GATA4

Chr 8AD

GATA binding protein 4

Also known as: ASD2, TACHD, TOF, VSD1

NCBI Gene: 2626 ENSG00000136574 UniProt: P43694 OMIM: 600576

This transcription factor binds to GATA DNA motifs and activates cardiac-specific gene expression during heart development, while also being required for normal testicular development. Mutations cause autosomal dominant congenital heart defects including atrial septal defects, ventricular septal defects, tetralogy of Fallot, and atrioventricular septal defects, with some patients also having testicular anomalies. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.53), and cardiac defects are typically present from birth.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the GATA family of zinc-finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function, and is necessary for normal testicular development. Mutations in this gene have been associated with cardiac septal defects. Additionally, alterations in gene expression have been associated with several cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.535 OMIM phenotypes

Clinical Summary— GATA4

🧬

Gene-Disease Validity (ClinGen)

structural congenital heart disease, multiple types - GATA4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.493

Z-score 2.83

OE 0.20 (0.09–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.67Z-score

OE missense 0.87 (0.77–0.98)

186 obs / 213.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.09–0.53)

0≤0.351.4

Missense OE?0.87 (0.77–0.98)

0≤0.61.4

Synonymous OE?1.31

0≤1.21.6

LoF obs/exp: 3 / 14.7Missense obs/exp: 186 / 213.6Syn Z: -2.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGATA4-related atrial septal defectLOFAD

This gene — mechanism propensity

0.5378th %ile

GOF

0.2597th %ile

LOF

0.83top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNCaspase-1 mediated cleavage of GATA4 generates a truncated protein that retains the ability to bind DNA but lacks transcriptional activation domains and acts as a dominant negative regulator of GATA4.1

GOFThis mapping assignment places the Gata4 gene in the vicinity of the mouse Ds (disorganization) locus, a dominant gain-of-function mutation affecting embryonic development. We speculate that Ds is caused by a mutation in the Gata4 gene, ectopic expression of GATA-4, or a mutation in another lineage 2

LOFGATA4 mutations cause human congenital heart defects and reveal an interaction with TBX53

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References