathological basis and guide therapeutic interventions. • Aberrant splicing events and regulators are linked to autism pathogenesis. • New technologies advance our knowledge of AS in ASD. • Splicing-based therapies hold promise for addressing clinical gaps in ASD treatment.