Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency
Year: 2025
Type: article
Study design: Observational Study
Abstract: 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.
DOI: 10.5167/uzh-283386
Authors: Kotmayer, Lili, Kozyra, Emilia J, Kang, Guolian, Strahm, Brigitte, Yoshimi, Ayami, Sahoo, Sushree S, Pastor, Victor B, Attardi, Enrico, Voss, Rebecca Katherina, Vinci, Luca, Kaiser, Max, Dworzak, Michael N, De Moerloose, Barbara, Sukova, Martina, Starý, 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
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7126061714
FWCI:
Cites:
Cited by:
Related to: