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<p>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 <i>GATA2</i> 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 <i>GATA2</i> 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, <i>p</i> = 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. <i>SETBP1</i> mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of <i>STAG2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月15日

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  • Lili Kotmayer,
  • Emilia J. Kozyra,
  • Guolian Kang,
  • Brigitte Strahm,
  • Ayami Yoshimi,
  • Sushree S. Sahoo,
  • Victor B. Pastor,
  • Enrico Attardi,
  • Rebecca Voss,
  • Luca Vinci,
  • Max Kaiser,
  • Michael N. Dworzak,
  • Barbara De Moerloose,
  • Martina Sukova,
  • Jan Starý,
  • Henrik Hasle,
  • Kirsi Jahnukainen,
  • Sophia Polychronopoulou,
  • Krisztián Kállay,
  • Owen P. Smith,
  • Andrea Malone,
  • Shlomit Barzilai Birenboim,
  • Riccardo Masetti,
  • Jochen Buechner,
  • Marek Ussowicz,
  • Paula Kjöllerström,
  • Ivana Bodova,
  • Marko Kavcic,
  • Albert Català,
  • Dominik Turkiewicz,
  • Markus Schmugge,
  • Valerie de Haas,
  • Victoria I. Okhomina,
  • Cristian Sotomayor,
  • Paula Catalán,
  • Claudia Wehr,
  • Ulrich Salzer,
  • Ulrich Germing,
  • Norbert Gattermann,
  • Csaba Bödör,
  • Nathan Gray,
  • Sara Lewis,
  • Akiko Shimamura,
  • Alessandra Giorgetti,
  • Miriam Erlacher,
  • Charlotte M. Niemeyer,
  • Marcin W. Wlodarski

摘要

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.