Co-occurrence of rare variants implicates gene pairs in cytoskeletal pathways and is associated with increased severity in autism spectrum disorder

Abstract Background The genetic basis of autism spectrum disorder (ASD) is complicated by high heritability and substantial heterogeneity, in which de novo variants and polygenic burden from common variants have not been comprehensively elucidated. Increasing evidence indicates that aggregates of rare variants can exert additive or synergistic effects that modulate disease risk. Using an approach that considers variant co-occurrence, we aim to detect the contribution of rare variants with modest effect in ASD. Results We analyze large-scale genomic data from individuals of East-Asian and European ancestry and identify disrupted gene pairs affected by co-occurring rare deleterious variants. Candidate genes comprising disrupted gene pairs are enriched in cytoskeletal pathways, and those involving cytoskeletal genes are highly co-expressed in neural precursor cells. Phenotype analysis reveals that affected males with co-occurring rare variants in disrupted gene pairs exhibit increased symptom severity, a pattern not observed in females. Unaffected parents harboring these variants display elevated autistic traits, suggesting potential impacts beyond diagnosed individuals. Conclusions This study employs large-scale, multi-ancestry genomic datasets to identify gene pairs affected by the co-occurrence of rare variants and assess their biological and clinical impact. Our findings highlight the significance of rare variants with modest effects in ASD and offer insights into the complex mechanisms underlying ASD.