ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21892158 Ostergaard et al. (2011): Reported eight mutations of the GATA2 gene which underlies Emberger syndrome, or cause primary lymphedema associated with a predisposition to acute myeloid leukemia (AML). Eight unrelated probands were recruited, one of Chinese ancestry and seven of European ancestry. Two individuals had familial history of primary lymphedema and six were sporadic occurrences. The mutation in both families was frameshift (family 1:Leu105ProfsX15, family 2:Arg78ProfsX107). In the sporadic cases, there were two missense mutations, three frame shift and one nonsense. The proband of Chinese ancestry carried the nonsense mutation (Arg337X) and had bilateral lower limb and genital lymphedema and myelodysplasia. The probands with frameshift mutations (p.Ala341ProfsX45, p.Ala341ArgfsX38, and p.Ala194SerfsX8) presented with left, bilateral, and right lower limb lymphedema, respectively.
21670465 Hsu et al. 2011 describe GATA2 variants identified in a cohort of individuals with the monoMAC phenotype, including 4 with insertion/deletion variants predicted to result in null alleles because of nonsense mediated decay.
22147895 Kazenwadel et al (2012) report several patients with familial or sporadic MDS/AML who had GATA2 mutations, including a familial deletion of the first 2 coding exons, a previously unreported frameshift and splice site variants predicted to result in loss of function, and 3 individuals with large contiguous deletions encompassing the GATA2 gene. The patients with the deletions and frameshift mutations also presented with primary lymphedema.

Haploinsufficiency phenotype comments:

Hsu et al. 2013 (PMID:23502222) provide a clear description of the phenotype associated with GATA2 deficiency and the observed mutation spectrum. From their text: "GATA2 deficiency is characterized by monocytopenia; B, natural killer (NK), and dendritic cell lymphopenia; and mycobacterial, fungal, and viral infection. It has been called both MonoMAC, for monocytopenia and Mycobacterium avium complex, and DCML deficiency, for dendritic cell, monocyte, B and NK lymphoid deficiency. Patients may present with myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) or pulmonary alveolar proteinosis. Unlike typical MDS, the marrow in patients with GATA2 deficiency is typically hypocellular and contains atypical and micro-megakaryocytes. Since GATA2 also plays a critical role in the development of the vascular and lymphatic systems, patients may present with lymphedema along with monosomy 7 and MDS, a triad known as Emberger syndrome. The GATA2 mutations reported previously cluster into 2 main groups. Mutations within the highly conserved C-terminal zinc finger include missense changes and deletions that result in loss of the C-terminus. They are predicted to allow production of a stable mRNA that is translated into an abnormal protein. In contrast, the other group of mutations includes full gene deletions, as well as frame shift or early stop mutations, predicted to cause nonsense-mediated decay (NMD) of the mRNA, as reported in both MonoMAC and Emberger syndrome." Of note, in addition to these more classic GATA2 variants, Hsu et al. report on individuals in whom no GATA2 coding region mutations were found, but who had intronic mutations or deletions in conserved enhancers. These patients also presented with monoMAC syndrome, which is characterized by lymphedema, mononuclear cytopenias, recurrent infections, and MDS/AML. Some patients may also be deaf.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity