Germline Biallelic Loss in MBD4 leading to Early Onset AML with Hyper-Mutator Genomic Signature

MBD4, a gene encoding a DNA glycosylase functioning in base excision repair, has recently been described in association with predisposition to early onset acute myeloid leukemia (AML), uveal melanoma and colorectal polyposis. MBD4 is essential for guarding against methylation damage due to spontaneous deamination of 5-methylcytosine and biallelic loss of MBD4 allows CG>TG mutations to accumulate in the genome predisposing to AML (Sanders et al. Blood 2018). Further understanding of the full phenotypic spectrum and mechanisms leading to cancer evolution for this predisposition syndrome is critical for informing early recognition, diagnosis, management, and treatment for these individuals and their at-risk family members with the ultimate goal of improving outcomes. Here we report novel germline mutations in MBD4, expand the spectrum of cancers and describe the mutational signatures associated with this cancer predisposition syndrome.