Prevalence of the Predisposing Gene MBD4 for Uveal Melanoma

Summary

MBD4 gene increased risk for developing uveal MM; found in 2.6% of MM patients, 31-fold increased risk vs the general population — 896 French patients.

Abstract

Importance: MBD4 monoallelic germline pathogenic and likely pathogenic variants have recently been identified as predisposing to uveal melanoma, a rare primary intraocular tumor, with an estimated 9.15-fold increased risk of developing the disease for pathogenic variant carriers.

Objective: To assess the risk of developing uveal melanoma for carriers of the MBD4 monoallelic germline pathogenic variant.

Design, setting, and participants: In a case series involving 896 individuals, including 319 who were previously evaluated, germline target-sequencing of MBD4 was offered to every new patient with uveal melanoma at Curie Institute from February 2021 to September 2025. Non-Finnish European participants from the Genome Aggregation Database were used as a reference population.

Exposure: Diagnosis of uveal melanoma genetic predisposition.

Main outcomes and measures: Prevalence of MBD4 variants.

Results: A total of 23 of 896 patients were identified as carrying an MBD4 germline pathogenic or likely pathogenic variant, corresponding to a relative risk of 31.44 (95% CI, 18.18-53.00) of developing uveal melanoma compared with the general population (2-sided Fisher exact test, P < .001).

Conclusions and relevance: These findings confirm that MBD4 is an important predisposing gene to uveal melanoma in the French population. This reinforces a strategy of broad patient screening given the therapeutic implications and the consequences of genetic counseling.