TMTC2 and OPTN‑related Open Angle Glaucoma

The association between TMTC2 and OPTN‑related open angle glaucoma has been evaluated in multiple population‐based studies, although the evidence remains conflicting. In one study conducted in southern Chinese cohorts investigating 462 primary open‑angle glaucoma patients (PMID:22773901), TMTC2 was included in a panel of candidate genes; however, the significant findings were driven by risk alleles in other genes such as TLR4 and a chromosome 2p16.3 marker. In contrast, a subsequent expansive marker analysis in a Korean cohort of 1115 participants (211 cases and 904 controls; PMID:23838595) specifically evaluated variants near TMTC2 and reported no significant association for SNPs upstream of TMTC2.

Overall, the clinical validity of the TMTC2–OPTN‑related open angle glaucoma association is best classified as Disputed. Although TMTC2 was included as a candidate in multi‐gene studies, its individual contribution is not supported by consistent statistical evidence. The discrepancy between the initial multi‐gene association and the focused analysis that revealed a lack of association diminishes the strength of the claim.

The genetic evidence is limited by the absence of TMTC2‐specific pathogenic variants. No compelling missense, loss‑of‑function, or splice variants (e.g., a variant such as c.123A>T (p.Lys41Asn)) were definitively linked to disease presentation in either study. Moreover, formal segregation data or multi‑family analyses are not provided, further restricting the strength of the genetic evidence.

Regarding functional data, no experimental studies or assay results were presented that directly implicate TMTC2 in the pathogenesis of OPTN‑related open angle glaucoma. There are no available cell or animal models, nor are there rescue experiments that support any specific mechanism of pathogenicity for TMTC2 in this condition.

In summary, while additional association studies have been conducted for primary open‑angle glaucoma and its related phenotypes, the evidence specific to TMTC2 remains inconclusive. The absence of both robust genetic and functional evidence indicates that TMTC2 should not currently be used as a definitive diagnostic marker for OPTN‑related open angle glaucoma, and further research is needed to clarify its role.

Key Take‑home: The current data do not support a clinically actionable association between TMTC2 and OPTN‑related open angle glaucoma, urging cautious interpretation in both diagnostic and research settings.

References

• Molecular Vision • 2012 • SNP rs1533428 at 2p16.3 as a marker for late‑onset primary open‑angle glaucoma PMID:22773901
• European Journal of Human Genetics • 2014 • Expansive marker analysis replicating the association of glaucoma susceptibility with human chromosome loci 1q43 and 10p12.31 PMID:23838595

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