GATA2 deficiency syndrome: A decade of discovery

Abstract

GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 465 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 231 of these confirmed to be familial and 22 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0-78 years) and myelodysplastic syndrome (MDS) is the first diagnosis in 75% of these cases with acute myeloid leukemia (AML) in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss-of-function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing and expression. In this review, we provide the first expert curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings.

GATA2 deficiency and MDS/AML: Experimental strategies for disease modelling and future therapeutic prospects

“…4,85,86 Mutational landscape of GATA2 deficiency includes a steadily increasing number of variants with approximately 500 published cases harbouring roughly 180 different familial or de novo germline mutations and partial or whole gene deletions. 11,20,87 The majority of reported pathogenic or probably pathogenic germline variants are inactivating (null) or loss-of-function (LOF) resulting in haploinsufficiency (~60% of all GATA2 deficient cases) either through truncating (nonsense), frameshift or splicing mutations and deletions. 1,19,22,27,[88][89][90][91] These confirmed germline variants along with less common in-frame deletions and insertions are scattered throughout the coding region of GATA2.…”

“…This might suggest an additional mechanism to LOF driving leukemogenesis, namely context-dependent gain of function. 20,92 Apart from missense variants, there are a few reports of synonymous GATA2 mutations in a handful of GATA2deficient cases to date. Despite the unaltered amino acid composition, the variants result in RNA degradation and can be categorized as null alleles.…”

“…The variant p.Thr117=, first described by Wehr and colleagues, [103][104][105] along with four additional mutations, namely p.Leu217=, p.Gly327=, p.Ala341 = and p.Phe472=, reported by Kozyra and colleagues, 104 was found to strongly alter splicing and induce selective loss of messenger RNA. 20,104,105 Although substantial phenotypic changes may support the putative role of synonymous GATA2 mutations, sequencing of GATA2 mRNA to confirm monoallelic loss and in silico analyses are essential to assess the actual impact of these seemingly innocuous, albeit potentially damaging variants on GATA2 expression for each individual case. 20,104 Regulatory variants (in approximately 10% of patients) constitute an important group of germline mutations affecting the GATA2 intronic +9.5 enhancer site and thus leading to haploinsufficiency via decreased GATA2 expression in HSPCs.…”

“…20,104,105 Although substantial phenotypic changes may support the putative role of synonymous GATA2 mutations, sequencing of GATA2 mRNA to confirm monoallelic loss and in silico analyses are essential to assess the actual impact of these seemingly innocuous, albeit potentially damaging variants on GATA2 expression for each individual case. 20,104 Regulatory variants (in approximately 10% of patients) constitute an important group of germline mutations affecting the GATA2 intronic +9.5 enhancer site and thus leading to haploinsufficiency via decreased GATA2 expression in HSPCs. Consequently, damaging mutations and deletions of intron 4 (NM_032638 isoform) perturb the dose-dependent transactivation activity of the Gata2 intronic enhancer disrupting haematopoietic cell development and cell differentiation fates.…”

“…Detailed description of the clinical presentations of GATA2 deficiency syndrome is beyond the scope of this review, therefore we refer to comprehensive reviews discussing GATA2-associated phenotypes 20,89 and previously published large cohort studies. 4,17 Myeloid malignancy is the most common phenotype associated with germline GATA2 mutations, manifesting in roughly 80% of reported carriers at a median age of approximately 20 years, 1,4,5,20,89 (Figure 1B). GATA2 deficiency is considered the most common germline predisposition in paediatric MDS, accounting for 15% of cases with MDS with excess blasts, and 7% of overall paediatric MDS within the co-operative European Working Group of MDS in Childhood (EWOG-MDS) cohort of 426 patients published by Wlodarski and colleagues.…”