Germline loss of function variants in the base excision repair gene MBD4 cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and AML


Session type:

Sara Galavotti, Claire Palles, Edward Chew, Judith E. Grolleman, Christoffer Flensburg, Helen Curley, Kitty Sherwood, Andrew W. Roberts, Lynn Martin, Edward Arbe Barnes, Demetra Georgiou, Huw Thomas, Yael Goldberg, Constantinos Deltas, Florentia Fostira, Laura Chegwidden, Celina Whalley, Viktor Koelzer, Ian P. Tomlinson, Ian J. Majewski, Richarda M. de Voer



The base excision repair (BER) pathway provides an important safeguard for genome integrity and inherited defects in this pathway predispose to cancer. BER gene methyl CpG binding domain protein 4 (MBD4) encodes a DNA glycosylase that repairs G:T mismatches resulting from deamination of 5’-methylcytosine.  Biallelic germline loss of MBD4 has been described in three acute myeloid leukaemia (AML) patients with tumours dominated by CpG>TpG transitions.


Whole-genome sequencing of 35 probands with colorectal polyposis was performed.  Loss of MBD4 protein was confirmed in tissue samples from a patient with a predicted biallelic loss of function mutation.    Exome sequencing was performed using adenoma and normal tissue samples from biallelic carriers of loss of function (LOF) mutations in MBD4.


We identified a polyposis patient who subsequently developed myelodysplasic syndrome (MDS) and AML that was homozygous for a LOF germline mutation (p.Ser205Thrfs*9) in MBD4.  Immunohistochemistry for MBD4 confirmed complete loss of the protein in this patient.  Relatives heterozygous for the mutation were unaffected.  Mutation signature analysis of colonic adenomas from this case and  from one of the previously reported AML cases with biallelic loss of MDB4 identified an elevated single nucleotide variation (SNV) burden and  a single mutation signature of C>Ts at CpGs (SBS1MBD4) very similar to COSMIC v3 SBS1.  >96% of the mutated bases were methylated in whole genome bisulfite (WGBS) sequencing data from normal sigmoid colon.


Biallelic germline mutations in MBD4 predispose to a rare tumour risk syndrome characterized by multiple adenomatous colorectal polyps and MDS/AML.  Tumours resulting from MBD4 deficiency have a raised SNV mutation burden and a mutation spectrum very similar to COSMIC signature SBS1. We advise that MBD4 should be included in germline mutation testing panels for polyposis and/or early-onset AML. 

Impact statement

Germline biallelic loss of MBD4 predisposes to a rare recessive inherited syndrome characterised by colorectal polyposis and AML.