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

Abstract

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.

GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes

“…Most patients had normal bone marrow cytogenetics (68%, 17/25) ( Figure 2 ). The most common abnormality in this cohort was isolated trisomy 8 (5/8), in contrast to another report that describes an association with monosomy 7 [ 7 , 30 ].…”

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

“…GATA2 deficiency follows an autosomal dominant inheritance pattern with the majority (up to 80%) of cases arising de novo [ 49 , [52] , [53] , [54] , [55] ]. Although the lifetime penetrance for the development of MN is very high, incomplete penetrance is possible, as suggested by the presence of several asymptomatic mutation carriers of various ages within affected families [ 50 , 52 , 53 , [56] , [57] , [58] ]. Recently, distinct patterns of GATA2 promoter methylation leading to disbalance in allelic expression have been identified in 2 patients and proposed as a mechanism for reduced clinical expressivity [ 59 , 60 ].…”

“…However, MDS can also manifest as a stand-alone diagnosis without preceding cytopenia. GATA2 deficient patients often suffer from preexisting monocytopenia, B-cell and NK-cell lymphopenia, reduction/lack of CD56 bright NK cells and dendritic cells, inverted ratio of CD4:CD8 cells, and chronic neutropenia [ 48 , 53 , 58 , [61] , [62] , [63] , [64] , [65] ]. Immune deficiency is typically recorded as a consequence of profound cytopenias and loss of functional stem cells [ 66 ].…”

Human mutational constraint as a tool to understand biology of rare and emerging bone marrow failure syndromes

“…34,35 According to estimates, 75% of patients with GATA2 haploinsufficiency progress to MDS/AML by ;18 years of age. 13,34,36,37 The phenotype severity and onset before and during reproductive age likely underlie significant selection against GATA2 LoF, a phenomenon we also observed in several other myeloid malignancy predisposition genes (eg, RUNX1, MECOM, ETV6). In contrast, germline heterozygous LoF variants in DDX41 have been implicated in the development of MDS/AML in older adults with a mean age of 62 years.…”

“…[6][7][8][9][10][11][12] They also include recently described disorders such as GATA2 haploinsufficiency and SAMD9/SAMD9L syndromes, which have variable impacts on hematopoietic function but carry a high risk of MDS transformation. [13][14][15] IBMF and hematologic malignancy predisposition syndromes have widely variable phenotypes and penetrance, even within families, making prognostic counseling of patients and families difficult. For example, not every patient with a heterozygous loss-of-function (LoF) RTEL1 variant will progress to BMF or develop other manifestations of short telomere syndromes, including pulmonary fibrosis; however, the likelihood of these outcomes remains poorly defined.…”