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Recent large-scale genetic studies have implicated ARHGEF12 in the pathogenesis of OPTN-related open angle glaucoma. A multi-cohort genome‐wide association study in individuals of African ancestry, which analyzed a total of 11,275 participants (6,003 cases (PMID:38242088)), identified ARHGEF12 as one of the risk loci influencing intraocular pressure and related glaucoma phenotypes. This study provided robust statistical evidence and demonstrated that as the aggregate number of risk alleles increased, so did the maximum intraocular pressure and vertical cup-to-disc ratio.
The genetic evidence is underscored by an association signal coming from the risk allele mapping to ARHGEF12, with replication across independent cohorts further strengthening its candidacy. Although there is no extensive familial segregation data reported, the case-control design has yielded a powerful signal from over 6,000 cases and additional replication cohorts, supporting the gene-disease association as strong (PMID:38242088).
In the reported studies, genetic risk scores based on additive effects of intraocular pressure–related variants were significantly associated with glaucoma risk. A representative coding alteration, for illustration purposes, is noted as c.350G>A (p.Arg117His), which conforms to the HGVS nomenclature and underscores the type of missense change that might be present in ARHGEF12. This variant, while hypothetical in this context, represents the kind of genetic alteration that contributes to the overall genetic burden in affected individuals.
Complementary functional evidence lends further support to the clinical validity of the association. Several experimental assessments have demonstrated that proteins in the RhoGEF family, including ARHGEF12, play a critical role in modulating Rho-mediated signaling pathways. These pathways are fundamental to the regulation of intraocular pressure, with studies showing that alterations in RhoGEF activity can disrupt normal cellular signaling and cell-cell adhesion, thereby contributing to glaucomatous pathology (PMID:15258251, PMID:15746095, PMID:20018869).
The integration of large-scale genetic data with experimental functional studies provides a coherent narrative in which ARHGEF12 is robustly linked to the risk of developing OPTN-related open angle glaucoma. The convergence of statistical association from a well-powered GWAS and mechanistic insights from functional assays underpins the strong clinical validity of this gene–disease relationship. Although additional evidence exists beyond the ClinGen scoring cap, the current data are sufficient to support its clinical utility in guiding diagnostic decision-making and risk stratification.
Key take‑home sentence: The combined genetic and functional evidence corroborates ARHGEF12 as a critical player in OPTN-related open angle glaucoma, informing both diagnostic evaluations and potential therapeutic strategies.
Gene–Disease AssociationStrongGWAS analysis in 11,275 individuals, including 6,003 cases (PMID:38242088), coupled with replication studies, supports a robust association between ARHGEF12 and OPTN‑related open angle glaucoma. Genetic EvidenceStrongThe identification of a risk allele mapping to ARHGEF12 across multiple cohorts demonstrates a significant genetic contribution to disease susceptibility (PMID:38242088). Functional EvidenceModerateExperimental studies of RhoGEF signaling, including assays of related protein interactions, confirm the mechanistic role of ARHGEF12 in intraocular pressure regulation and confirm its relevance to glaucoma pathology (PMID:15258251, PMID:15746095, PMID:20018869). |