Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Research output: Contribution to journalResearch articleContributedpeer-review


  • Genomics England Research Consortium - (Author)
  • The CORGI Consortium - (Author)
  • WGS500 Consortium - (Author)
  • Department of Surgical Research
  • Department of Visceral, Thoracic and Vascular Surgery
  • University of Birmingham
  • Cardiff University
  • Walter and Eliza Hall Institute of Medical Research (WEHI)
  • Radboud University Nijmegen
  • University of Oxford
  • University of Edinburgh
  • Peter Maccallum Cancer Centre
  • Imperial College London
  • Imperial College Healthcare NHS Trust
  • Demokritos National Centre for Scientific Research
  • Rabin Medical Center Israel
  • Tel Aviv University
  • Wellcome Sanger Institute
  • University of Melbourne
  • Swansea University
  • University of Cyprus
  • SS Cyril and Methodius University in Skopje
  • Pomeranian Medical University in Szczecin
  • Erasmus University Rotterdam
  • University Hospital Carl Gustav Carus Dresden
  • Institute of Cancer Research
  • Leiden University
  • Institute for Research in Biomedicine
  • University College London
  • University of Manchester
  • Queen Mary University of London


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 pages9
JournalAmerican journal of human genetics
Issue number5
Publication statusPublished - 5 May 2022

External IDs

PubMed 35460607


Sustainable Development Goals

ASJC Scopus subject areas


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

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