Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency

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dc.article.number121
dc.catalogadorgrr
dc.contributor.authorKotmayer, L.
dc.contributor.authorKozyra, E.J.
dc.contributor.authorKang, G.
dc.contributor.authorStrahm, B.
dc.contributor.authorYoshimi, A.
dc.contributor.authorSahoo, S.S.
dc.contributor.authorPastor, V.B.
dc.contributor.authorAttardi, E.
dc.contributor.authorVoss, R.
dc.contributor.authorVinci, L.
dc.contributor.authorKaiser, M.
dc.contributor.authorDworzak, M.N.
dc.contributor.authorDe Moerloose, B.
dc.contributor.authorSukova, M.
dc.contributor.authorStary, J.
dc.contributor.authorHasle, H.
dc.contributor.authorJahnukainen, K.
dc.contributor.authorPolychronopoulou, S.
dc.contributor.authorKallay, K.
dc.contributor.authorCatalan Martinez, Paula Valentina
dc.date.accessioned2025-08-26T15:59:30Z
dc.date.available2025-08-26T15:59:30Z
dc.date.issued2025
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.
dc.description.funderAIL
dc.description.funderAplastic Anemia & MDS International Foundation
dc.description.funderSt. Jude
dc.description.funderEuropean Hematology Association
dc.description.funderSSS
dc.description.funderVera and Joseph Dresner Foundation
dc.description.funderMWW
dc.description.funderFundació La Marató TV3
dc.description.funderNCI
dc.description.funderBMBF
dc.description.funderEuropean Union Horizon Program
dc.description.funderRD-Instituto de Salud Carlos III
dc.description.funderSpanish Ministry of Science
dc.description.funderHungarian Academy of Sciences
dc.description.funderNIH
dc.description.funderAssociazione Italiana Contro le Leucemie-Linfomi e Mieloma ONLUS
dc.fuente.origenSCOPUS
dc.identifier.doi10.1038/s41408-025-01309-6
dc.identifier.issn2044-5385
dc.identifier.scopusidSCOPUS_ID:105010620403
dc.identifier.urihttp://doi.org/10.1038/s41408-025-01309-6
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/105283
dc.information.autorucEscuela de Medicina; Catalan Martinez, Paula Valentina; S/I; 1199784
dc.language.isoen
dc.nota.accesocontenido completo
dc.revistaBlood Cancer Journal
dc.rightsacceso abierto
dc.rights.licenseCC BY 4.0 Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.titleAge-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency
dc.typeartículo
dc.volumen15
sipa.codpersvinculados1199784
sipa.trazabilidadSCOPUS;2025-07-27
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