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.
Highlights
Germline mutations in the GATA2 gene, mostly arising de novo, had been reported to cause an immunodeficiency/ myelodysplasia syndrome manifesting with a multitude of clinical phenotypes
GATA2 deficiency is a monogenic disorder known so far to be caused by heterozygous nonsynonymous mutations, whole gene deletions or intronic enhancer mutations, all of which result in haploinsufficiency
All of the patients were alive at last follow-up with exception of one patient who died from hematopoietic stem cell transplantation (HSCT)-related complications
Summary
Germline mutations in the GATA2 gene, mostly arising de novo, had been reported to cause an immunodeficiency/ myelodysplasia syndrome manifesting with a multitude of clinical phenotypes. The variant was recently reported in an adult patient (the mother of two siblings studied here) presenting with immunodeficiency, severe infections and lung disease [25] This prompted us to study the contribution of synonymous alterations to the genetic spectrum of GATA2 deficiency and to assess their pathogenic role. We discovered and characterized five distinct synonymous mutations with RNA-deleterious effect in nine patients They represent a new type of mutation in GATA2 deficiency and have broad implications for both the discovery of disease-causing mutations and genetic counseling.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
