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

Lookup NU author(s): Dr Preeti Singh, Professor Matthew CollinORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020, The Author(s). 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.

Publication metadata

Author(s): Kozyra EJ, Pastor VB, Lefkopoulos S, Sahoo SS, Busch H, Voss RK, Erlacher M, Lebrecht D, Szvetnik EA, Hirabayashi S, Pasauliene R, Pedace L, Tartaglia M, Klemann C, Metzger P, Boerries M, Catala A, Hasle H, de Haas V, Kallay K, Masetti R, De Moerloose B, Dworzak M, Schmugge M, Smith O, Stary J, Mejstrikova E, Ussowicz M, Morris E, Singh P, Collin M, Derecka M, Gohring G, Flotho C, Strahm B, Locatelli F, Niemeyer CM, Trompouki E, Wlodarski MW

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2020

Volume: 34

Pages: 2673-2687

Print publication date: 01/10/2020

Online publication date: 18/06/2020

Acceptance date: 29/05/2020

Date deposited: 10/07/2020

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Springer Nature


DOI: 10.1038/s41375-020-0899-5

PubMed id: 32555368


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