A Novel Deleterious Variant and a Founder Effect in Four New Families of MBD4-Associated Neoplasia Syndrome Recruited Over a Period of 20 Years.

DNA glycosylases play a crucial role in DNA repair mediated by the base excision repair (BER) pathway, and alterations in these enzymes have been associated with hereditary cancer predisposition. Recently, germline biallelic loss-of-function variants in MBD4 were shown to be responsible for a novel autosomal recessive multi-tumor predisposition syndrome, provisionally denominated as MBD4-associated neoplasia syndrome and characterized by the association of adenomatous polyposis, colorectal cancer, and acute myeloid leukemia (AML). Here, we studied the MBD4 gene in five individuals from four families affected by adenomatous polyposis and AML, who had been referred for genetic counselling at a single institution over a period of approximately 20 years. All patients with this phenotype presented homozygous deleterious germline variants in MBD4, of which one is a founder variant recurrent in three of the families, and another variant has not been previously described in the literature. Our work allowed a molecular diagnosis for these families and significantly contributes to expanding the knowledge about this emerging syndrome caused by MBD4 constitutional deficiency.