Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Am J Hum Genet. 2022 May 5;109(5):953-960. doi: 10.1016/j.ajhg.2022.03.018. Epub 2022 Apr 22.


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.

Keywords: 5′-methylcytosine deamination; colorectal cancer; mutational signature; mutator phenotype; polyposis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli* / genetics
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / pathology
  • Endodeoxyribonucleases / genetics
  • Genetic Predisposition to Disease
  • Germ Cells / pathology
  • Germ-Line Mutation / genetics
  • Humans
  • Uveal Neoplasms* / genetics


  • Endodeoxyribonucleases
  • MBD4 protein, human