Genomic and epigenomic profiling of GATA2 deficiency reveals aberrant hypermethylation pattern in Bone Marrow and Peripheral Blood

The majority (72%) of adolescents with myelodysplastic syndrome and monosomy 7 carry an underlying GATA2 deficiency. Nowadays, chemotherapy and allogenic hematopoietic stem cell transplantation (HSCT) are the only cure, pointing out the urgent need to develop reliable predictive tools. Familial cases carrying the same mutation in the GATA2 gene develop the disease at different age. The trigger of the disease is still unknown. Therefore, it is needed to understand the genetic mechanisms (mutations) and epigenetic mechanism, such as, DNA methylation, a cellular mechanism to control gene expression. Abnormal DNA methylation has been linked to several adverse outcomes, including human diseases. In this study, we deeply characterized 20 Spanish GATA2 deficient patients; study the presence of secondary mutations, clinical phenotype and DNA methylation. We have found that the most frequent secondary mutations are in STAG2 and ASXL1 genes, detected in 30% and 20% of the patients, respectively, a similar ratio has been described in a bigger cohort, showing that our 20-patient cohort is representative of the GATA2 deficiency scenario. For the first time, we found a specific hypermethylated signature in GATA2 patients, opening a novel point of view in the GATA2-patient diagnostic and facilitating the risk estimation of themselves. Furthermore, whether the methylation profiling is accurate enough, it will be useful to predict the onset of the disease progression. Bisulphite converted DNA from 28 samples (bone marrow and peripheral blood from gata2 mutant patients and healthy donors) were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2.