Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.

Bone Marrow Transplant London UK

Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases Budapest Hungary

CIBSS Centre for Integrative Biological Signaling Studies Freiburg Germany

Comprehensive Cancer Center Freiburg University Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Department of Cellular and Molecular Immunology Max Planck Institute of Immunobiology and Epigenetics Freiburg Germany

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

Department of Hematology and Oncology University Children's Hospital Zurich Switzerland

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

Department of Immunology Royal Free London NHS FT London UK

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

Department of Pediatric Hematology and Oncology Charles University and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù Rome Italy

Department of Pediatric Hematology Oncology and Stem Cell Transplantation Ghent University Hospital Ghent Belgium

Department of Pediatric Oncology and Hematology University of Bologna Bologna Italy

Department of Pediatric Pneumology Allergy and Neonatology Hannover Medical School Hannover Germany

Department of Pediatrics Aarhus University Hospital Skejby Aarhus Denmark

Department of Pediatrics Hokkaido University Graduate School of Medicine Sapporo Japan

Department of Pediatrics Sapienza University of Rome Rome Italy

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

Dutch Childhood Oncology Group Princess Máxima Centre Utrecht The Netherlands

Faculty of Biology University of Freiburg Schänzlestraße 1 79104 Freiburg Germany

Genetics and Rare Diseases Research Division Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù Rome Italy

German Cancer Consortium Freiburg Germany

German Cancer Research Center Heidelberg Germany

Institute of Cellular Medicine Newcastle University Newcastle upon Tyne UK

Institute of Human Genetics Hannover Medical School Hannover Germany

Institute of Immunity and Transplantation University College London London UK

Institute of Medical Bioinformatics and Systems Medicine Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Institute of Molecular Medicine and Cell Research University of Freiburg Freiburg Germany

Lübeck Institute of Experimental Dermatology and Institute of Cardiogenetics University of Lübeck Lübeck Germany

NIHR Newcastle Biomedical Research Centre at Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

Paediatric Oncology and Haematology Our Lady's Children's Hospital Crumlin Dublin Ireland

St Anna Children´s Hospital and Cancer Research Institute Pediatric Clinic Medical University of Vienna Vienna Austria

Vilnius University Hospital Santaros Klinikos Center for Pediatric Oncology and Hematology Bone Marrow Transplantations Unit Vilnius Lithuania

Zobrazit více v PubMed

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

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

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

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

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

Dorn JM, Patnaik MS, Van Hee M, Smith MJ, Lagerstedt SA, Newman CC, et al. WILD syndrome is GATA2 deficiency: a novel deletion in the GATA2 gene. J Allergy Clin Immunol Pract. 2017;5:1149–52. PubMed

Wlodarski MW, Hirabayashi S, Pastor V, Stary 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

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

Wlodarski M, Collin M, Horwitz MS. GATA2 deficiency and related myeloid neoplasms. Seminars in Hematology. 2017;54:81–6. 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

Hahn CN, Brautigan PJ, Chong CE, Janssan A, Venugopal P, Lee Y, et al. Characterisation of a compound in-cis GATA2 germline mutation in a pedigree presenting with myelodysplastic syndrome/acute myeloid leukemia with concurrent thrombocytopenia. Leukemia. 2015;29:1795–7. PubMed

Cortes-Lavaud X, Landecho MF, Maicas M, Urquiza L, Merino J, Moreno-Miralles I, et al. GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation. J Immunol. 2015;194:2190–8. PubMed

Sologuren I, Martinez-Saavedra MT, Sole-Violan J, de Borges de Oliveira E, Jr, Betancor E, Casas I, et al. Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency. J Clin Immunol. 2018;38:513–26. PubMed PMC

Chong CE, Venugopal P, Stokes PH, Lee YK, Brautigan PJ, Yeung DTO, et al. Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes. Leukemia. 2018;32:194–202. PubMed PMC

D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, et al. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci USA. 1999;96:5598–603. PubMed PMC

Cartegni L, Krainer AR. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat Genet. 2002;30:377–84. PubMed

Macaya D, Katsanis SH, Hefferon TW, Audlin S, Mendelsohn NJ, Roggenbuck J, et al. A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon. Am J Med Genet A. 2009;149A:1624–7. PubMed

Vidal C, Cachia A, Xuereb-Anastasi A. Effects of a synonymous variant in exon 9 of the CD44 gene on pre-mRNA splicing in a family with osteoporosis. Bone. 2009;45:736–42. PubMed

Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet. 2003;12:205–16. PubMed

Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W. Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics. 2005;15:693–704. PubMed

Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science. 2006;314:1930–3. PubMed

Buhr F, Jha S, Thommen M, Mittelstaet J, Kutz F, Schwalbe H, et al. Synonymous Codons Direct Cotranslational Folding toward Different Protein Conformations. Mol cell. 2016;61:341–51. PubMed PMC

Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, et al. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet. 2011;43:242–5. PubMed

Simhadri VL, Hamasaki-Katagiri N, Lin BC, Hunt R, Jha S, Tseng SC, et al. Single synonymous mutation in factor IX alters protein properties and underlies haemophilia B. J Med Genet. 2017;54:338–45. 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

Baumann I, Niemeyer CMBJ, Shannon K WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008. p. 104–7.

Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51. PubMed

Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405. PubMed

Pastor V, Hirabayashi S, Karow A, Wehrle J, Kozyra EJ, Nienhold R, et al. Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants. Leukemia. 2016;31:759–62. PubMed

Bluteau O, Sebert M, Leblanc T, Peffault de Latour R, Quentin S, Lainey E, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood. 2018;131:717–32.. PubMed

Buonocore F, Kuhnen P, Suntharalingham JP, Del Valle I, Digweed M, Stachelscheid H, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest. 2017;127:1700–13. PubMed PMC

Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792–7. PubMed

Huang Z, Dore LC, Li Z, Orkin SH, Feng G, Lin S, et al. GATA-2 reinforces megakaryocyte development in the absence of GATA-1. Mol Cell Biol. 2009;29:5168–80. PubMed PMC

Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S, et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell. 2011;19:138–52. PubMed

Butko E, Distel M, Pouget C, Weijts B, Kobayashi I, Ng K, et al. Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo. Development. 2015;142:1050–61. PubMed PMC

Schwartz JR, Wang S, Ma J, Lamprecht T, Walsh M, Song G, et al. Germline SAMD9 mutation in siblings with monosomy 7 and myelodysplastic syndrome. Leukemia. 2017;31:1827–30. PubMed PMC

Novakova M, Zaliova M, Sukova M, Wlodarski M, Janda A, Fronkova E, et al. Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome. Haematologica. 2016;101:707–16. PubMed PMC

Abdulhay NJ, Fiorini C, Verboon JM, Ludwig LS, Ulirsch JC, Zieger B, et al. Impaired human hematopoiesis due to a cryptic intronic GATA1 splicing mutation. J Exp Med. 2019;216:1050–60. PubMed PMC

Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Rodger E, Kelley ML, et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol. 2015;22:3–11. PubMed PMC

Supek F, Minana B, Valcarcel J, Gabaldon T, Lehner B. Synonymous mutations frequently act as driver mutations in human cancers. Cell. 2014;156:1324–35. PubMed

Pirinen M, Lappalainen T, Zaitlen NA, Consortium GT, Dermitzakis ET, Donnelly P, et al. Assessing allele-specific expression across multiple tissues from RNA-seq read data. Bioinformatics. 2015;31:2497–504. PubMed PMC

Wilkins JM, Southam L, Price AJ, Mustafa Z, Carr A, Loughlin J. Extreme context specificity in differential allelic expression. Hum Mol Genet. 2007;16:537–46. PubMed

Serre D, Gurd S, Ge B, Sladek R, Sinnett D, Harmsen E, et al. Differential allelic expression in the human genome: a robust approach to identify genetic and epigenetic cis-acting mechanisms regulating gene expression. PLoS Genet. 2008;4:e1000006. PubMed PMC

Al Seraihi AF, Rio-Machin A, Tawana K, Bodor C, Wang J, Nagano A, et al. GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2-mutated MDS/AML. Leukemia. 2018;32:2502–7. PubMed PMC

Nandakumar SK, Johnson K, Throm SL, Pestina TI, Neale G, Persons DA. Low-level GATA2 overexpression promotes myeloid progenitor self-renewal and blocks lymphoid differentiation in mice. Exp Hematol. 2015;43:565–77.e1-10. PubMed

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015;47:717–26. PubMed PMC

Ji J, Shen L, Bootwalla M, Quindipan C, Tatarinova T, Maglinte DT, et al. A semi-automated whole exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. Cold Spring Harb Mol Case Stud. 2019;5:a003756. PubMed PMC

Cummings BB, Marshall JL, Tukiainen T, Lek M, Donkervoort S, Foley AR, et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med. 2017;9:eaal5209. PubMed PMC

Kremer LS, Bader DM, Mertes C, Kopajtich R, Pichler G, Iuso A, et al. Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat Commun. 2017;8:15824. PubMed PMC

Association of unbalanced translocation der(1;7) with germline GATA2 mutations

Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome