GATA4

Chr 8AD

GATA binding protein 4

Also known as: ASD2, TACHD, TOF, VSD1

NCBI Gene: 2626 ENSG00000136574 UniProt: P43694

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]

Primary Disease Associations & Inheritance

?Testicular anomalies with or without congenital heart diseaseMIM #615542

Atrial septal defect 2MIM #607941

Atrioventricular septal defect 4MIM #614430

Tetralogy of FallotMIM #187500

Ventricular septal defect 1MIM #614429

Active trials

Pathogenic / LP

ClinVar variants

175

Pubs (1 yr)

0.7

Missense Z

0.53

LOEUF

Clinical Summary— GATA4

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Gene-Disease Validity (ClinGen)

structural congenital heart disease, multiple types - GATA4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

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

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Clinical Trials

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

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 OE0.20 (0.09–0.53)

0≤0.351.4

Missense OE0.87 (0.77–0.98)

0≤0.61.4

Synonymous OE1.31

0≤1.21.6

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

LOFDNGOF

Badonyi & Marsh 2024 ↗

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

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.PMID:25501827

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 PMID:7665171

LOFGATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5PMID:12845333

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.