GATA6
protein-codingGATA binding protein 6, the group of GATA zinc finger domain containing
Gene summary
This gene is a member of a small family of zinc finger transcription factors that play an important role in the regulation of cellular differentiation and organogenesis during vertebrate development. This gene is expressed during early embryogenesis and localizes to endo- and mesodermally derived cells during later embryogenesis and thereby plays an important role in gut, lung, and heart development. Mutations in this gene are associated with several congenital defects. [provided by RefSeq, Mar 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~32.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018054
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010802
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008542
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0016581
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100540
Submitter: ClinGen
*GATA6* was first reported in relation to autosomal dominant *GATA6*- related congenital heart disease with or without pancreatic agenesis or diabetes in 2009 (Kodo et al. 2009, PMID: 19666519). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Atrial septal defect 9, Conotruncal heart malformations, Tetralogy of Fallot, Ventricular septal defect, Atrioventricular septal defect, Bicuspid aortic valve, Transposition of the great arteries, Persistent truncus arteriosus, Congenital heart disease with pancreatic agenesis, and Congenital heart disease with neonatal diabetes. At least ten unique variants (missense, nonsense, frameshift) that have been reported in ten probands in seven publications (PMIDs: 19666519, 23020118, 25937001, 28049534, 29653232, 31301121, 35595280) are included in this curation. Four of the ten variants were de novo occurrences. Variants in *GATA6* co-segregated in at least 4 members in a family with bicuspid aortic valve (PMID: 29653232). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by biochemical function study, functional alteration data, and protein interaction data (PMIDs: 10330176, 32442395, 36525927, 10330176). Experimental evidence also includes a mouse model with conditional deletion of *GATA6* that recapitulated the CHD phenotype (PMID: 16557299), a hIPSC cell culture model showing the importance of *GATA6* in development of the heart, endodermal lineages, pancreas, and diaphragm (PMID: 33054971), and rescue in a zebrafish *GATA6* knockout mutant line (PMID: 36525927). In summary, *GATA6* is definitively associated with autosomal dominant *GATA6*- related congenital heart disease with or without pancreatic agenesis or diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 11/21/2023 (SOP Version 9). Monogenic Diabetes Gene Curation Expert Panel Addendum: Haploinsufficiency due to heterozygous loss of function (LOF) variants in *GATA6* was reported as the most common cause of pancreatic agenesis in 2011 (PMID: 22158542), with 14/15 cases having congenital heart defects. Further studies of cohorts with pancreatic agenesis and/or neonatal diabetes (PMID: 22806356, 23223019) showed that congenital heart disease was highly penetrant, including in one parent of a neonatal diabetes case who did not have diabetes and had mosaic expression of the pathogenic variant. Two studies demonstrated that loss of both *GATA6* and *GATA4* expression results in failure of pancreas development in mice, whereas several studies in humans have shown that loss of either *GATA6* (see below) or *GATA4* alone (PMID: 20854389, 24696446, 38375489, 38408297, 39457190, 41006196) can cause pancreatic agenesis/hypoplasia, highlighting species-specific dependence on these important transcription factors. Since then, at least 20 other case reports or case series (PMID: 23635550, 23639568, 24310933, 24433315, 25356219, 25706805, 25708516, 27098067, 28049534, 31051468, 31271559, 32207556, 37204622, 37700164, 38105674, 38408297, 38574486, 39373086, 39596087, 40476119, 41006196) have reported a similar phenotype of neonatal diabetes due to pancreatic agenesis/hypoplasia, usually also with congenital heart disease, as well as some having additional digestive tract and/or renal anomalies. Several cases with *GATA6* variants have also been reported to have congenital heart disease but had developed diabetes well after the neonatal period, even well into adulthood (PMID: 28938416, 31700519, 32245430, 32524025). Both congenital heart disease and diabetes may have incomplete penetrance. One study reviewing genotype-phenotype correlations provided evidence that diabetes appears more prevalent in individuals with missense or LOF variants in the second zinc finger domain than the first zinc finger domain (PMID: 31301121). In summary, heterozygous loss of function *GATA6* variants are a cause of neonatal and occasionally later onset diabetes, usually involving pancreatic agenesis/hypoplasia in addition to congenital heart disease with or without other features. Testing of *GATA6* (and *GATA4*) should also be considered in an individual who develops diabetes at any age and is also known to have a congenital heart defect. Individuals with a heart defect who are found to have a pathogenic *GATA6* or *GATA4* variant should have ongoing monitoring for hyperglycemia and possible diabetes development. Pancreatic imaging and testing for exocrine pancreatic insufficiency could also be considered. This addendum was approved by the ClinGen Monogenic Diabetes GCEP on the meeting date 02/25/2026.
Inheritance Pattern: AD
Disease ID:MONDO:0013770
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0004955
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0010802
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0010802
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016391
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013769
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010802
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013770
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0010802
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100540
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013769
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: ClinGen
GATA binding protein 6 (GATA6) was evaluated for autosomal dominant dilated cardiomyopathy (DCM). GATA6 is a member of the GATA family of zinc finger transcription factors. Its role is to direct tissue-specific gene expression during formation of the mammalian heart where it is highly expressed (Huggon IC et al. 1997; PMID: 9294001). To date, defects in GATA6 have been associated with various types of congenital heart disease (Kodo K et al. 2009; PMID: 19666519) and atrial fibrillation (Yang YQ et al. 2012; PMID: 22257684). In a study by Xu L et al. 2014 (PMID: 25119427), two missense GATA6 variants (c.1340G>A; p.C447Y and c.1424A>G; p.H475R) were reported in two DCM pedigrees from China. Dual-luciferase reporter assays in HEK-293 cells showed significantly reduced transcriptional activation by GATA6 proteins with the p.C447Y and p.H475R variants (Xu L et al. 2014; PMID: 25119427). However, due to concerns related to suspect data from the authors, a decision was made by the expert DCM curation panel not to score evidence in this publication. Another study screened a family with DCM by WES and Sanger sequencing and reported a novel GATA6 missense variant (c.985C>T, p.H329Y) in four affected individuals (Khazamipour A et al. 2022; PMID: 35962153). The authors performed in silico molecular dynamics simulation of the wild-type GATA6 structure and the H329Y variant which indicated that the H329Y variant could affect the protein structure (Khazamipour A et al. 2022; PMID: 35962153). There are no other genetic or functional studies implicating GATA6 with DCM. In summary, this gene-disease relationship has a Limited evidence clinical validity classification for AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 12/13/2024 (SOP Version 10).
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic
Intervention: Cardiovascular; Gastrointestinal
Rationale: In Heart defects, congenital, and other congenital anomalies, the condition may include pancreatic a/hypogenesis, and individuals may manifest neonatally with severe sequelae of endocrine and exocrine pancreatic insufficiency, and prompt detection can allow potentially beneficial management (eg, with insulin treatment and replacement of exocrine pancreatic enzymes); In conditions that involve congenital heart anomalies, individuals may present with frank, obvious congenital cardiac malformations that require intervention, and more subtle presentations in individuals with variants in this gene have also been described, including valvular anomalies, and surveillance (eg, with electrocardiogram and echocardiogram) may allow early detection and treatment of manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GATA6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005257.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 206 | 2 | 211 | ||
| missense | 6 | 6 | 414 | 21 | 1 | 448 |
| nonsense | 14 | 7 | 1 | 22 | ||
| start loss | 1 | 1 | ||||
| frameshift | 17 | 9 | 4 | 30 | ||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 2 | 9 | ||
| Total | 38 | 28 | 425 | 227 | 3 | 721 |
Highest pathogenic variant AF is 0.0000069400394
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005248.2 | 6 | MANE Select | |
| Ensembl | ENSP00000269216.3 | 6 | MANE Select | |
| Ensembl | ENSP00000462313.1 | 6 | Standard | |
| Ensembl | ENSP00000462313.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gata6 | Danio rerio | Structure: heart tube Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Heart Development
- Endoderm Differentiation
- Mesodermal Commitment Pathway
- Ectoderm Differentiation
- POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation
Biological Process
- negative regulation of transcription by RNA polymerase II
- in utero embryonic development
- liver development
- outflow tract septum morphogenesis
- type B pancreatic cell differentiation
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II repressing transcription factor binding
- chromatin binding
- DNA-binding transcription factor activity
Cellular Component
- nucleus
- nucleoplasm
- transcription factor complex
- nuclear membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000269216
- Coding exons
- 6
- Length
- 33088
- Individuals with no LoFs
- 116244
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 116245
- p
- 0.00000430
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.28 | 222 | 283 | 0.785 | 0.0000147 | 3705 |
| Missense (PolyPhen) | 57 | 98.178 | 0.58058 | 1220 | ||
| Synonymous | -0.171 | 134 | 132 | 1.02 | 0.00000764 | 1320 |
| Loss of Function | 3.84 | 0 | 17.2 | 0.00 | 8.35e-7 | 214 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000094 | 0.0000094 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcriptional activator (PubMed:19666519, PubMed:27756709, PubMed:22750565, PubMed:22824924). Regulates SEMA3C and PLXNA2 (PubMed:19666519). Involved in gene regulation specifically in the gastric epithelium (PubMed:9315713). May regulate genes that protect epithelial cells from bacterial infection (PubMed:16968778). Involved in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression (By similarity). Binds to BMP response element (BMPRE) DNA sequences within cardiac activating regions (By similarity). {ECO:0000250|UniProtKB:Q61169, ECO:0000269|PubMed:16968778, ECO:0000269|PubMed:19666519, ECO:0000269|PubMed:22750565, ECO:0000269|PubMed:22824924, ECO:0000269|PubMed:27756709, ECO:0000269|PubMed:9315713}.;
- Disease
- DISEASE: Note=Rare variants in GATA6 may be a cause of susceptibility to atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. {ECO:0000269|PubMed:22750565, ECO:0000269|PubMed:22824924, ECO:0000269|PubMed:27756709}.; DISEASE: Conotruncal heart malformations (CTHM) [MIM:217095]: A group of congenital heart defects involving the outflow tracts. Examples include truncus arteriosus communis, double-outlet right ventricle and transposition of great arteries. Truncus arteriosus communis is characterized by a single outflow tract instead of a separate aorta and pulmonary artery. In transposition of the great arteries, the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. In double outlet of the right ventricle, both the pulmonary artery and aorta arise from the right ventricle. {ECO:0000269|PubMed:19666519}. Note=The disease is caused by mutations affecting the gene represented in this entry. GATA6 mutations have been found in patients with non- syndromic persistent truncus arteriosus (PubMed:19666519). {ECO:0000269|PubMed:19666519}.; DISEASE: Atrial septal defect 9 (ASD9) [MIM:614475]: A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. Some patients manifest tricuspid valve disease, pulmonary valve disease, and pulmonary artery hypertension. {ECO:0000269|PubMed:20631719}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tetralogy of Fallot (TOF) [MIM:187500]: A congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. In this condition, blood from both ventricles (oxygen-rich and oxygen-poor) is pumped into the body often causing cyanosis. {ECO:0000269|PubMed:20581743, ECO:0000269|PubMed:20631719}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrioventricular septal defect 5 (AVSD5) [MIM:614474]: A congenital heart malformation characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. The complete form involves underdevelopment of the lower part of the atrial septum and the upper part of the ventricular septum; the valve itself is also shared. A less severe form, known as ostium primum atrial septal defect, is characterized by separate atrioventricular valvar orifices despite a common junction. {ECO:0000269|PubMed:20581743}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pancreatic agenesis and congenital heart defects (PACHD) [MIM:600001]: An autosomal dominant disease characterized by pancreatic severe hypoplasia or agenesis, diabetes mellitus, and congenital heart abnormalities including ventricular septal defect, patent ductus arteriosus, pulmonary artery stenosis, truncus arteriosus and tetralogy of Fallot. {ECO:0000269|PubMed:22158542}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.409
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.947
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |