Germline MBD4 deficiency causes a multi-tumor predisposition syndrome.
Palles C., West HD., Chew E., Galavotti S., Flensburg C., Grolleman JE., Jansen EAM., Curley H., Chegwidden L., Arbe-Barnes EH., Lander N., Truscott R., Pagan J., Bajel A., Sherwood K., Martin L., Thomas H., Georgiou D., Fostira F., Goldberg Y., Adams DJ., van der Biezen SAM., Christie M., Clendenning M., Thomas LE., Deltas C., Dimovski AJ., Dymerska D., Lubinski J., Mahmood K., van der Post RS., Sanders M., Weitz J., Taylor JC., Turnbull C., Vreede L., van Wezel T., Whalley C., Arnedo-Pac C., Caravagna G., Cross W., Chubb D., Frangou A., Gruber AJ., Kinnersley B., Noyvert B., Church D., Graham T., Houlston R., Lopez-Bigas N., Sottoriva A., Wedge D., Genomics England Research Consortium None., CORGI Consortium None., WGS500 Consortium None., Jenkins MA., Kuiper RP., Roberts AW., Cheadle JP., Ligtenberg MJL., Hoogerbrugge N., Koelzer VH., Rivas AD., Winship IM., Ponte CR., Buchanan DD., Power DG., Green A., Tomlinson IPM., Sampson JR., Majewski IJ., de Voer RM.
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.