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

Abstract

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.

• Authors: Emilia J Kozyra, Victor B Pastor, Stylianos Lefkopoulos, Sushree S Sahoo, Hauke Busch, Rebecca K Voss, Miriam Erlacher, Dirk Lebrecht, Enikoe A Szvetnik, Shinsuke Hirabayashi, Ramunė Pasaulienė, Lucia Pedace, Marco Tartaglia, Christian Klemann, Patrick Metzger, Melanie Boerries, Albert Catala, Henrik Hasle, Valerie de Haas, Krisztián Kállay, Riccardo Masetti, Barbara De Moerloose, Michael Dworzak, Markus Schmugge, Owen Smith, Jan Starý, Ester Mejstrikova, Marek Ussowicz, Emma Morris, Preeti Singh, Matthew Collin, Marta Derecka, Gudrun Göhring, Christian Flotho, Brigitte Strahm, Franco Locatelli, Charlotte M Niemeyer, Eirini Trompouki, Marcin W Wlodarski, European Working Group of MDS in Childhood (EWOG-MDS)
• Journal: Leukemia (Leukemia) Vol. 34 Issue 10 Pg. 2673-2687 (10 2020) ISSN: 1476-5551 [Electronic] England
• PMID: 32555368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GATA2 Transcription Factor
• GATA2 protein, human
• RNA

Topics

• Adolescent
• Adult
• Child
• Child, Preschool
• Female
• GATA2 Deficiency (genetics)
• GATA2 Transcription Factor (deficiency, genetics)
• Genetic Association Studies
• Genetic Predisposition to Disease (genetics)
• Germ-Line Mutation (genetics)
• Heterozygote
• Humans
• Immunologic Deficiency Syndromes (genetics)
• Male
• Myelodysplastic Syndromes (genetics)
• Phenotype
• RNA (genetics)
• Silent Mutation (genetics)
• Young Adult