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Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

2022; Elsevier BV; Volume: 109; Issue: 5 Linguagem: Inglês

10.1016/j.ajhg.2022.03.018

1537-6605

Claire Palles, Hannah D. West, Edward Chew, Sara Galavotti, Christoffer Flensburg, Judith E. Grolleman, Erik A. M. Jansen, Helen Curley, Laura Chegwidden, Edward H. Arbe-Barnes, Nicola Lander, Rebekah Truscott, Judith Pagan, Ashish Bajel, Kitty Sherwood, Lynn Martin, Huw Thomas, Demetra Georgiou, Florentia Fostira, Yael Goldberg, David J. Adams, Simone A.M. van der Biezen, Michael Christie, Mark Clendenning, Laura E. Thomas, Constantinos Deltas, Aleksandar Dimovski, Dagmara Dymerska, Jan Lubiński, Khalid Mahmood, Rachel S. van der Post, Mathijs A. Sanders, Jürgen Weitz, Jenny C. Taylor, Clare Turnbull, Lilian Vreede, Tom van Wezel, Celina Whalley, Claudia Arnedo-Pac, Giulio Caravagna, William Cross, Daniel Chubb, Anna Frangou, Andreas Gruber, Ben Kinnersley, Boris Noyvert, David N. Church, Trevor A. Graham, Richard S. Houlston, Núria López-Bigas, Andrea Sottoriva, David C. Wedge, Mark A. Jenkins, Roland P. Kuiper, Andrew W. Roberts, Jeremy P. Cheadle, Marjolijn J. L. Ligtenberg, Nicoline Hoogerbrugge, Viktor H. Koelzer, Andrés Dacal Rivas, Ingrid Winship, Clara Ruiz Ponte, Daniel D. Buchanan, Derek G. Power, Andrew Green, Ian Tomlinson, Julian R. Sampson, Ian J. Majewski, Richarda M. de Voer,

DNA Repair Mechanisms

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.