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Prevalence of the Predisposing Gene <i>MBD4</i> for Uveal Melanoma

Prevalence of the Predisposing Gene <i>MBD4</i> for Uveal Melanoma

1 Jun 2026JAMA Ophthalmology

DOI : 10.1001/jamaophthalmol.2026.1071

Authors

Anaïs Le Ven, Marie-Charlotte Villy, Marine Le Mentec, Alexandre Houy, Catherine Dubois d’Enghien, Alexandre Matet, Denis Malaise, Virginie Bubien, Alain Lortholary, Amal Ait Omar, Dominique Stoppa-Lyonnet, Nathalie Cassoux, Manuel Rodrigues, Lisa Golmard, Marc-Henri Stern, Chrystelle Colas

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 &lt; .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.