American journal of human genetics · 2022

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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Palles Claire, West Hannah D, 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, Genomics England Research Consortium, CORGI Consortium, WGS500 Consortium, 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, Majewski Ian J, de Voer Richarda M

Аннотация

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.

Предметные рубрики MeSH

Adenomatous Polyposis Coli Colorectal Neoplasms Endodeoxyribonucleases Genetic Predisposition to Disease Germ Cells Germ-Line Mutation Humans Uveal Neoplasms

Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.

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Аннотация

Предметные рубрики MeSH