Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Genomics England Research Consortium, Colorectal Tumour Gene Identification (CORGI) Consortium, WGS500 Consortium

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We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.

Original languageEnglish
Pages (from-to)953-960
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number5
Early online date22 Apr 2022
Publication statusPublished - 5 May 2022

Bibliographical note

Funding Information:
This study was funded by the Dutch Cancer Society ( KUN2015-7740 ; 12174/2019-1 ), the Sacha Swarttouw-Hijmans Foundation , Cancer Research UK C6199 , Bowel Cancer West David Darke grant , the EU ERC (EVOCAN), the National Health and Medical Research Council of Australia (project 1145912 , program 1113577 , investigator 1174902 ) and the Cancer Council Victoria ( 1181108 ), with fellowship support from the Victorian Cancer Agency (I.J.M., MCRF15018 ), the Alfred Felton Bequest (I.J.M.) and the Leukaemia Foundation of Australia (Bill Long Charitable Trust PhD Clinical Scholarship to E.C.), and Bowel Cancer UK ( CP 18PG0010 ). H.W. is supported by a Ser Cymru II Precision Medicine Fellowship award. Research was also supported by the Australian Cancer Research Foundation , Victorian State Government Operational Infrastructure Support , and Australian Government NHMRC IRIISS. D.D.B. is supported by an NHMRC R.D. Wright Career Development Fellowship ( GNT1125268 ) and NHMRC Emerging Leadership Fellowship ( GNT1194896 ). M.A.J. is supported by NHMRC Leadership Fellowship. The ACCFR is supported by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551 ). The research was also supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Center based at Oxford University Hospitals NHS Trust and University of Oxford . J.C.T. discloses that the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. This work received networking support by the Cooperation in Science and Technology Action CA17118 , supported by the European Cooperation in Science and Technology . Further acknowledgments are described in the supplemental information .

Publisher Copyright:
© 2022 The Author(s)


  • 5′-methylcytosine deamination
  • colorectal cancer
  • mutational signature
  • mutator phenotype
  • polyposis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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