Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency

E.J. Kozyra, V.B. Pastor, S. Lefkopoulos, S.S. Sahoo, H. Busch, R.K. Voss, M. Erlacher, D. Lebrecht, E.A. Szvetnik, S. Hirabayashi, R. Pasaulienė, L. Pedace, M. Tartaglia, C. Klemann, P. Metzger, M. Boerries, A. Catala, H. Hasle, V. de Haas, K. KállayR. Masetti, B. De Moerloose, M. Dworzak, M. Schmugge, O. Smith, J. Starý, E. Mejstrikova, M. Ussowicz, E. Morris, P. Singh, M. Collin, M. Derecka, G. Göhring, C. Flotho, B. Strahm, F. Locatelli, C.M. Niemeyer, E. Trompouki, M.W. Wlodarski, European Working Group of MDS in Childhood (EWOG-MDS)

Research output: Contribution to journalArticlepeer-review


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. © 2020, The Author(s).
Original languageEnglish
Pages (from-to)2673-2687
Number of pages15
Issue number10
Publication statusPublished - 2020


  • cysteine
  • genomic DNA
  • glycine
  • messenger RNA
  • threonine
  • transcription factor GATA 2
  • GATA2 protein, human
  • RNA
  • adolescent
  • adult
  • amino acid substitution
  • animal cell
  • Article
  • causal attribution
  • child
  • cohort analysis
  • embryo
  • exome
  • exon
  • female
  • GATA2 deficiency
  • GATA2 gene
  • gene frequency
  • gene loss
  • gene sequence
  • genetic code
  • genetic counseling
  • genetic predisposition
  • heterozygote
  • human
  • major clinical study
  • male
  • missense mutation
  • mutational analysis
  • myelodysplastic syndrome
  • nonhuman
  • phenotype
  • preschool child
  • priority journal
  • protein expression
  • protein stability
  • RNA splicing
  • school child
  • young adult
  • genetic association study
  • genetics
  • germline mutation
  • immune deficiency
  • silent mutation
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Female
  • GATA2 Deficiency
  • GATA2 Transcription Factor
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Heterozygote
  • Humans
  • Immunologic Deficiency Syndromes
  • Male
  • Myelodysplastic Syndromes
  • Phenotype
  • Silent Mutation
  • Young Adult


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