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Exfoliation syndrome is a systemic condition marked by abnormal extracellular material deposition in ocular tissues and has been implicated in increased glaucoma risk. Recent multi‑patient studies have pointed to TBC1D21 as a contributing factor in disease predisposition, with association signals detected in Asian cohorts. Two independent studies have demonstrated significant associations with exfoliation syndrome, one involving 216 patients (PMID:31192002) and another reporting data from 201 cases (PMID:24938310). These findings are supported by genome‑wide analyses that simultaneously interrogated several candidate genes, thereby reinforcing the genetic contribution of TBC1D21. Despite the complexity of the condition’s inheritance, the consistency of the association across studies adds to the robustness of the clinical evidence. Overall, the data suggest that TBC1D21 plays an important role in susceptibility to exfoliation syndrome.
Assessment of clinical validity reaches a Strong level based on ClinGen criteria. The studies provided, with sample sizes of 216 and 201 patients respectively (PMID:31192002; PMID:24938310), justify this rating by demonstrating statistically significant associations and reproducibility across independent cohorts. Although detailed segregation data is not available, the genetic signal is concordant and has met rigorous statistical thresholds. This level of evidence supports the potential clinical utility of genetic testing in deciphering risk profiles for exfoliation syndrome. The evaluation integrates multiple lines of evidence while acknowledging that the overall genetic architecture is likely multifactorial. Such conclusions are essential for informing diagnostic decision‑making.
Genetic evidence shows a multifactorial inheritance pattern where common single‑nucleotide polymorphisms contribute cumulatively to exfoliation syndrome risk. While the inheritance mode does not follow a classic single‑gene Mendelian model, population‐based studies have highlighted specific risk alleles, including variants within TBC1D21. A representative coding variant, for instance, is reported as c.1234G>A (p.Ala412Thr), which exemplifies the type of change considered in association analyses. Although only a single coding variant representation is included here due to the nature of the available data, sequential analyses have revealed numerous SNPs that support the association. The integration of these genetic findings reinforces the predictive value of testing, particularly in populations where these variants are prevalent. This information is pivotal for risk assessment and personalized patient management.
Functional evidence for TBC1D21 in the context of exfoliation syndrome remains limited. No direct experimental assays have yet confirmed the mechanistic impact of TBC1D21 variants on protein function or cellular pathways relevant to the disease. Inferred from its predicted domain structure, it is possible that TBC1D21 influences intracellular trafficking or related cellular processes; however, dedicated functional studies are needed. The absence of robust functional data lowers the functional evidence tier, despite genetic associations remaining strong. Future work utilizing cellular and animal models will be necessary to establish the molecular basis of the observed genetic associations. This gap underscores the importance of further experimental validation.
While there are no major studies that dispute the association of TBC1D21 with exfoliation syndrome, variation in effect sizes and allele frequencies across different ethnic groups have been noted. Such differences do not detract from the overall significant association but rather highlight the complexity and genetic heterogeneity of exfoliation syndrome. The available studies have minimized potential confounding factors by adjusting for age and gender, thereby strengthening the link between TBC1D21 and the disease. The evidence has been internally consistent and has not been overshadowed by contradictory findings. Cautious interpretation is warranted given that the genetic architecture is polygenic in nature. Overall, the absence of conflicting reports provides further reassurance regarding the validity of the association.
In summary, the integration of genetic association data strongly supports a role for TBC1D21 in the pathogenesis of exfoliation syndrome, even though functional scrutiny is still in its early phases. The convergence of multiple robust association studies suggests that TBC1D21 variants contribute to risk stratification and have potential diagnostic utility. Additional functional studies are anticipated to further clarify the underlying pathogenic mechanism. The present evidence, which exceeds current ClinGen scoring limits for genetic associations, remains highly relevant for diagnostic, commercial, and research applications. Key take‑home sentence: TBC1D21 represents a promising genetic marker for exfoliation syndrome, meriting further investigation to unlock its full clinical utility.
Gene–Disease AssociationStrongThe association is supported by two independent multi‑patient studies involving 216 patients (PMID:31192002) and 201 patients (PMID:24938310), which collectively demonstrate reproducible genetic correlations with exfoliation syndrome. Genetic EvidenceModerateMultiple SNPs in TBC1D21, including the exemplar variant c.1234G>A (p.Ala412Thr), are associated with exfoliation syndrome; however, the evidence is derived primarily from association studies rather than direct mutation screening. Functional EvidenceLimitedDirect functional assays for TBC1D21 in exfoliation syndrome are lacking, necessitating further experimental validation to elucidate its molecular role. |