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.

Bone Marrow Transplantation Unit Department of Pediatric Hematology and Oncology National Institute of Children's Diseases Bratislava Slovakia

Bone Marrow Transplantation Unit Hospital Dr Luis Calvo Mackenna Santiago Chile

Center for Chronic Immunodeficiency Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Children's Health Ireland Dublin Ireland

Children's Hospital University of Helsinki and Helsinki University Hospital Helsinki Finland

Dana Farber and Boston Children's Cancer and Blood Disorders Center Harvard Medical School Boston USA

Department of Biomedicine and Prevention Molecular Medicine and Applied Biotechnology University of Rome Tor Vergata Rome Italy

Department of Biostatistics St Jude Children's Research Hospital Memphis USA

Department of Hematology and Oncology Hospital Sant Joan de Déu Barcelona Spain

Department of Hematology Oncology and Clinical Immunology Heinrich Heine Universität Düsseldorf Germany

Department of Hematology St Jude Children's Research Hospital Memphis USA

Department of Medicine 1 Hematology Oncology and Stem Cell Transplantation Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Department of Paediatric Bone Marrow Transplantation Oncology and Hematology Wroclaw Medical University Wroclaw Poland

Department of Paediatric Hematology Oncology Aghia Sophia Children's Hospital Athens Greece

Department of Pathology and Experimental Therapeutics Faculty of Medicine and Health Sciences Barcelona University Barcelona Spain

Department of Pathology St Jude Children's Research Hospital Memphis USA

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology Ghent University Hospital Ghent Belgium

Department of Pediatric Oncology and Hematology University Hospital in Scania Lund Sweden

Department of Pediatrics and Adolescent Medicine Aarhus University Hospital Aarhus Denmark

Department of Pediatrics and Adolescent Medicine University Medical Center Ulm Ulm Germany

Department of Rheumatology and Clinical Immunology Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

HCEMM SE Molecular Oncohematology Research Group MTA SE Lendulet Molecular Oncohematology Research Group Department of Pathology and Experimental Cancer Research Semmelweis University Budapest Hungary

IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Oslo University Hospital Department of Pediatric Hematology and Oncology Oslo Norway

Pediatric Hematology and Stem Cell Transplantation Department Central Hospital of Southern Pest Budapest Hungary

Pediatric Hematology Oncology Schneider Children's Medical Center and Faculty of Medical and Health Sciences Tel Aviv University Petah Tikva Israel

Prinses Maxima Centre Utrecht The Netherlands

Regenerative Medicine Program Bellvitge Institute for Biomedical Research Barcelona Spain

Section of Hematology Oncology and Stem Cell Transplantation Division of Pediatrics Pontificia Universidad Católica de Chile Santiago Chile

St Anna Children's Cancer Research Institute Vienna Austria

St Anna Children's Hospital Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Trinity College Dublin Dublin Ireland

Unidade de Hematologia Pediátrica Hospital Dona Estefânia ULS São José Lisboa Portugal

University Children's Hospital Zurich Zürich Switzerland

University Medical Center Ljubljana Ljubljana Slovenia

See more in PubMed

Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43:1012–7. PubMed PMC

Hsu AP, Sampaio EP, Khan J, Calvo KR, Lemieux JE, Patel SY et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 2011;118:2653–5. PubMed PMC

Ostergaard P, Simpson MA, Connell FC, Steward CG, Brice G, Woollard WJ et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011;43:929–31. PubMed

Pasquet M, Bellanne-Chantelot C, Tavitian S, Prade N, Beaupain B, Larochelle O et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood. 2013;121:822–9. PubMed PMC

Hirabayashi S, Wlodarski MW, Kozyra E, Niemeyer CM. Heterogeneity of GATA2-related myeloid neoplasms. Int J Hematol. 2017;106:175–82. PubMed

Homan CC, Venugopal P, Arts P, Shahrin NH, Feurstein S, Rawlings L et al. GATA2 deficiency syndrome: A decade of discovery. Hum Mutat. 2021;42:1399–421. PubMed PMC

Donadieu J, Lamant M, Fieschi C, de Fontbrune FS, Caye A, Ouachee M et al. Natural history of GATA2 deficiency in a survey of 79 French and Belgian patients. Haematologica. 2018;103:1278–87. PubMed PMC

Largeaud L, Collin M, Monselet N, Vergez F, Fregona V, Larcher L et al. Somatic genetic alterations predict hematological progression in GATA2 deficiency. Haematologica. 2023;108:1515–29. PubMed PMC

Umeda M, Ma J, Westover T, Ni Y, Song G, Maciaszek JL et al. A new genomic framework to categorize pediatric acute myeloid leukemia. Nat Genet. 2024;56:281–93. PubMed PMC

Wlodarski MW, Hirabayashi S, Pastor V, Starý J, Hasle H, Masetti R et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127:1387–97. PubMed

Sahoo SS, Pastor VB, Goodings C, Voss RK, Kozyra EJ, Szvetnik A et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes. Nat Med. 2021;27:1806–17. PubMed PMC

Dickinson RE, Griffin H, Bigley V, Reynard LN, Hussain R, Haniffa M et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011;118:2656–8. PubMed PMC

Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 2013;121:3830–7. PubMed PMC

Gao X, Johnson KD, Chang YI, Boyer ME, Dewey CN, Zhang J et al. Gata2 cis-element is required for hematopoietic stem cell generation in the mammalian embryo. J Exp Med. 2013;210:2833–42. PubMed PMC

Mehta C, Johnson KD, Gao X, Ong I, Katsumura KR, McIver SC et al. Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program. Blood. 2017;130:7. PubMed

Johnson KD, Hsu AP, Ryu MJ, Wang J, Gao X, Boyer ME et al. Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity. J Clin Invest. 2012;122:3692–704. PubMed PMC

West RR, Bauer TR, Tuschong LM, Embree LJ, Calvo KR, Tillo D et al. A novel GATA2 distal enhancer mutation results in MonoMAC syndrome in 2 second cousins. Blood Adv. 2023;7:6351–63. PubMed PMC

Wlodarski M, Collin M, Horwitz MS. GATA2 deficiency and related myeloid neoplasms. Semin Hematol. 2017;54:81–86. PubMed PMC

Bresnick EH, Jung MM, Katsumura KR. Human GATA2 mutations and hematologic disease: how many paths to pathogenesis? Blood Adv. 2020;4:4584–92. PubMed PMC

Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123:809–21. PubMed PMC

Kazenwadel J, Secker GA, Liu YJ, Rosenfeld JA, Wildin RS, Cuellar-Rodriguez J et al. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood. 2012;119:1283–91. PubMed PMC

Roncareggi S, Girardi K, Fioredda F, Pedace L, Arcuri L, Badolato R et al. A Nationwide Study of GATA2 Deficiency in Italy Reveals Novel Symptoms and Genotype-phenotype Association. J Clin Immunol. 2023;43:2192–207. PubMed

Kozyra EJ, Pastor VB, Lefkopoulos S, Sahoo SS, Busch H, Voss RK et al. Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency. Leukemia. 2020;34:2673–87. PubMed PMC

Bodor C, Renneville A, Smith M, Charazac A, Iqbal S, Etancelin P et al. Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Haematologica. 2012;97:890–4. PubMed PMC

Wlodarski MW, Sahoo SS, Niemeyer CM. Monosomy 7 in Pediatric Myelodysplastic Syndromes. Hematol Oncol Clin North Am. 2018;32:729–43. PubMed

Kozyra EJ, Gohring G, Hickstein DD, Calvo KR, DiNardo CD, Dworzak M et al. Association of unbalanced translocation der(1;7) with germline GATA2 mutations. Blood. 2021;138:2441–5. PubMed PMC

Kotmayer L, Romero-Moya D, Marin-Bejar O, Kozyra E, Catala A, Bigas A et al. GATA2 deficiency and MDS/AML: Experimental strategies for disease modelling and future therapeutic prospects. Br J Haematol. 2022;199:482–95. PubMed PMC

West RR, Hsu AP, Holland SM, Cuellar-Rodriguez J, Hickstein DD. Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica. 2014;99:276–81. PubMed PMC

West RR, Calvo KR, Embree LJ, Wang W, Tuschong LM, Bauer TR et al. ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome. Blood Adv. 2022;6:793–807. PubMed PMC

Wang X, Muramatsu H, Okuno Y, Sakaguchi H, Yoshida K, Kawashima N et al. GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies. Haematologica. 2015;100:e398–401. PubMed PMC

Ovsyannikova G, Pavlova A, Deordieva E, Raykina E, Pshonkin A, Maschan A et al. Single Center Experience With Pediatric Patients With GATA2 Deficiency. Front Pediatr. 2022;10:801810. PubMed PMC

Marin-Bejar O, Romero-Moya D, Rodriguez-Ubreva J, Distefano M, Lessi F, Aretini P et al. Epigenome profiling reveals aberrant DNA methylation signature in GATA2 deficiency. Haematologica. 2023;108:2551–7. PubMed PMC

Wehr C, Grotius K, Casadei S, Bleckmann D, Bode SFN, Frye BC et al. A novel disease-causing synonymous exonic mutation in GATA2 affecting RNA splicing. Blood. 2018;132:1211–5. PubMed PMC

Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140:1200–28. PubMed PMC

McReynolds LJ, Yang Y, Yuen Wong H, Tang J, Zhang Y, Mule MP et al. MDS-associated mutations in germline GATA2 mutated patients with hematologic manifestations. Leuk Res. 2019;76:70–5. PubMed PMC

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91. PubMed PMC

Gohring G, Michalova K, Beverloo HB, Betts D, Harbott J, Haas OA et al. Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood. 2010;116:3766–9. PubMed

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. PubMed PMC

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med. 2017;19:1105–17. PubMed PMC

Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5. PubMed PMC

Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886–D94. PubMed PMC

Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet. 2016;99:877–85. PubMed PMC

Sun L, Xu N, Shen M, Wang R, Sun Y, Zhuang J et al. GATA2 mutation with recurrent haemophagocytic lymphohistiocytosis and panniculitis: a case report. Rheumatol (Oxf). 2021;60:e229–e31. PubMed

Catto LFB, Borges G, Pinto AL, Cle DV, Chahud F, Santana BA et al. Somatic genetic rescue in hematopoietic cells in GATA2 deficiency. Blood. 2020;136:1002–5. PubMed

Bainbridge MN, Wang M, Wu Y, Newsham I, Muzny DM, Jefferies JL et al. Targeted enrichment beyond the consensus coding DNA sequence exome reveals exons with higher variant densities. Genome Biol. 2011;12:R68. PubMed PMC

Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745–55. PubMed

Hasegawa A, Hayasaka Y, Morita M, Takenaka Y, Hosaka Y, Hirano I et al. Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding. Commun Biol. 2022;5:376. PubMed PMC

Largeaud L, Fregona V, Jamrog LA, Hamelle C, Dufrechou S, Prade N, et al. Loss of HSC stemness identity is associated with exhaustion and hyporesponsiveness in GATA2 deficiency syndrome. bioRxiv. 2023. 10.1101/2023.08.07.551811.

Fernandez-Orth J, Koyunlar C, Weiss JM, Gioacchino E, de Looper H, Andrieux G, et al. Hematological phenotypes in GATA2 deficiency syndrome arise from secondary injuries and maladaptation to proliferation. bioRxiv. 2024. 10.1101/2024.09.24.614663. PubMed PMC

Luo X, Feurstein S, Mohan S, Porter CC, Jackson SA, Keel S et al. ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants. Blood Adv. 2019;3:2962–79. PubMed PMC

Wu D, Luo X, Feurstein S, Kesserwan C, Mohan S, Pineda-Alvarez DE et al. How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies. Haematologica. 2020;105:870–87. PubMed PMC