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

• DOI: 10.1038/s41375-020-0899-5
• Publication Date: 2020-06-18T10:04:33Z
• Authors: Emilia J. Kozyra; Victor B. Pastor; Stylianos Lefkopo...; 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. Niem...; Eirini Trompouki; Marcin W. Wlodarski
• Keywords: EXPRESSION; Adult; Male; Heterozygote; Adolescent; GATA2 Deficiency; VARIANT; 610; WORLD-HEALTH-ORGANIZATION; CLASSIFICATION; Article; GATA-2; Young Adult; 03 medical and health sciences; GATA2 mutations, children, myelodysplastic syndromes; Medicine and Health Sciences; Humans; Genetic Predisposition to Disease; TRANSCRIPTION; MYELOID NEOPLASMS; Child; Genetic Association Studies; Germ-Line Mutation; Silent Mutation; 0303 health sciences; GATA2; RNA; MDS; Immunologic Deficiency Syndromes; ABSENCE; REVISION; 3. Good health; GATA2 Transcription Factor; DIFFERENTIATION; Phenotype; Child, Preschool; Myelodysplastic Syndromes; RNA; Female; LEUKEMIA

AbstractDeficiency 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.