Prevalence of the Predisposing Gene MBD4 for Uveal Melanoma.

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.