Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

Claire Palles, Hannah West, Edward Chew, Sara Galavotti, Christoffer Flensburg, Judith Grolleman, Erik Jansen, Helen Curley, Laura Chedwiggen, Edward Arbe-Barnes, Nicola Lander, Rebekah Truscot, Judith Pagan, Ashish Bajel, Kitty Sherwood, Lynn Martin, Huw Thomas, Demetra Georgiou, Florentia Fostira, Yael GoldbergDavid Adams, Simone van der Biezen, Michael Christie, Mark Clendenning, Laura Thomas, Constantinos Deltas, Aleksandar Dimovski, Dagmara Dymerska, Jan Lubinski, Khalid Mahmood, Rachel van der Post, Mathijs Sanders, Jurgen Weitz, Jenny Taylor, Clare Turnbull, Lilian Vreede, Tom van Wezel, Celina Whalley, Claudia Arnedo, Giulo Caravagna, William Cross, Daniel Chubb, Anna Frangou, Andreas Gruber, Ben Kinnersley, Boris Noyvert, David Church, Trevor Graham, Richard Houlston, Nuria Lopez, Andrea Sottoriva, David Wedge, Mark Jenkins, Roland Kuiper, Andrew Roberts, Jeremy Cheadle, Marjolijn Ligtenberg, Nicoline Hoogerbrugge, Viktor Koelzer, Andres Dacal Rivas, Ingrid Winship, Clare Ruiz Ponte, Daniel Buchanan, Derek Power, Andrew Green, Ian P.M. Tomlinson*, Julian Sampson, Ian Majewski, Richard M. de Voer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 22 Apr 2022


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


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