Abstract / Summary
Abstract The contribution of postzygotically acquired hematopoietic somatic mutations to autism spectrum disorder (ASD) remains largely unexplored.In this study, we performed whole-exome sequencing on pediatric blood samples and found clonal hematopoiesis in predisposed individuals (CHIPI) as a potential and significant genetic risk factor for ASD. We identified 286 CHIPI-related genes loci enriched in ASD. Critically, the overlap with known ASD germline risk genes (SFARI) was minimal (< 1.6%), establishing these mutations as a distinct genetic risk architecture that operates independently of established germline pathways. Furthermore, Multidimensional profiling revealed that these somatic alterations are associated with a spectrum of systemic physiological perturbations, including immune dysregulation, oxidative stress, intestinal inflammation, and mitochondrial dysfunction. Importantly, our analyses indicated that these CHIPI-related mutations significantly mediated the adverse effects of endocrine-disrupting chemicals on these pathological pathways. Collectively, our results identify CHIPI as a novel genetic factor of ASD and further reveal its connection to systemic immune and metabolic dysregulation.