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Multiple independent genetic studies have implicated GPRASP2 in autism spectrum disorder (ASD). In a systematic resequencing study of X‑linked synaptic genes in ASD and schizophrenia, GPRASP2 was identified among several candidate genes showing an excess of rare damaging variants (PMID:20479760). A subsequent whole exome sequencing study in females with autism also nominated GPRASP2 along with other X‑linked genes, suggesting its potential contribution to the ASD phenotype (PMID:25574603). Furthermore, two independent X‑chromosome‑wide association studies reported statistically significant regions including GPRASP2 in large ASD cohorts (PMID:39108515, PMID:39706197).
Although the genetic evidence across these studies is supported by large sample sizes and replication in independent cohorts, detailed familial segregation data and clear phenotype–genotype correlations are presently limited. The reported candidate variants have not yet been thoroughly validated by segregation analysis in extended pedigrees (PMID:20479760).
The observed variant burden in GPRASP2 supports a model in which altered gene function via rare or common variants on the X‑chromosome contributes to ASD risk. In the available evidence, one X‑linked variant—c.1717_1719delinsAAT (p.Ala573Asn)—has been reported in functional studies; although this specific variant was initially characterized in the context of syndromic hearing loss, its presence underscores the importance of GPRASP2 in neural function and supports its candidacy in neurodevelopmental conditions.
Functional studies to date have largely focused on the role of GPRASP2 in neuronal maintenance and synaptic transmission. However, direct experimental evidence linking GPRASP2 dysfunction to ASD pathobiology remains sparse. Laboratory evidence from models of neuronal dysfunction and apoptosis provides plausible mechanistic insights, yet further targeted functional assays in ASD models are needed (PMID:28096187, PMID:39253164).
In summary, the genetic association of GPRASP2 with ASD is supported by multiple independent sequencing and association studies, placing its gene‑disease association in the moderate range. While the current genetic evidence is compelling, the lack of comprehensive segregation and directly relevant functional studies tempers the overall interpretability.
Key Take‑home: GPRASP2 represents a moderately supported, X‑linked candidate gene for ASD, meriting further functional characterization to solidify its clinical utility in diagnostic decision‑making.
Gene–Disease AssociationModerateMultiple independent genetic studies—including targeted resequencing and X‑chromosome-wide association analyses in ASD cohorts—implicate GPRASP2, although detailed segregation and direct functional validation in the ASD context remain limited (PMID:20479760, PMID:25574603, PMID:39108515, PMID:39706197). Genetic EvidenceModerateA combination of candidate variant discovery and significant association signals from large-scale X‑chromosome analyses supports a moderate contribution of GPRASP2 to ASD risk. Functional EvidenceLimitedWhile studies in neuronal models underscore GPRASP2’s role in neural maintenance, direct functional assays linking its altered activity to ASD are currently sparse. |