“…These mutants appear to impact on disease subtypes (for example, MDS/AML and chronic myelomonocytic leukemia) and exhibit differences in age of onset. Recently, Ding et al 40 reported two cases of gR396Q mutation in patients who developed MDS at younger age, consistent with our data that it predisposes predominantly to MDS and with early onset. These data support the concept of genetic ‘predestination’ where initiator or founder mutations in a protein or even domain confer increased tendency to direct or constrain the impact of subsequent mutations and phenotypes.…”
Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.
“…These mutants appear to impact on disease subtypes (for example, MDS/AML and chronic myelomonocytic leukemia) and exhibit differences in age of onset. Recently, Ding et al 40 reported two cases of gR396Q mutation in patients who developed MDS at younger age, consistent with our data that it predisposes predominantly to MDS and with early onset. These data support the concept of genetic ‘predestination’ where initiator or founder mutations in a protein or even domain confer increased tendency to direct or constrain the impact of subsequent mutations and phenotypes.…”
Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.
“…Others have identified mutations in SETBP1, ASXL1, STAG2, RUNX1, CBL, EZH2, NRAS/KRAS, JAK3, and PTPN11 in a cohort of pediatric GATA2-related MDS cohort (Loyola VBP 2015). Fisher et al identified RUNX1, SETBP1, IKZF1 and CRLF2 variants in two pediatric GATA2-associated MDS cases (Fisher , et al 2017) Ding et al described a father-son pair with GATA2 germline mutation and MDS who both had STAG2 mutations, but in different genomic locations (Ding , et al 2017). Bodor et al described a patient with MDS, a somatic ASXL1 mutation and monosomy 7 with poor outcome (Bodor , et al 2012).…”
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.
Increasing awareness about germline predisposition and the widespread application of unbiased whole exome sequencing contributed to the discovery of new clinical entities with high risk for the development of haematopoietic malignancies. The revised 2016 WHO classification introduced a novel category of “myeloid neoplasms with germline predisposition” with
GATA2
,
CEBPA
,
DDX41
,
RUNX1
,
ANKRD26
, and
ETV6
genes expanding the spectrum of hereditary myeloid neoplasms (MN). Since then, more germline causes of MN were identified, including
SAMD9
,
SAMD9L
, and
ERCC6L2
. This review describes the genetic and clinical spectrum of predisposition to MN. The main focus lies in delineation of phenotypes, genetics and management of GATA2 deficiency and the novel SAMD9/SAMD9L-related disorders. Combined, GATA2 and SAMD9/SAMD9L (SAMD9/9L) syndromes are recognized as most frequent causes of primary pediatric myelodysplastic syndromes, particularly in setting of monosomy 7. To date, ∼550 cases with germline
GATA2
mutations, and ∼130 patients with
SAMD9/9L
mutations had been reported in literature. GATA2 deficiency is a highly penetrant disorder with a progressive course that often rapidly necessitates bone marrow transplantation. In contrast, SAMD9/SAMD9L disorders show incomplete penetrance with various clinical outcomes ranging from spontaneous haematological remission observed in young children to malignant progression.
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