MBD4-associated neoplasia syndrome
Last update: September 2025
MBD4-associated neoplasia syndrome (or MBD4-related tumour predisposition syndrome (ORPHA:661526, OMIM:619975, MONDO:0859267)) is a recently described condition reported in few individuals so far. It is suggested that MBD4-associated neoplasia syndrome leads to an increased risk of early-onset acute myeloid leukaemia (AML) preceded by myelodysplastic syndrome (MDS), adenomatous polyposis, colorectal cancer, and, less frequently, uveal melanoma, and schwannomas.
The phenotypic spectrum may extend to other tumours, but the number of cases reported is still too small to confirm any association.
This syndrome is considered an ultra-rare condition, with an estimated prevalence of 1: > 1,000,000.
MBD4-associated neoplasia syndrome is caused by pathogenic variants affecting both alleles of the MBD4 gene, that is involved in the repair of specific DNA lesions. Biallelic inactivation of this gene causes increased mutation rates that are visible as a specific mutation signature in tumour DNA.
MBD4-associated neoplasia syndrome is inherited in an autosomal recessive manner, meaning that siblings of individuals with MBD4-associated neoplasia syndrome have a 25% risk of having the condition.
Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified. Depending on the country there might be options for prenatal testing and preimplantation genetic testing when the causative pathogenic variants are known.
Since only few cases have been reported, surveillance is based on expert opinion and knowledge from similar conditions. Surveillance should preferably be performed at specialised centres.
Clinical surveillance should focus on the suggested high MDS/AML risk and gastrointestinal manifestations. Colonoscopy surveillance is suggested to be similar to that offered to individuals with MUTYH-associated polyposis.
Due to recurrence of uveal melanoma and schwannomas, routine ophthalmological (eye) exams and monitoring of schwannomas may be considered.
For surveillance baseline complete blood count is suggested. As for other MDS/AML predisposing conditions (according to Baliakas et al. 2019, guideline not endorsed by ERN GENTURIS), it is advisable to consider repeating it every 6 months. Symptoms possibly indicating a haematological (in particular fatigue, infections, bleeding, skin changes), or gastrointestinal disease (persistent diarrhoea or constipation, blood in the stool) should be investigated immediately.
This paragraph discusses aspects of the disease for which there is currently limited evidence. These aspects can be the subject of studies and research but are not yet part of current clinical practice.
Future research, including the identification and detailed characterization of additional cases, will be crucial. Such knowledge may ultimately inform revisions to current surveillance strategies. Tumours may be considered good candidates for immune checkpoint inhibitor-based therapies. However, their clinical application in this context remains investigational, and further research is required before they can be implemented in routine practice.
More Information regarding MBD4-associated neoplasia syndrome can be found on:
Orphanet: MBD4-related tumor predisposition syndrome
OMIM: tumor predisposition syndrome 2
ClinGen: tumor predisposition syndrome 2
Palles et al. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. Am J Hum Genet. 2022 May 5;109(5):953-960. doi: 10.1016/j.ajhg.2022.03.018
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MBD4-associated neoplasia syndrome
A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.