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Age-Dependent Phenotypic and Molecular Evolution of Pediatric MDS Arising from GATA2 Deficiency

2025-07-15Text Open access
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dc.contributor.authorKotmayer, Lili
dc.contributor.authorKozyra, Emilia J
dc.contributor.authorKang, Guolian
dc.contributor.authorStrahm, Brigitte
dc.contributor.authorYoshimi, Ayami
dc.contributor.authorSahoo, Sushree S
dc.contributor.authorPastor, Victor B
dc.contributor.authorAttardi, Enrico
dc.contributor.authorVoss, Rebecca
dc.contributor.authorVinci, Luca
dc.contributor.authorKaiser, Max
dc.contributor.authorDworzak, Michael N
dc.contributor.authorDe Moerloose, Barbara
dc.contributor.authorSukova, Martina
dc.contributor.authorStarý, Jan
dc.contributor.authorHasle, Henrik
dc.contributor.authorJahnukainen, Kirsi
dc.contributor.authorPolychronopoulou, Sophia
dc.contributor.authorKállay, Krisztián
dc.contributor.authorSmith, Owen P
dc.contributor.authorMalone, Andrea
dc.contributor.authorBarzilai Birenboim, Shlomit
dc.contributor.authorMasetti, Riccardo
dc.contributor.authorBuechner, Jochen
dc.contributor.authorUssowicz, Marek
dc.contributor.authorKjöllerström, Paula
dc.contributor.authorBodova, Ivana
dc.contributor.authorKavcic, Marko
dc.contributor.authorCatalà, Albert
dc.contributor.authorTurkiewicz, Dominik
dc.contributor.authorSchmugge, Markus
dc.contributor.authorde Haas, Valerie
dc.contributor.authorOkhomina, Victoria I
dc.contributor.authorSotomayor, Cristian
dc.contributor.authorCatalán, Paula
dc.contributor.authorWehr, Claudia
dc.contributor.authorSalzer, Ulrich
dc.contributor.authorGerming, Ulrich
dc.contributor.authorGattermann, Norbert
dc.contributor.authorBödör, Csaba
dc.contributor.authorGray, Nathan
dc.contributor.authorLewis, Sara
dc.contributor.authorShimamura, Akiko
dc.contributor.authorGiorgetti, Alessandra
dc.contributor.authorErlacher, Miriam
dc.contributor.authorNiemeyer, Charlotte M
dc.contributor.authorWlodarski, Marcin W
dc.date.accessioned2025-08-26T14:19:55Z
dc.date.available2025-08-26T14:19:55Z
dc.date.issued2025-07-15
dc.description.abstractGATA2 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.eng
dc.identifier.citationBlood Cancer J . 2025 Jul 15;15(1):121.
dc.identifier.doi10.1038/s41408-025-01309-6
dc.identifier.other40664679
dc.identifier.urihttp://hdl.handle.net/10400.17/5147
dc.language.isoen
dc.peerreviewedyes
dc.publisherNature
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAge Factors
dc.subjectChild
dc.subjectPreschool
dc.subjectFemale
dc.subjectGATA2 Deficiency* / complications
dc.subjectGATA2 Deficiency* / genetics
dc.subjectGATA2 Deficiency* / pathology
dc.subjectGATA2 Transcription Factor* / deficiency
dc.subjectGATA2 Transcription Factor* / genetics
dc.subjectMutation
dc.subjectMyelodysplastic Syndromes* / etiology
dc.subjectMyelodysplastic Syndromes* / genetics
dc.subjectMyelodysplastic Syndromes* / pathology
dc.subjectPhenotype
dc.subjectYoung Adult
dc.subjectHDE HEM PED
dc.titleAge-Dependent Phenotypic and Molecular Evolution of Pediatric MDS Arising from GATA2 Deficiencypor
dc.typetext
dspace.entity.typePublication
oaire.citation.issue1
oaire.citation.startPage121
oaire.citation.volume15
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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