Collectively, our findings provide a step forward in understanding the molecular mechanisms underlying reduced penetrance in GATA2-mutated MDS/AML pedigrees, which may be governed by the acquisition of additional co-operating mutations (e.g., ASXL1) combined with dynamic epigenetic reprogramming and subsequent allele-specific expression of GATA2 mutant allele, adding another level of complexity to the (epi)genetic basis of familial MDS/AML. Here, ASXL1 is linked to myelodysplastic syndrome.