Multiple phenotypes and epigenetic profiles in a three-generation family history with GATA2 deficiency

Abstract

Germline heterozygous GATA2 mutations cause GATA2 deficiency, a complex disorder characterized by bone marrow failure, immunodeficiency, and a high risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The disease evolves variably among patients, leading to anxiety for families. Due to phenotypic diversity and clinical overlap, timely diagnosis is often challenging. GATA2 carriers exhibit variable expressivity, with some developing early-onset MDS while others remain asymptomatic, suggesting that genetic and epigenetic factors influence disease progression. While advances in diagnostics through whole-exome sequencing (WES) and whole genome sequencing (WGS) have been made, few epigenetic studies have focused on GATA-related MDS. We present a familial case of four GATA2 carriers, two of whom are asymptomatic and two have developed MDS. Notably, we conducted a longitudinal epigenome analysis of one patient, tracking progression from asymptomatic to MDS, providing key insights with potential clinical applications.