Kotmayer, LiliKozyra, Emilia JKang, GuolianStrahm, BrigitteYoshimi, AyamiSahoo, Sushree SPastor, Victor BAttardi, EnricoVoss, RebeccaVinci, LucaKaiser, MaxDworzak, Michael NDe Moerloose, BarbaraSukova, MartinaStarý, JanHasle, HenrikJahnukainen, KirsiPolychronopoulou, SophiaKállay, KrisztiánSmith, Owen PMalone, AndreaBarzilai Birenboim, ShlomitMasetti, RiccardoBuechner, JochenUssowicz, MarekKjöllerström, PaulaBodova, IvanaKavcic, MarkoCatalà, AlbertTurkiewicz, DominikSchmugge, Markusde Haas, ValerieOkhomina, Victoria ISotomayor, CristianCatalán, PaulaWehr, ClaudiaSalzer, UlrichGerming, UlrichGattermann, NorbertBödör, CsabaGray, NathanLewis, SaraShimamura, AkikoGiorgetti, AlessandraErlacher, MiriamNiemeyer, Charlotte MWlodarski, Marcin W2025-08-262025-08-262025-07-15Blood Cancer J . 2025 Jul 15;15(1):121.40664679http://hdl.handle.net/10400.17/5147GATA2 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.enAdolescentAdultAge FactorsChildPreschoolFemaleGATA2 Deficiency* / complicationsGATA2 Deficiency* / geneticsGATA2 Deficiency* / pathologyGATA2 Transcription Factor* / deficiencyGATA2 Transcription Factor* / geneticsMutationMyelodysplastic Syndromes* / etiologyMyelodysplastic Syndromes* / geneticsMyelodysplastic Syndromes* / pathologyPhenotypeYoung AdultHDE HEM PEDtext10.1038/s41408-025-01309-6