Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Palles, Claire, West, Hannah D. ORCID: https://orcid.org/0000-0002-6104-6534, Chew, Edward, Galavotti, Sara, Flensburg, Christoffer, Grolleman, Judith E., Jansen, Erik A.M., Curley, Helen, Chegwidden, Laura, Arbe-Barnes, Edward H., Lander, Nicola, Truscott, Rebekah, Pagan, Judith, Bajel, Ashish, Sherwood, Kitty, Martin, Lynn, Thomas, Huw, Georgiou, Demetra, Fostira, Florentia, Goldberg, Yael, Adams, David J., van der Biezen, Simone A.M., Christie, Michael, Clendenning, Mark, Thomas, Laura E., Deltas, Constantinos, Dimovski, Aleksandar J., Dymerska, Dagmara, Lubinski, Jan, Mahmood, Khalid, van der Post, Rachel S., Sanders, Mathijs, Weitz, Jürgen, Taylor, Jenny C., Turnbull, Clare, Vreede, Lilian, van Wezel, Tom, Whalley, Celina, Arnedo-Pac, Claudia, Caravagna, Giulio, Cross, William, Chubb, Daniel, Frangou, Anna, Gruber, Andreas J., Kinnersley, Ben, Noyvert, Boris, Church, David, Graham, Trevor, Houlston, Richard, Lopez-Bigas, Nuria, Sottoriva, Andrea, Wedge, David, Jenkins, Mark A., Kuiper, Roland P., Roberts, Andrew W., Cheadle, Jeremy P., Ligtenberg, Marjolijn J.L., Hoogerbrugge, Nicoline, Koelzer, Viktor H., Rivas, Andres Dacal, Winship, Ingrid M., Ponte, Clara Ruiz, Buchanan, Daniel D., Power, Derek G., Green, Andrew, Tomlinson, Ian P.M., Sampson, Julian R. ORCID: https://orcid.org/0000-0002-2902-2348, Majewski, Ian J. and de Voer, Richarda M. 2022. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. American Journal of Human Genetics 109 (5) , pp. 953-960. 10.1016/j.ajhg.2022.03.018

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cell Press
ISSN:	0002-9297
Date of First Compliant Deposit:	25 May 2022
Date of Acceptance:	20 April 2022
Last Modified:	16 May 2023 04:55
URI:	https://orca.cardiff.ac.uk/id/eprint/150030

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