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Advisor(s)
Abstract(s)
GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.
Description
Keywords
Adolescent Adult Age Factors Child Preschool Female GATA2 Deficiency* / complications GATA2 Deficiency* / genetics GATA2 Deficiency* / pathology GATA2 Transcription Factor* / deficiency GATA2 Transcription Factor* / genetics Mutation Myelodysplastic Syndromes* / etiology Myelodysplastic Syndromes* / genetics Myelodysplastic Syndromes* / pathology Phenotype Young Adult HDE HEM PED
Pedagogical Context
Citation
Blood Cancer J . 2025 Jul 15;15(1):121.
Publisher
Nature