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Familial pedigree Heredogram representing three generations of the family analyzed in this study. GATA2 mutation (GATA2mut) and GATA2 wild-type (GATA2WT) subjects are represented; the arrow indicates the proband; individuals with numbers were studied
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Background:
GATA2 is a transcription factor that is a critical regulator of gene expression in hematopoietic cells. GATA2 deficiency presents with multi-lineage cytopenia, mycobacterial, fungal and viral infections. Patients with GATA2 mutation have a high risk of developing myelodysplastic syndrome or acute myeloid leukemia.
Case presentation:...
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Background: GATA2 is a transcription factor that is a critical regulator of gene expression in hematopoietic cells. GATA2 deficiency presents with multi-lineage cytopenia, mycobacterial, fungal and viral infections. Patients with GATA2 mutation have a high risk of developing myelodysplastic syndrome or acute myeloid leukemia.
Case presentation: We...
Citations
... This syndrome is caused by GATA2 germline mutations [54,112], often occurring as a result of rare autosomal dominant mutations such as (E.G. c.1186C > T;p.R396W), resulting in loss of function in one allele of GATA2 [54,113]. These mutations can occur across the GATA2 gene, with causal mutations reported in both TAD domains, the NRD domain, the NLS, and in both zinc finger domains (Fig. 1C) [114][115][116][117][118][119][120][121][122][123][124][125]. MonoMAC syndrome can also be caused by frameshift, nonsense, splicesite mutations, and deletion mutations, with these mutations typically inactivating one GATA2 allele [124,125] those with rarer GATA2 mutations where the underlying germline mutation had not yet been identified. ...
The transcription factor GATA2 is involved in human diseases ranging from hematopoietic disorders, to cancer, to infectious diseases. GATA2 is one of six GATA-family transcription factors that act as pioneering transcription factors which facilitate the opening of heterochromatin and the subsequent binding of other transcription factors to induce gene expression from previously inaccessible regions of the genome. Although GATA2 is essential for hematopoiesis and lymphangiogenesis, it is also expressed in other tissues such as the lung, prostate gland, gastrointestinal tract, central nervous system, placenta, fetal liver, and fetal heart. Gene or transcriptional abnormalities of GATA2 causes or predisposes patients to several diseases including the hematological cancers acute myeloid leukemia and acute lymphoblastic leukemia, the primary immunodeficiency MonoMAC syndrome, and to cancers of the lung, prostate, uterus, kidney, breast, gastric tract, and ovaries. Recent data has also linked GATA2 expression and mutations to responses to infectious diseases including SARS-CoV-2 and Pneumocystis carinii pneumonia, and to inflammatory disorders such as atherosclerosis. In this article we review the role of GATA2 in the etiology and progression of these various diseases.
... In contrast, ARID5B rs10821936 is associated with an increased risk of AL with MLL-MLLT3 in both ALL and AML (32). Recently, we observed an increasing number of families with multiple MDS/AL and GATA2 mutations in germline cells (18,33). ...
Background
Familial aggregation in childhood leukemia is associated with epidemiological and genomic factors. Albeit epidemiological studies on the familial history of hematological malignancies (FHHMs) are scarce, genome-wide studies have identified inherited gene variants associated with leukemia risk. We revisited a dataset of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients to explore the familial aggregation of malignancies among their relatives.
Methods
A series of 5,878 childhood leukemia (≤21 years of age) from the EMiLI study (2000–2019) were assessed. Lack of well-documented familial history of cancer (FHC) and 670 cases associated with genetic phenotypic syndromes were excluded. Leukemia subtypes were established according to World Health Organization recommendations. Logistic regression-derived odds ratios (ORs) and 95% confidence intervals (CIs) were performed and adjusted by age as a continuous variable, where ALL was the reference group for AML and conversely. The pedigree of 18 families with excess hematological malignancy was constructed.
Results
FHC was identified in 472 of 3,618 eligible cases (13%). Ninety-six of the 472 patients (20.3%) had an occurrence of FHHMs among relatives. Overall, FHC was significantly associated with AML (OR, 1.36; 95% CI, 1.01–1.82; p = 0.040). Regarding the first-degree relatives, the OR, 2.92 95% CI,1.57-5.42 and the adjOR, 1.16 (1.03-1.30; p0.001) were found for FHC and FHHM, respectively.
Conclusion
Our findings confirmed that AML subtypes presented a significant association with hematological malignancies in first-degree relatives. Genomic studies are needed to identify germline mutations that significantly increase the risk of developing myeloid malignancies in Brazil.
... GATA2 gene is located on chromosome 3q21 and encodes a master transcription factor that is key to the proliferation and maintenance of hematopoietic stem cells and lymphatic angiogenesis [4,5]. GATA2 mutations can lead to a state of haploinsufficiency [5]. ...
GATA2 mutation can result in profoundly reduced monocytes, dendritic cells, natural killer cells, and B cells, and is associated with a predisposition for recurrent and disseminated nontuberculous mycobacterial (NTM) infections and myelodysplasias. Herein, we describe a unique case of 3 simultaneous disseminated NTM infections in a patient with GATA2 mutations.
... GATA2 regulates the transcription of genes involved in hematopoietic and endocrine cell lineage formation and proliferation. Mutation in the GATA2 gene leads to the development syndrome and is prone to mycobacterial infections [27]. ...
... Since 2011, 77 GATA2-deficient patients from 74 kindreds with a history of mycobacterial disease have been reported [3,4,8,9,20,22,[25][26][27][28][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]. Mean age at first mycobacterial infection in these patients was 26 years (range: 8-51, including 57 patients with available information), and these patients had experienced a total of 92 mycobacterial episodes among them. ...
PurposeGermline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown.Methods
We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives.ResultsWe identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic.Conclusion
Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.
... Two diseases included in the category "Congenital defects of phagocyte number or function", X-linked chronic granulomatous disease and GATA2 deficiency (MonoMac syndrome), with defects in CYBB and GATA2 genes, respectively, has been reported with increased susceptibility to NTM [84,[90][91][92][93]. ...
Currently, there is a trend of increasing incidence in pulmonary non-tuberculous mycobacterial infections (PNTM) together with a decrease in tuberculosis (TB) incidence, particularly in developed countries. The prevalence of PNTM in underdeveloped and developing countries remains unclear as there is still a lack of detection methods that could clearly diagnose PNTM applicable in these low-resource settings. Since non-tuberculous mycobacteria (NTM) are environmental pathogens, the vicinity favouring host-pathogen interactions is known as important predisposing factor for PNTM. The ongoing changes in world population, as well as socio-political and economic factors, are linked to the rise in the incidence of PNTM. Development is an important factor for the improvement of population well-being, but it has also been linked, in general, to detrimental environmental consequences, including the rise of emergent (usually neglected) infectious diseases, such as PNTM. The rise of neglected PNTM infections requires the expansion of the current efforts on the development of diagnostics, therapies and vaccines for mycobacterial diseases, which at present, are mainly focused on TB. This review discuss the current situation of PNTM and its predisposing factors, as well as the efforts and challenges for their control.
Mutations in genes encoding transcription factors inactivate or generate ectopic activities to instigate pathogenesis. By disrupting hematopoietic stem/progenitor cells, GATA2 germline variants create a bone marrow failure and leukemia predisposition, GATA2 deficiency syndrome, yet mechanisms underlying the complex phenotypic constellation are unresolved. We used a GATA2-deficient progenitor rescue system to analyze how genetic variation influences GATA2 functions. Pathogenic variants impaired, without abrogating, GATA2-dependent transcriptional regulation. Variants promoted eosinophil and repressed monocytic differentiation without regulating mast cell and erythroid differentiation. While GATA2 and T354M required the DNA-binding C-terminal zinc finger, T354M disproportionately required the N-terminal finger and N terminus. GATA2 and T354M activated a CCAAT/Enhancer Binding Protein-ε (C/EBPε) enhancer, creating a feedforward loop operating with the T-cell Acute Lymphocyte Leukemia-1 (TAL1) transcription factor. Elevating C/EBPε partially normalized hematopoietic defects of GATA2-deficient progenitors. Thus, pathogenic germline variation discriminatively spares or compromises transcription factor attributes, and retaining an obligate enhancer mechanism distorts a multilineage differentiation program.
Introduction
Haploinsufficiency of the hematopoietic transcription factor GATA2 is associated with a broad spectrum of diseases, including infection susceptibility and neoplasms. We aimed to investigate GATA2 variants in patients with non-tuberculous mycobacterial (NTM) and/or fungal infections (FI) without known immunodeficiencies.
Method
We performed GATA2 genotyping in patients with NTM and/or FI.
Results
Twenty-two patients were enrolled (seventeen FI, four NTM and one with both infections). The pathogenic variant NG_029334.1:g.16287C>T was found in one patient (4.5%) and two asymptomatic offsprings. We also found the likely-benign variant NG_029334.1:g.12080G>A (rs2335052), the benign variant NG_029334.1:g.16225C>T (rs11708606) and the variant of uncertain significance NG_029334.1:g.16201G>A (rs369850507) in 18.2%, 27.3%, and 4.5% of the cases, respectively. Malignant diseases were additionally diagnosed in six patients.
Conclusion
Although detected in 45.4% of the patients, most GATA2 variants were benign or likely benign. Identifying a pathogenic variant was essential for driving both the patient's treatment and familial counseling. Pathogenic variants carriers should receive genetic counseling, subsequent infection prevention measures and malignancies surveillance. Additionally, case-control genotyping should be carried out in Brazil to investigate whether the observed variants may be associated with susceptibility to opportunistic infections and/or concurrent neoplasms.
Monocytopenia and mycobacterial infection (MonoMAC) syndrome is a rare disease. Herein, we reported a 65-year-old Asian woman, previously diagnosed with myelodysplastic syndrome (MDS), suffering from recurrent pneumonia, intermittent fever, fatigue, and chest tightness lasting for five months. She was ultimately diagnosed with MonoMAC syndrome with Mycobacterium kansasii (M. kansasii) infection and GATA2 mutation through metagenomic generation sequencing (mNGS) of peripheral blood specimen, for which she was given anti-NTM therapy. Her situation significantly improved within 2 weeks of therapy. We discussed the clinical features, genetic characteristic, and prognosis of this disorder, aiming to further elucidate this rare syndrome. For MDS/AML patient with recurrent mixed infection and pancytopenia (especially with monocyte absence), MonoMAC syndrome should be highly suspected, and germline mutation and pathogen sequencing should be performed.
Susceptibility to infection from phagocytic dysfunction ranges from mild and recurrent skin infections to overwhelming, fatal systemic infection. Affected patients are more susceptible to bacterial and fungal infections but have normal resistance to viral infections. Most cases are diagnosed in infancy due to the severity of the infection or the unusual presentation of the organism, but some escape diagnosis until adulthood. In this chapter we have provided a practical guideline to approach patients with phagocyte defects.
