Association of Copy Number Variations in PTEN with Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic basis. While copy number variations (CNVs) significantly contribute to ASD risk, the specific role of individual genes within these variants remains unclear. This study investigates the contribution of CNVs in the PTEN gene to ASD pathophysiology by integrating population-level genetic analysis with multi-dimensional biological evidence. Methods: The biological plausibility of PTEN in ASD was first assessed using public multi-omics data, including tissue expression profiles, protein-protein interaction networks, and published cell-type-specific differential-expression data derived from single-nucleus RNA sequencing. Subsequently, a group-matched case-control study was conducted in a Han Chinese population (121 ASD cases and 110 controls) to evaluate the association between PTEN CNVs and ASD susceptibility. One-way ANOVA was performed to compare the differences in ASD clinical phenotype scores among groups with different CNV types of PTEN. Results: Integrative biological analyses revealed that PTEN is enriched in ASD-relevant brain regions (e.g., cerebellum) and exhibits cell-type-specific expression in neurons and glia. Furthermore, protein network analysis confirmed its central position within the PI3K/AKT signaling pathway, a critical regulator of neurodevelopment. In the Han Chinese population, no significant association was detected between PTEN CNVs and ASD risks or clinical phenotype scores. Conclusions:PTEN CNVs may not be independently associated with ASD, but may contribute to susceptibility through broader neurodevelopmental networks and molecular pathways.