Germline loss-of-function variants in the base-excision repair geneMBD4cause a Mendelian recessive syndrome of adenomatous colorectal polyposis and acute myeloid leukaemia

Abstract

Inherited defects in base-excision repair (BER) predispose to adenomatous polyposis and colorectal cancer (CRC), yet our understanding of this important DNA repair pathway remains incomplete. By combining detailed clinical, histological and molecular profiling, we reveal biallelic germline loss-of-function (LOF) variants in the BER gene MBD4 to predispose to adenomatous polyposis and -uniquely amongst CRC predisposition syndromes- to myeloid neoplasms. Neoplasms from MBD4-deficient patients almost exclusively accumulate somatic CpG>TpG mutations, resembling mutational signature SBS1. MBD4-deficient adenomas harbour mutations in known CRC driver genes, although AMER1 mutations were more common and KRAS mutations less frequent. We did not find an increased risk for colorectal tumours in individuals with a monoallelic MBD4 LOF variant. We suggest that this condition should be termed MBD4-associated neoplasia syndrome (MANS) and that MBD4 is included in testing for the genetic diagnosis of polyposis and/or early-onset AML.

Novel Genetic Causes of Gastrointestinal Polyposis Syndromes

“…36 Palles et al recently coined the term "MBD4-associated neoplasia syndrome" (MANS) and linked MBD4 to polyposis based on the report of a homozygous 4bp deletion in MPD4 in a patient with approximately 60 colonic and rectal adenomas at age 36. 37 No upper gastrointestinal polyps were reported. A few months after the detection of polyposis and a subsequent proctocolectomy, the patient was diagnosed with myelodysplastic syndrome, which progressed to AML.…”

“…38 Palles et al did not find that monoallelic carriers had an increased risk of polyposis and CRC. 37…”

Methyl‐CpG binding domain 4, DNA glycosylase (MBD4)‐associated neoplasia syndrome associated with a homozygous missense variant in MBD4: Expansion of an emerging phenotype

“…2 To date, four patients (from three families) have been identified with MANS harbouring deleterious variants in MBD4 (NM_003925.2) including an in-frame deletion (p.(His567del)), canonical splice site (c.1562-1G>T) and truncating variants (p.(Glu314Argfs*13) and p.(Ser-205Thrfs*9)). 1,2 Here, we describe a patient with MANS as a result of a homozygous missense germline variant in MBD4 providing novel insights into the clinicobiological features of this emerging phenotype.…”

“…Methyl-CpG binding domain 4, DNA glycosylase (MBD4)-associated neoplasia syndrome associated with a homozygous missense variant in MBD4: Expansion of an emerging phenotype Germline biallelic loss-of-function variants in methyl-CpG binding domain 4, DNA glycosylase (MBD4) have recently been associated with a syndrome characterised by early onset haematological malignancy and colonic polyposis (provisionally termed MBD4-associated neoplasia syndrome [MANS]). 1,2 This clinical phenotype is caused by a base excision repair (BER) defect as a result of loss of MBD4 function and the subsequent accumulation of C>T transitions at CpG dinucleotides after spontaneous 5-methylcytosine deamination. 2 To date, four patients (from three families) have been identified with MANS harbouring deleterious variants in MBD4 (NM_003925.2) including an in-frame deletion (p.(His567del)), canonical splice site (c.1562-1G>T) and truncating variants (p.(Glu314Argfs*13) and p.(Ser-205Thrfs*9)).…”

“…The overall risk is estimated two-to 20-fold greater than in the general population. 1 Immunosuppression represents the main risk factor, depending on the type, its extent and duration. In comparison, transmission of donor-derived cancer is rare and reported in 0.01% to 0.2% of solid organ recipients.…”