Germline heterozygous GATA2 mutations underlie a complex disorder characterized by bone marrow failure, immunodeficiency and high risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). GATA2 deficiency has been established as the most common hereditary cause of MDS in children and adolescents. Hematopoietic Stem Cell transplantation is the only cure. Since its discovery in 2011, important questions pertaining to mechanism of GATA2 deficiency remain unanswered: (i) Can GATA2 mutation itself promote MDS/AML development? (ii) Is there a genotype-phenotype association? (iii) What factors control disease penetrance? (iv) Which genetic or epigenetic lesions are essential for MDS/AML development? (v) Is there a GATA2-specific clonal architecture in patients´ bone marrow? (vi) What is the role of microenvironment? Answering these questions has been hampered by the absence of robust disease models and by decentralized efforts. Here we propose to unravel the mechanisms of malignant progression of GATA2 deficiency by combining centralized registry with multi-OMICs approaches, and in vitro and in vivo modelling. The overarching vision is to build an international consortium of GATA2 experts that through integrative approaches will acquire a precise understanding on the origins, and biological significance of initiating driver events thus allowing for personalized therapeutic decisions.