Rare Variants in Purinergic P2X Receptor Genes (P2RX4, P2RX5, P2RX7) in Individuals With Autism Spectrum Disorder: An Exploratory Study

Abstract

Background Purinergic P2X receptors (P2RX) play key roles in neuroinflammatory processes through ATP‐gated ion channel signaling. Dysregulation of P2RX receptor activity has been implicated in maternal immune activation, mitochondrial dysfunction, oxidative stress, and synaptic abnormalities associated with autism spectrum disorder (ASD). Despite increasing mechanistic evidence, the contribution of P2RX gene variants to ASD remains poorly understood. Methods We retrospectively evaluated whole‐exome sequencing (WES) data from individuals diagnosed with ASD according to DSM‐5 criteria. Variants in the P2RX1–P2RX7 genes were identified. Clinical, genetic, and in silico data were reviewed, and variants were classified according to ACMG/AMP guidelines. Results Eleven individuals were identified with heterozygous P2RX variants, most frequently in P2RX7 (54.5%), followed by P2RX5 (27.3%) and P2RX4 (18.2%). Core clinical features across all genes included ASD, intellectual disability (ID), and epilepsy. P2RX4 variants included an in‐frame deletion (p.Ile322del) and a truncating variant (p.Tyr366LeufsTer7), both observed in individuals with ASD and ID. P2RX5 variants comprised rare missense substitutions with variable in silico pathogenicity. Several P2RX7 variants, most notably the canonical splice‐site variant c.614 + 1G > A fulfilling ACMG/AMP PVS1 and PM2 criteria, were predicted to alter receptor function. Overall, in silico analyses indicated moderate to high predicted functional impact; however, most variants lacked segregation and functional validation data. Conclusion Our findings provide preliminary, exploratory observations suggesting that rare P2RX variants may represent biologically plausible candidates relevant to ASD‐related pathways; however, no conclusions regarding disease association or causality can be drawn. These findings should be considered hypothesis‐generating and require validation through larger controlled genetic studies and functional investigations.