Project description:Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), "MonoMAC" syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.

| S-EPMC3277359 | biostudies-literature

MDS-associated mutations in germline GATA2 mutated patients with hematologic manifestations.

Project description:Germline mutation in GATA2 can lead to GATA2 deficiency characterized by a complex multi-system disorder that can present with many manifestations including variable cytopenias, bone marrow failure, myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), and severe immunodeficiency. Penetrance and expressivity within families is often variable. There is a spectrum of bone marrow disease in symptomatic cytopenic patients ranging from hypocellular marrows without overt dysplasia to those with definitive MDS, AML, or chronic myelomonocytic leukemia. Relatives of probands with the same mutations may demonstrate minimal disease manifestations and normal marrows. A comprehensive clinical, hematological and genetic assessment of 25 patients with germline GATA2 mutation was performed. MDS-associated mutations were identified in symptomatic GATA2 patients both with overt MDS and in those with hypocellular/aplastic bone marrows without definitive dysplasia. Healthy relatives of probands harboring the same germline GATA2 mutations had essentially normal marrows that were overall devoid of MDS-associated mutations. The findings suggest that abnormal clonal hematopoiesis is a common event in symptomatic germline mutated GATA2 patients with MDS and also in those with hypocellular marrows without overt morphologic evidence of dysplasia, possibly indicating a pre-MDS stage warranting close monitoring for disease progression.

| S-EPMC6340496 | biostudies-literature

Heritable GATA2 mutations associated with familial AML-MDS: a case report and review of literature.

Project description:A 50-year-old woman was diagnosed with acute myeloid leukemia (AML). She has history of thrombocytopenia for 25 years and a significant family history of thrombocytopenia, affecting her mother, siblings and their children, as well as her own children. Both her mother and maternal aunt died from myelodysplastic syndrome (MDS). Additional genetic analysis was performed and identified two heterozygous missence mutations in the second zinc finger domain of GATA2 gene (p.Thr358Lys, and p.Leu359Val), occurring in cis on the same allele. Given the patient's family history and clinical manifestation, this was interpreted as an acute myeloid leukemia with heritable GATA2 mutations associated with familial AML-MDS. Germline GATA2 mutations are involved in a group of complex syndromes with overlapping clinical features of immune deficiency, lymphedema and propensity to acute myeloid leukemia or myelodysplastic syndrome (AML-MDS). Here we reported a case of familial AML-MDS with two novel GATA2 mutations. This case illustrates the importance of recognizing the clinical features for this rare category of AML-MDS and performing the appropriate molecular testing. The diagnosis of heritable gene mutations associated familial AML-MDS has significant clinical implication for the patients and affected families. Clinical trials are available to further investigate the role of allogeneic hematopoietic stem cell transplant in managing these patients.

| S-EPMC4006458 | biostudies-literature

RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML.

Project description:First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

| S-EPMC7094007 | biostudies-literature

Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML.

Project description:Using metaphase cytogenetics (MC), chromosomal abnormalities are found in only a proportion of patients with myelodysplastic syndrome (MDS). We hypothesized that with new precise methods more cryptic karyotypic lesions can be uncovered that may show important clinical implications. We have applied 250K single nucleotide polymorphisms (SNP) arrays (SNP-A) to study chromosomal lesions in samples from 174 patients (94 MDS, 33 secondary acute myeloid leukemia [sAML], and 47 myelodysplastic/myeloproliferative disease [MDS/MPD]) and 76 controls. Using SNP-A, aberrations were found in around three-fourths of MDS, MDS/MPD, and sAML (vs 59%, 37%, 53% by MC; in 8% of patients MC was unsuccessful). Previously unrecognized lesions were detected in patients with normal MC and in those with known lesions. Moreover, segmental uniparental disomy (UPD) was found in 20% of MDS, 23% of sAML, and 35% of MDS/MPD patients, a lesion resulting in copy-neutral loss of heterozygosity undetectable by MC. The potential clinical significance of abnormalities detected by SNP-A, but not seen on MC, was demonstrated by their impact on overall survival. UPD involving chromosomes frequently affected by deletions may have prognostic implications similar to the deletions visible by MC. SNP-A-based karyotyping shows superior resolution for chromosomal defects, including UPD. This technique further complements MC to improve clinical prognosis and targeted therapies.

| S-EPMC2214746 | biostudies-literature

A patient with a germline GATA2 mutation and primary myelofibrosis.

Project description: Not available

| S-EPMC7876883 | biostudies-literature

Fanconi Anemia germline variants as susceptibility factors in aplastic anemia, MDS and AML.

Project description:Using next generation sequencing we have systematically analyzed a large cohort of 489 patients with bone marrow failure (BMF), including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), aplastic anemia (AA), and related conditions for the presence of germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes. We have detected an increased frequency of heterozygous FA gene mutations in MDS and to lesser degree in AML suggesting that the presence of one normal allele may not be completely protective and indeed heterozygous FA lesions may have a long latency period before hematologic manifestation. In contrast, GL telomerase gene mutations were not associated with increased disease risk. When compared to large control cohorts, we have not detected an increased frequency of damaging variants among telomerase complex genes, including those previously believed to be involved in the pathogenesis of AA. Our results may suggest that while low penetrance and delayed disease onset can confound identification of genetic predisposition factors, GL FA alterations can be also associated with MDS.

| S-EPMC5788620 | biostudies-literature

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants.

Project description:The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.

| S-EPMC7042299 | biostudies-literature

GATA2 monoallelic expression underlies reduced penetrance in inherited GATA2- mutated MDS/AML

Project description:Although familial myelodysplasia and acute myeloid leukemia (MDS/AML) is rare, its true prevalence is likely underestimated due to wide variations in the age of onset, disease latency and outcome between and within families, with some mutation carriers remaining asymptomatic into late adulthood. Reduced penetrance is a notable feature of germline GATA2 p.Thr354Met pedigrees. In this study, we demonstrate that silencing of the wildtype (WT) GATA2 allele discriminates between symptomatic and asymptomatic carriers and is linked with allele-specific differences in DNA methylation and H3K4me3 promotor deposition, providing a molecular explanation for the clinical heterogeneity observed within a GATA2-mutated AML family.

2018-09-21 | GSE104570 | GEO