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Published on: June 7, 2019
Prevalence of the Predisposing Gene MBD4 for Uveal Melanoma
Anaïs Le Ven1,2,3, Marie-Charlotte Villy2,3, Marine Le Mentec1,2
1Department of Genetics, Institut Curie, Paris, France.
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.
Insights
Pathogenic variants in the MBD4 gene significantly increase the risk of developing uveal melanoma. This study confirms MBD4 as a key predisposing gene, supporting broader patient screening for this rare eye cancer.
Area of Science:
- Ophthalmology
- Genetics
- Oncology
Background:
- MBD4 monoallelic germline pathogenic variants are recently identified as predisposing to uveal melanoma.
- Uveal melanoma is a rare primary intraocular tumor.
- Pathogenic variant carriers have an estimated 9.15-fold increased risk.
Purpose of the Study:
- To assess the risk of developing uveal melanoma for carriers of the MBD4 monoallelic germline pathogenic variant.
- To evaluate the prevalence of MBD4 variants in uveal melanoma patients.
Main Methods:
- Case series of 896 individuals with uveal melanoma.
- Germline target-sequencing of MBD4 offered to new patients.
- Non-Finnish European participants from the Genome Aggregation Database as reference.
Main Results:
- 23 out of 896 patients carried an MBD4 germline pathogenic or likely pathogenic variant.
- This corresponds to a 31.44-fold increased relative risk of developing uveal melanoma.
- The association was statistically significant (P < .001).
Conclusions:
- MBD4 is confirmed as an important predisposing gene for uveal melanoma in the French population.
- Findings support a strategy of broad patient screening.
- Highlights implications for therapeutic decisions and genetic counseling.
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