ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000008.10) (NC_000008.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
12845333 Loss of function frameshift mutation in GATA4 described in a multi-generation family: mutation segregated with disease.
15863664 Searched for mutations in GATA4 in diseased heart tissues of 68 patients with complex heart malformations, encompassing atrial (ASD), ventricular (VSD), and atrioventricular septal defects (AVSD) - found a nonsense mutation and a frameshift mutation.
24000169 Yang et al. (2013) describe three novel missense variants identified in individuals with Tetralogy of Fallot. The authors report results of functional studies indicating that these variants were loss of function: "the GATA4 mutants were consistently associated with diminished DNA-binding affinity and decreased transcriptional activity...furthermore, the N285S mutation completely disrupted the physical interaction between GATA4 and TBX5."

Haploinsufficiency phenotype comments:

Intragenic exonic deletions of GATA4 have not been described. Only large deletions (for example, PMID:10096597) , missense mutations, and frameshift mutations have been reported. GATA4 haploinsufficiency may show variable expressivity with a wide spectrum of clinical findings, including CHD.

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

Triplosensitivity phenotype comment:

This review pertains to evidence linking focal duplication of GATA4 to clinical phenotypes; currently this evidence is scored as a 0. Note that GATA4 resides within the recurrent 8p23.1 duplication region and is a candidate gene for congenital heart defects in the disorder. Please see the linked region for further evidence relating to the 8p23.1 recurrent deletion/duplication region. Joziasse et al. 2009 report a male individual with mild developmental delay, bilateral inguinal hernias, unilateral club foot, unilateral cryptorchidism, and a congenital heart defect who was found to have a 133 kb duplication of 8p23.1 involving only GATA4. This duplication was inherited from his reportedly normal mother, and was also identified in several other reportedly normal maternal relatives. Of note, the proband was also found to have "1-3 distinct, supernumerary small ring chromosomes" that were not identified in his mother and consisted of "pericentromic material of chromosomes 11, 12, and X." Barber et al, (2015) PMID 26097203 reported 8 atypical microduplications within the recurrent 8p23.1 duplication region. The authors noted no CHD in the 6/8 microduplications that did not include GATA4 and non-syndromic CHD in 1 of the 2 microduplications that did include GATA4, suggesting this as a causal gene in the region for CHD. However, due to the presence of other genes in these duplications, and the variability of phenotypes, there is insufficient evidence to conclude triplosensitivity for GATA4.