Clinical characteristics.

MBD4-related tumor predisposition syndrome (MBD4-TPDS) is characterized by early-onset gastrointestinal polyposis and acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Most reported polyps are adenomatous; some are hyperplastic. Schwannoma, colorectal carcinoma, uveal melanoma, meningioma, and papillary thyroid cancer have been reported in more than one individual with MBD4-TPDS.

Diagnosis/testing.

The diagnosis of MBD4-TPDS is established in a proband with suggestive findings and biallelic pathogenic variants in MBD4 identified by molecular genetic testing.

Management.

Treatment of manifestations: Polyp resection during colonoscopy; subtotal colectomy or proctocolectomy when colonoscopy with polypectomy can no longer manage size and density of polyps; standard treatment for AML, MDS, schwannoma, colorectal carcinoma, uveal melanoma, meningioma, and papillary thyroid cancer.

Surveillance: Colonoscopy every two years starting at age 18-20 years; recommended frequency of complete blood count is undetermined; annual dilated eye exam beginning in adulthood; annual assessment for social work, care coordination, and genetic counseling needs.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with MBD4-TPDS in order to identify as early as possible sibs with biallelic MBD4 pathogenic variants who would benefit from appropriate surveillance, early diagnosis, and treatment of MBD4-associated tumors.

Genetic counseling.

MBD4-TPDS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an MBD4 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having MBD4-TPDS, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous family members of an individual with MBD4-TPDS have a relative risk of 9.15-31.44 to develop uveal melanoma compared to the general population. Once the MBD4 pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

MBD4-TPDS should be suspected in probands with the following clinical and laboratory findings and family history.

Clinical findings

• Early-onset gastrointestinal polyposis
• Acute myeloid leukemia / myelodysplastic syndrome
• Schwannoma
• Colorectal carcinoma
• Uveal melanoma

Molecular findings on tumor tissue. Due to a high accumulation of CpG > TpG variants, COSMIC signature SBS96 is identified on tumor testing (see Molecular Pathogenesis).

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of MBD4-TPDS is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in MBD4 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic MBD4 variants of uncertain significance (or of one known MBD4 pathogenic variant and one MBD4 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

MBD4-related tumor predisposition syndrome (MBD4-TPDS) is characterized by early-onset gastrointestinal polyposis and acute myeloid leukemia. Schwannoma, colorectal carcinoma, uveal melanoma, meningioma, and papillary thyroid cancers have been reported in more than one individual with MBD4-TPDS. To date, 21 individuals from 18 families have been identified with biallelic pathogenic variants in MBD4 [Sanders et al 2018, Griffin et al 2021, Blombery et al 2022, Palles et al 2022, Cooper et al 2026, Dadi et al 2026, Figueiredo et al 2026, Martins et al 2026, Querido et al 2026]. The following description of the phenotypic features associated with this condition is based on these reports.

Gastrointestinal polyposis. All reported individuals evaluated by colonoscopy (n=19) were found to have colorectal polyps, with a range of 5 to 130 polyps [Sanders et al 2018, Griffin et al 2021, Blombery et al 2022, Palles et al 2022, Cooper et al 2026, Figueiredo et al 2026, Martins et al 2026, Querido et al 2026]. Median age at identification of polyps was 34 years (range: age 18-54 years). Most reported polyps were adenomatous. However, four individuals were found to have hyperplastic polyps [Griffin et al 2021, Cooper et al 2026, Querido et al 2026]. Notably, a polyp in one individual had a small focus of intramucosal adenocarcinoma [Querido et al 2026]. One individual had an upper gastrointestinal tract tubulovillous adenoma as well as colorectal polyps [Palles et al 2022]. Colectomy was the only reported treatment (n=10), with a median age of 38 years (range: age 31-53 years). In one individual, polyps were found in the remaining colon after hemicolectomy [Palles et al 2022].

Colorectal cancer. Four out of 21 (19%) individuals developed colorectal cancer. Ages at diagnosis were 30, 33, 40, and 52 years [Sanders et al 2018, Figueiredo et al 2026, Martins et al 2026, Querido et al 2026].

Acute myeloid leukemia (AML) was observed in 16 individuals [Sanders et al 2018, Griffin et al 2021, Blombery et al 2022, Palles et al 2022, Cooper et al 2026, Figueiredo et al 2026, Querido et al 2026]. The median age of diagnosis was 35 years (range: age 27-55 years). Notably, 13/16 individuals were diagnosed before age 40 years. In two individuals, AML was preceded by myelodysplastic syndrome (MDS) [Blombery et al 2022, Palles et al 2022]. In 13/16 (81%) individuals with AML, identification of gastrointestinal polyposis preceded the diagnosis of AML.

Schwannoma. Six individuals were diagnosed with a schwannoma [Griffin et al 2021, Blombery et al 2022, Palles et al 2022, Cooper et al 2026, Querido et al 2026]. When specified, reported ages at diagnosis were 30, 34, 44, 45, and 50 years. Reported tumor locations included chest wall, cervical [Palles et al 2022], (right) vestibular [Blombery et al 2022, Cooper et al 2026], and bilateral vestibular [Griffin et al 2021, Cooper et al 2026].

Uveal melanoma. Four individuals were diagnosed with uveal melanoma [Palles et al 2022, Figueiredo et al 2026, Martins et al 2026]. One individual was diagnosed with two uveal melanomas at ages 38 and 45 years (location was not reported). The other individuals were diagnosed at age 33, 53, and 61 years. Notably, one individual was simultaneously diagnosed with bilateral diffuse uveal melanocytic proliferation (BDUMP) [Figueiredo et al 2026]. Systemic workup showed a hypermetabolic nodule in hepatic segment V, warranting close surveillance.

Meningioma. To date, two individuals have been reported with meningiomas; age at diagnosis was 41 and 55 years [Palles et al 2022, Querido et al 2026].

Papillary thyroid cancer. Two individuals have been reported with papillary thyroid cancer, both diagnosed at age 44 [Griffin et al 2021, Cooper et al 2026].

Other

• Ovarian granulosa cell tumor (1 individual) diagnosed at age 12 years [Palles et al 2022].
• Basal cell carcinoma (1 individual) diagnosed at age 33 years [Querido et al 2026]
• Ductal carcinoma in situ of the breast (1 individual) diagnosed at age 50 years [Palles et al 2022]
• Multiple liver cysts (1 individual) identified at age 53 years [Palles et al 2022]
• Kidney cysts. Small bilateral kidney cysts (1 individual) identified at age 53 years [Palles et al 2022]
• Bone tumor. One individual presented with a benign bone tumor at age 38 years [Querido et al 2026]. Distinction between giant cell tumor or aneurysmal bone cyst could not be established.

Heterozygotes. An increased risk of uveal melanoma has been reported in MBD4 heterozygotes [Rodrigues et al 2018, Johansson et al 2019, Repo et al 2020, Derrien et al 2021, Saint-Ghislain et al 2022, Villy et al 2024, Byrne et al 2026, Le Ven et al 2026]. The prevalence of heterozygous germline pathogenic variants in MBD4 among individuals with uveal melanoma is 0%-2.6% [Repo et al 2020, Derrien et al 2021, Saint-Ghislain et al 2022, Le Ven et al 2026]. A relative risk of 9.15-31.44 for uveal melanoma was reported in individuals heterozygous for a germline MBD4 pathogenic variant compared to the general population [Derrien et al 2021, Le Ven et al 2026].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Penetrance

To date, no unaffected individuals with biallelic germline MBD4 pathogenic variants have been reported. Given the limited number of individuals identified to date with MBD4-TPDS, it is difficult to confirm complete penetrance in all individuals.

Prevalence

To date, 21 individuals with MBD4-TPDS have been reported. The estimated population incidence is less than one in 1,000,000 [Terradas et al 2023].

A suspected ancient founder pathogenic variant (c.1544-1G>T) has been reported in several populations [Querido et al 2026]. Another founder pathogenic variant (c.612_615delCTCT) was reported in Israeli Christian Arabs [Dadi et al 2026].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MBD4-TPDS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with MBD4-TPDS in order to identify as early as possible sibs with biallelic MBD4 pathogenic variants who would benefit from appropriate surveillance, early diagnosis, and treatment of MBD4-associated tumors. For unaffected individuals with biallelic MBD4 pathogenic variants, surveillance should begin by age 18-20 years.

In general, molecular genetic testing for MBD4-TPDS is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. A history of early cancers in the family may warrant testing prior to age 18 [NCCN 2024].

Heterozygous family members

• Currently, there is no evidence that individuals with a heterozygous MBD4 pathogenic variant have a comparable increased risk to develop colorectal cancer (CRC) and/or polyposis [Sherwood et al 2026]. No colonoscopy surveillance beyond population screening or local guidelines based on familial history for CRC is recommended.
• Compared to the general population, a relative risk of 9.15-31.44 to develop uveal melanoma has been reported in individuals with a heterozygous MBD4 pathogenic variant [Derrien et al 2021, Le Ven et al 2026]. However, based on the low incidence of uveal melanoma, ophthalmologic surveillance for uveal melanoma is not recommended for family members who have heterozygous MBD4 pathogenic variants (see Clinical Description, Heterozygotes.)

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

MBD4-related tumor predisposition syndrome (MBD4-TPDS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for an MBD4 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an MBD4 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygous parents of an individual with MBD4-TPDS have a relative risk of 9.15-31.44 of developing uveal melanoma compared to the general population [Derrien et al 2021, Le Ven et al 2026]. However, due to the low incidence of uveal melanoma, ophthalmologic surveillance for uveal melanoma is not recommended (see Clinical Description, Heterozygotes).

Sibs of a proband

• If both parents are known to be heterozygous for an MBD4 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having MBD4-TPDS, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygous sibs of an individual with MBD4-TPDS have a relative risk of 9.15-31.44 of developing uveal melanoma compared to the general population [Derrien et al 2021, Le Ven et al 2026]. However, due to the low incidence of uveal melanoma, ophthalmologic surveillance for uveal melanoma is not recommended (see Clinical Description, Heterozygotes).

Offspring of a proband. Unless an affected individual's reproductive partner also has MBD4-TPDS or is heterozygous for an MBD4 pathogenic variant, offspring will be obligate heterozygotes for a pathogenic variant in MBD4.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an MBD4 pathogenic variant.

Heterozygote Detection

Heterozygote testing for at-risk relatives requires prior identification of the MBD4 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic sibs requires prior identification of the germline MBD4 pathogenic variants in the family.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – Health Professional Version (part of PDQ®, National Cancer Institute).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having germline MBD4 pathogenic variant(s).

Prenatal Testing and Preimplantation Genetic Testing

Once the MBD4 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Pathogenesis

MBD4 encodes methyl-CpG-binding domain protein 4 (MBD4), a DNA glycosylase that identifies and removes mismatched bases that arise from the naturally occurring deamination of 5-methylcytosine (5mC) and cytosine at CpG sites [Koliadenko & Wilanowski 2020]. MBD4 prevents further accumulation of C-to-T transitions upon DNA replications. MBD4 loss-of-function variants lead to an accumulation of CpG > TpG variants (COSMIC signature SBS96) [Degasperi et al 2022, Palles et al 2022], therefore likely leading to a higher tumor mutational burden.

Mice studies have shown that biallelic inactivation of MBD4 by itself does not cause cancer predisposition; it can alter the mutation spectrum in cancer cells and modify the cancer predisposition phenotype [Wong et al 2002, Sansom et al 2004].

Molecular testing in adenomas of individuals with MBD4-related tumor predisposition syndrome (MBD4-TPDS) show similar driver pathogenic variants as those found in sporadic adenomas (e.g., APC, TTN, AMER1, and KRAS) [Sanders et al 2018, Palles et al 2022, Cooper et al 2026].

Notably, somatic pathogenic variants identified in acute myeloid leukemia (AML) in individuals with MBD4-TPDS include biallelic DNMT3A pathogenic variants as well as IDH1 or IDH2 hot spot pathogenic variants. These are relatively rare pathogenic variants (<3%) in sporadic AML [Sanders et al 2018, Griffin et al 2021, Blombery et al 2022, Cooper et al 2026, Dadi et al 2026].

Molecular testing was performed on three vestibular schwannomas from individuals with MBD4-TPDS. In all instances biallelic NF2 pathogenic variants were identified in tumor tissue. Acquired NF2 pathogenic variants are ubiquitous early molecular events in sporadic vestibular schwannomas [Griffin et al 2021, Blombery et al 2022, Cooper et al 2026].

Mechanism of disease causation. Loss of function

Author Notes

Coen Bijns (ln.cmul@snjib.m.c), Claire Palles (ku.ca.mahb@sellap.c), Richarda de Voer (ln.cmuduobdar@reoved.adrahcir), and Maartje Nielsen (ln.cmul@neslein.m) are actively involved in clinical research regarding individuals with MBD4-related tumor predisposition syndrome (MBD4-TPDS). They would be happy to communicate with individuals who have questions regarding diagnosis of MBD4-TPDS or other considerations.

Revision History

• 13 August 2026 (sw) Review posted live
• 21 January 2026 (cb) Original submission

Literature Cited

• Blombery P, Ryland GL, Fox LC, Stark Z, Wall M, Jarmolowicz A, Roesley A, Thompson ER, Grimmond SM, Panicker S, Kwok F. Methyl-CpG binding domain 4, DNA glycosylase (MBD4)-associated neoplasia syndrome associated with a homozygous missense variant in MBD4: Expansion of an emerging phenotype. Br J Haematol. 2022;198:196-9. [PubMed: 35381620]
• Byrne L, Gray I, Ramsey K, McElroy J, Schreiner E, Wolfe J, Taylor OB, Davidorf F, Cebulla CM, Abdel-Rahman MH. Impact of multigene panel testing in high-risk uveal melanoma patients. Pigment Cell Melanoma Res. 2026;39:e70108. [PMC free article: PMC13356236] [PubMed: 42415513]
• Calvo KR, Hickstein DD. The spectrum of GATA2 deficiency syndrome. Blood. 2023;141:1524-32. [PMC free article: PMC10082373] [PubMed: 36455197]
• Cooper J, Stewart BL, Bokovitz L, Carraway H, Mukherjee S, Liska D, Vasu S, Lesmana H, Blachly JS. Biallelic germline MBD4 mutations predispose to colorectal polyposis, hypermutated AML, and schwannomas. Fam Cancer. 2026;25:50. [PMC free article: PMC13156161] [PubMed: 42101541]
• Dadi G, Rosen S, Naor H, Hellou E, Chapal-Ilani N, Bacharach T, Kaushansky N, Shlush LL. A founder heterozygous mutation in Methyl-CpG binding domain protein 4 (MBD4) prevalent among Israeli Christian Arabs predisposes to increased mutagenesis. Haematologica. 2026;111:1034-38. [PMC free article: PMC12951175] [PubMed: 40905073]
• Degasperi A, Zou X, Amarante TD, Martinez-Martinez A, Koh GCC, Dias JML, Heskin L, Chmelova L, Rinaldi G, Wang VYW, Nanda AS, Bernstein A, Momen SE, Young J, Perez-Gil D, Memari Y, Badja C, Shooter S, Czarnecki J, Brown MA, Davies HR, Genomics England Research C, Nik-Zainal S. Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science. 2022;376:science.abl9283. [PMC free article: PMC7613262] [PubMed: 35949260]
• Derrien AC, Rodrigues M, Eeckhoutte A, Dayot S, Houy A, Mobuchon L, Gardrat S, Lequin D, Ballet S, Pierron G, Alsafadi S, Mariani O, El-Marjou A, Matet A, Colas C, Cassoux N, Stern MH. Germline MBD4 mutations and predisposition to uveal melanoma. J Natl Cancer Inst. 2021;113:80-7. [PMC free article: PMC7781447] [PubMed: 32239153]
• Figueiredo I, Maia S, Simoes P, Fonseca C. Diagnostic pitfall in MBD4-associated neoplasia syndrome after hematopoietic stem cell transplantation. Can J Ophthalmol. 2026. Epub ahead of print. [PubMed: 41942066]
• Griffin BL, Majhail NS, Lesmana H. Germline biallelic loss in leading to early onset AML with hyper-mutator genomic signature. Blood. 2021;138:3385-.
• Johansson PA, Stark A, Palmer JM, Bigby K, Brooks K, Rolfe O, Pritchard AL, Whitehead K, Warrier S, Glasson W, Hayward NK. Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab. Immunogenetics. 2019;71:433-6. [PubMed: 30714079]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Koliadenko V, Wilanowski T. Additional functions of selected proteins involved in DNA repair. Free Radic Biol Med. 2020;146:1-15. [PubMed: 31639437]
• Le Ven A, Villy MC, Le Mentec M, Houy A, Dubois d'Enghien C, Matet A, Malaise D, Bubien V, Lortholary A, Ait Omar A, Stoppa-Lyonnet D, Cassoux N, Rodrigues M, Golmard L, Stern MH, Colas C. Prevalence of the predisposing gene MBD4 for uveal melanoma. JAMA Ophthalmol. 2026;144:536-40. [PMC free article: PMC13133719] [PubMed: 42060275]
• Lipton L, Tomlinson I. The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006;5:221-6. [PubMed: 16998667]
• Martins N, Terradas M, Garcia-Pelaez J, Sommer AK, Demidov G, Matalonga L, Ramos-Muntada M, Te Paske I, Spier I, Mensenkamp A, Schuurs-Hoeijmakers J, Gullo I, Sao Jose C, Pedro AM, Gouveia Silva R, Sousa AB, Amoroso Canao P, Fernandes S, Garrido L, Dupont J, Maia S, Sousa G, Irmejs A, Barili V, Blatnik A, Rofes P, Brunet J, Capella G, Laurie S, Lazaro C, Hoogerbrugge N, de Voer RM, Aretz S, Oliveira C, Valle L. Genome sequencing of undiagnosed European patients suspected of hereditary cancer: diagnostic yield and identification of candidate causative variants. JCO Precis Oncol. 2026;10:e2500354. [PMC free article: PMC13098671] [PubMed: 41990296]
• NCCN. NCCN Guidelines Version 2.2024 Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric. 2024. Available online (purchase or subscription required).
• Nogué C, Chong AS, Grau E, Han H, Dorca E, Roca C, Mosquera JL, Lázaro C, Foulkes WD, Brunet J, Rivera B. DGCR8 and the six hit, three-step model of schwannomatosis. Acta Neuropathol. 2022;143:115-7. [PubMed: 34821987]
• Palles C, West HD, Chew E, Galavotti S, Flensburg C, Grolleman JE, Jansen EAM, Curley H, Chegwidden L, Arbe-Barnes EH, Lander N, Truscott R, Pagan J, Bajel A, Sherwood K, Martin L, Thomas H, Georgiou D, Fostira F, Goldberg Y, Adams DJ, van der Biezen SAM, Christie M, Clendenning M, Thomas LE, Deltas C, Dimovski AJ, Dymerska D, Lubinski J, Mahmood K, van der Post RS, Sanders M, Weitz J, Taylor JC, Turnbull C, Vreede L, van Wezel T, Whalley C, Arnedo-Pac C, Caravagna G, Cross W, Chubb D, Frangou A, Gruber AJ, Kinnersley B, Noyvert B, Church D, Graham T, Houlston R, Lopez-Bigas N, Sottoriva A, Wedge D, Genomics England Research C, Consortium C, Consortium WGS, Jenkins MA, Kuiper RP, Roberts AW, Cheadle JP, Ligtenberg MJL, Hoogerbrugge N, Koelzer VH, Rivas AD, Winship IM, Ponte CR, Buchanan DD, Power DG, Green A, Tomlinson IPM, Sampson JR, Majewski IJ, de Voer RM. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. Am J Hum Genet. 2022;109:953-60. [PMC free article: PMC9118112] [PubMed: 35460607]
• Perez-Becerril C, Evans DG, Smith MJ. Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes. Hum Mutat. 2021;42:1187-207. [PubMed: 34273915]
• Querido I, Pinto C, Arinto P, Brandao A, Santos C, Pinheiro M, Guerra J, Silva J, Peixoto A, Teixeira MR. A novel deleterious variant and a founder effect in four new families of MBD4-associated neoplasia syndrome recruited over a period of 20 years. Clin Genet. 2026;109:50-59. [PubMed: 40605265]
• Repo P, Jantti JE, Jarvinen RS, Rantala ES, Tall M, Raivio V, Kivela TT, Turunen JA. Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma. Pigment Cell Melanoma Res. 2020;33:756-62. [PubMed: 32421892]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, Committee ALQA. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rodrigues M, Mobuchon L, Houy A, Fievet A, Gardrat S, Barnhill RL, Popova T, Servois V, Rampanou A, Mouton A, Dayot S, Raynal V, Galut M, Putterman M, Tick S, Cassoux N, Roman-Roman S, Bidard FC, Lantz O, Mariani P, Piperno-Neumann S, Stern MH. Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. Nat Commun. 2018;9:1866. [PMC free article: PMC5951831] [PubMed: 29760383]
• Saint-Ghislain M, Derrien AC, Geoffrois L, Gastaud L, Lesimple T, Negrier S, Penel N, Kurtz JE, Le Corre Y, Dutriaux C, Gardrat S, Barnhill R, Matet A, Cassoux N, Houy A, Ramtohul T, Servois V, Mariani P, Piperno-Neumann S, Stern MH, Rodrigues M. MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients. Eur J Cancer. 2022;173:105-12. [PubMed: 35863105]
• Sampson JR, Jones N. MUTYH-associated polyposis. Best Pract Res Clin Gastroenterol. 2009;23:209-18. [PubMed: 19414147]
• Sanders MA, Chew E, Flensburg C, Zeilemaker A, Miller SE, Al Hinai AS, Bajel A, Luiken B, Rijken M, McLennan T, Hoogenboezem RM, Kavelaars FG, Frohling S, Blewitt ME, Bindels EM, Alexander WS, Lowenberg B, Roberts AW, Valk PJM, Majewski IJ. MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood. 2018;132:1526-34. [PMC free article: PMC6172562] [PubMed: 30049810]
• Sansom OJ, Bishop SM, Bird A, Clarke AR. MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR. Oncogene. 2004;23:5693-6. [PubMed: 15184874]
• Sherwood K, Fernandez-Tajes J, Gul G, Thorn S, Ward JC, Wilson JF, Palles C, Bishop DT, Houlston RS, Dunlop MG, Tomlinson IPM. Germline haploinsufficiency of MUTYH causes mutational signature SBS18 in multiple tumour types and specifically raises colorectal cancer risk. NPJ Precis Oncol. 2026;10:275. [PMC free article: PMC13358035] [PubMed: 42092060]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD((R))): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Terradas M, Gonzalez-Abuin N, Garcia-Mulero S, Viana-Errasti J, Aiza G, Piulats JM, Brunet J, Capella G, Valle L. MBD4-associated neoplasia syndrome: screening of cases with suggestive phenotypes. Eur J Hum Genet. 2023;31:1185-9. [PMC free article: PMC10545785] [PubMed: 37402954]
• Villy MC, Le Ven A, Le Mentec M, Masliah-Planchon J, Houy A, Bieche I, Vacher S, Vincent-Salomon A, Dubois d'Enghien C, Schwartz M, Piperno-Neumann S, Matet A, Malaise D, Bubien V, Lortholary A, Ait Omar A, Cavaille M, Stoppa-Lyonnet D, Cassoux N, Stern MH, Rodrigues M, Golmard L, Colas C. Familial uveal melanoma and other tumors in 25 families with monoallelic germline MBD4 variants. J Natl Cancer Inst. 2024;116:580-7. [PubMed: 38060262]
• Wong E, Yang K, Kuraguchi M, Werling U, Avdievich E, Fan K, Fazzari M, Jin B, Brown AM, Lipkin M, Edelmann W. Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation. Proc Natl Acad Sci U S A. 2002;99:14937-42. [PMC free article: PMC137523] [PubMed: 12417741]