2026-04-13T01:19:35Zhttps://recercat.cat/oai/requestoai:recercat.cat:2445/2229212025-12-05T00:57:29Zcom_2072_1057col_2072_478916col_2072_478917col_2072_478929
Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency
Kotmayer, Lili
Kozyra, Emilia
Kang, Guolian
Strahm, Brigitte
Yoshimi, Ayami
Sahoo, Sushree S.
Pastor, Victor B.
Attardi, Enrico
Voss, Rebecca
Vinci, Luca
Kaiser, Max
Dworzak, Michael N.
De Moerloose, Barbara
Sukova, Martina
Stary, Jan
Hasle, Henrik
Jahnukainen, Kirsi
Polychronopoulou, Sophia
Kállay, Krisztián
Smith, Owen P.
Malone, Andrea
Barzilai Birenboim, Shlomit
Masetti, Riccardo
Buechner, Jochen
Ussowicz, Marek
Kjöllerström, Paula
Bodova, Ivana
Kavcic, Marko
Català, Albert
Turkiewicz, Dominik
Schmugge, Markus
de Haas, Valerie
Okhomina, Victoria I.
Sotomayor, Cristian
Catalán, Paula
Wehr, Claudia
Salzer, Ulrich
Germing, Ulrich
Gattermann, Norbert
Bödör, Csaba
Gray, Nathan
Lewis, Sara
Shimamura, Akiko
Giorgetti, Alessandra
Erlacher, Miriam
Niemeyer, Charlotte M.
Wlodarski, Marcin W.
Proteïnes
Hematologia pediàtrica
Malalties hematològiques
Mutació (Biologia)
Proteins
Pediatric hematology
Hematologic diseases
Mutation (Biology)
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.
2025-09-02T18:06:20Z
2025-09-02T18:06:20Z
2025-12-01
2025-09-02T18:06:20Z
info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Reproducció del document publicat a: https://doi.org/10.1038/s41408-025-01309-6
Blood Cancer Journal, 2025, vol. 15, num.1
https://doi.org/10.1038/s41408-025-01309-6
cc-by (c) Kotmayer, L. et al., 2025
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
Springer Nature
Articles publicats en revistes (Patologia i Terapèutica Experimental)