TLCD5 – Exfoliation Syndrome

TLCD5 has emerged as a candidate gene from several large-scale genetic association studies investigating exfoliation syndrome, a systemic condition characterized by the deposition of fibrillar exfoliative material in ocular tissues (PMID:28553957, PMID:31687947). However, despite its consistent inclusion in multi‐locus screening panels, no reports have yet documented specific deleterious coding variants or provided robust familial segregation data for TLCD5.

The genetic evidence for TLCD5 is primarily based on common variant signals detected in genome‑wide association study cohorts. Neither a clearly defined variant with a complete HGVS coding change nor reproducible segregation in affected families has been reported, limiting the strength of the gene‑disease association (PMID:28553957).

Functional studies using CRISPR/Cas9‐induced mouse models targeting several candidate genes, including TLCD5, did not recapitulate the hallmark ocular features—specifically the deposition of exfoliative material—observed in human patients (PMID:38770563). This negative functional data further tempers confidence in TLCD5 as the sole effector via a monogenic loss‑of‑function mechanism.

In addition, while two independent multi‐patient studies have implicated TLCD5 among other susceptibility loci, the lack of quantitative data on affected relatives or specific variant classes restricts the cumulative genetic evidence to being modest compared to established monogenic disorders.

The overall assessment indicates that the TLCD5–exfoliation syndrome association currently falls into the Limited category. The combined genetic association signals and insufficient functional corroboration suggest that TLCD5 might contribute to a multifactorial risk landscape rather than represent a high‐penetrance, standalone disease gene.

Key take‑home: Although TLCD5 is consistently identified in genetic screens of exfoliation syndrome, its clinical utility for diagnostic decision‑making remains limited until further variant‐level and mechanistic studies can substantiate its role.

References

• Human Molecular Genetics • 2024 • Lack of evidence for GWAS signals of exfoliation glaucoma working via monogenic loss-of-function mutation in the nearest gene PMID:38770563
• Nature Genetics • 2017 • Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci PMID:28553957
• Georgian Medical News • 2019 • NEW GENETIC MARKERS ASSOCIATED WITH SUSCEPTIBILITY TO EXFOLIATION SYNDROME AMONG GEORGIAN POPULATION PMID:31687947

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