ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.