<i>GATA2</i> null mutation associated with incomplete penetrance in a family with Emberger syndrome

Brambila-Tapia, Aniel Jessica Leticia; Garcı́a-Ortiz, José Elı́as; Brouillard, Pascal; Nguyen, Ha‐Long; Vikkula, Miikka; Ríos-González, Blanca Estela; Sandoval-Muñiz, Roberto de Jesús; Sandoval-Talamantes, Ana Karen; Bobadilla‐Morales, Lucina; Corona‐Rivera, Jorge Román; Arnaud-López, L.

doi:10.1080/10245332.2017.1294551

Cited by 8 publications

(5 citation statements)

References 19 publications

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“…These asymptomatic patients were identified by family screening after the proband tested positive for GATA2 mutation, constituted ∼13% of the cohort, and have been reported elsewhere at ∼10% to 30% of the studied cohort. 6,8,33 , 36-38 In this and other studies, the asymptomatic group was the oldest, suggesting that a mutation in GATA2 alone is necessary but not sufficient for the development of disease. Indeed, the most critically ill patients are the youngest group.…”

Section: Discussionsupporting

confidence: 51%

ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

et al. 2022

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GATA2 Deficiency patients harbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 Deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic Syndrome (MDS) was the most common diagnosis (~44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID) (~37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between patient age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (~43%)- notably trisomy 8 (~23%) and monosomy 7 (~12%), but these changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ~25% of patients, though these mutations were rarely concomitant. Mutations in DNMT3A were found in ~10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 Deficiency

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Section: Discussionsupporting

confidence: 51%

ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

et al. 2022

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“…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 ].…”

Section: Gata2 Deficiencymentioning

confidence: 99%

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

Sahoo

Kozyra

Wlodarski

2020

Best Practice & Research Clinical Haematology

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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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“…The development of myeloid neoplasms is remarkably inconsistent within families. The underlying biology of these differences is not understood 28 .…”

Section: Clinical Manifestationsmentioning

confidence: 99%

Germline GATA2 Mutation and Bone Marrow Failure

McReynolds

Calvo

Holland

2018

Hematology/Oncology Clinics of North America

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GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can be due to de novo sporadic germline mutation. Patients commonly have B-cell, dendritic cell, natural killer cell, and monocytopenias, and are predisposed to myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Patients may suffer from disseminated human papilloma virus and mycobacterial infections, pulmonary alveolar proteinosis, and lymphedema. The bone marrow eventually takes on a characteristic hypocellular myelodysplasia with loss of monocytes and hematogones, megakaryocytes with separated nuclear lobes, micromegakaryocytes, and megakaryocytes with hypolobated nuclei.

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GATA2 null mutation associated with incomplete penetrance in a family with Emberger syndrome

Cited by 8 publications

References 19 publications

ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

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

Germline GATA2 Mutation and Bone Marrow Failure

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