The GATA2 gene encodes a transcription factor protein, GATA2, which is
expressed in hematopoietic stem cells. This protein contains two zinc finger
domains that promote protein-protein and protein-DNA communication. GATA2
functions in the formation of early blood and lymphatic vessels.
Heterozygous mutations in GATA2 demonstrate considerable
phenotypic heterogeneity and have been reported in association with Emberger
syndrome (primary lymphedema and MDS/AML, with or without congenital deafness),
immunodeficiency-21 (profound decrease or absence of monocytes, B lymphocytes,
NK lymphocytes and dendritic cells with no effect on T cell numbers with resulting
opportunistic infections, pulmonary alveolar proteinosis and hypoplastic bone
marrow/aplastic anemia) as well as in familial MDS/AML. Spinner (2014) recently
summarized clinical findings in 57 patients with GATA2 mutations. Neutropenia
was identified in about one half at presentation. Pasquet et al. (2013) described
14 patients who initially presented with congenital neutropenia secondary to a heterozygous
mutation in GATA2, and 10 of 14
patients progressed to MDS/AML over the course of study.
GATA2 deficiency is highly variable; however, outcome
in patients summarized by Spinner et al. (2014) was guarded and hematopoietic
stem cell transplantation (HSCT) may be a consideration in patients with severe
disease. Presentation may be delayed
into adulthood and presymptomatic screening of at-risk relatives is recommended
for appropriate disease management, prophylaxis and consideration of HSCT.
Confirmation of diagnosis in a patient with the following:
- Emberger syndrome (primary lymphedema with myelodysplastic
- Familial myelodysplastic syndrome
- Dendritic cell, monocyte, B, and natural killer (NK)
- Family member with previously identified GATA2 mutation
Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the GATA2 gene.
Unknown due to the phenotypic heterogeneity of
this condition. In one study of 14 cases of WHIM-like syndrome with negative
sequencing for ELANE, CXCR4, SBDS, and G6PC, sequence
changes were identified in 5 probands (approximately 35%) (Pasquet et al. 2013)
The sensitivity of DNA sequencing is over 99% for the
detection of nucleotide base changes, small deletions and insertions in the
Mutations in regulatory regions or other untranslated
regions are not detected by this test. Large deletions involving entire single
exons or multiple exons, large insertions and other complex genetic events have
been reported in many of these genes and will not be identified using this test
methodology. Rare primer site variants may lead to erroneous results.
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al. (2011). "The human syndrome of dendritic cell, monocyte, B and NK
lymphoid deficiency." J Exp Med 208(2): 227-234.
Dickinson, R. E., H. Griffin,
et al. (2011). "Exome sequencing identifies GATA-2 mutation as the cause
of dendritic cell, monocyte, B and NK lymphoid deficiency." Blood 118(10):
Hahn, C. N., C. E. Chong, et
al. (2011). "Heritable GATA2 mutations associated with familial
myelodysplastic syndrome and acute myeloid leukemia." Nat Genet 43(10):
Hsu, A. P., E. P. Sampaio, et
al. (2011). "Mutations in GATA2 are associated with the autosomal dominant
and sporadic monocytopenia and mycobacterial infection (MonoMAC)
syndrome." Blood 118(10): 2653-2655.
Mace, E. M., A. P. Hsu, et
al. (2013). "Mutations in GATA2 cause human NK cell deficiency with
specific loss of the CD56 (bright) subset." Blood 121(14): 2669-2677.
Mansour, S., F. Connell, et
al. (2010). "Emberger syndrome-primary lymphedema with myelodysplasia:
report of seven new cases." Am J Med Genet A 152A(9): 2287-2296.
Ostergaard, P., M. A.
Simpson, et al. (2011). "Mutations in GATA2 cause primary lymphedema
associated with a predisposition to acute myeloid leukemia (Emberger
syndrome)." Nat Genet 43(10): 929-931.
Pasquet, M., C.
Bellanne-Chantelot, et al. (2013). "High frequency of GATA2 mutations in
patients with mild chronic neutropenia evolving to MonoMac syndrome,
myelodysplasia, and acute myeloid leukemia." Blood 121(5): 822-829.
Spinner, M. A., L. A. Sanchez, et al. (2014).
"GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and
immunity." Blood 123(6): 809-821.