Isolated Nonsyndromic Congenital Heart Defects via the GATA4 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
943 GATA4$650.00 81479 Add to Order
Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Mutations in the GATA4 gene have been reported in 1-2% of patients with sporadic cases of ASD, VSD, AVSD and in less than 1% of patients with conotruncal defects (Tomita-Mitchell et al. J Med Genet 44:779-783, 2007; Zhang et al. Eur J Med Genet 51:527-535, 2008; Moskowitz et al. PNAS 108:4006-4011, 2011).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 GATA4$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Features
Congenital heart defects (CHDs) are the most common birth defect, occurring in 6 to 10:1,000 live births and are a major cause of infant morbidity and mortality (Hoffman and Kaplan J Am Coll Cardiol 39:1890-1900, 2002; Oyen et al. Circulation 120:295-301, 2009). Congenital heart diseases arise due to defects in cardiac morphogenesis during embryonic development, which leads to structural malformations in the heart and great vessels. Cardiac septal defects, which include atrial septal defects (ASD), ventricular septal defects (VSD), and atrioventricular septal defects (AVSD), are common, with an estimated incidence of 5:1,000 live births (Wessels et al. Clin Genet 78:103-123, 2010).
CHDs have genetic and non-genetic causes. The majority of patients with CHDs are thought to have a complex, multifactorial etiology. CHDs can be caused by single gene or chromosomal abnormalities, exposure to teratogens, and other unknown mechanisms. Non-cardiac malformations are found in roughly one-fifth of patients with CHD, and chromosomal abnormalities account for ~7% of patients with CHDs (Eskedal et al. Cardiol Young 14:600-607, 2004; Oyen et al. Circulation 120:295-301, 2009). Monogenic non-syndromic CHDs are caused by mutations in regulators of heart development (reviewed by Bruneau Nature 451:943-948, 2008). Atrial septal defect 2 (ASD2; OMIM 607941) is inherited as an autosomal dominant trait caused by mutations in the zinc finger DNA binding protein GATA4. Mutations in GATA4 have been reported in familial and sporadic cases of cardiac septal defects (ASD, VSD, and AVSD) with and without conotruncal defects, such as tetralogy of Fallot (TOF) (Garg et al. Nature 424:443-447, 2003; Nemer et al. Hum Mutat 27:293-294, 2006; Tomita-Mitchell et al. J Med Genet 44:779-783, 2007; Moskowitz et al. PNAS 108:4006-4011, 2011). The majority of documented causative variants in GATA4 are missense mutations; however, nonsense, small insertions, and small deletions have also been reported. In addition to congenital heart diseases, missense mutations in GATA4 have also been found in patients with lone atrial fibrillation (Posch et al. Eur J Med Genet 53:201-203, 2010) and in 46XY disorders of sexual development (Lourenco et al. PNAS 108:1597-1602, 2011).
Testing Strategy
This test involves bidirectional DNA sequencing of all 6 coding exons of the GATA4 gene plus ~10 bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test #100) in family members of patients with known mutations or to confirm research results.
Indications for Test
Patients with non-syndromic CHDs, including cardiac septal defects (ASD, VSD, AVSD) and/or TOF, are candidates for this test.


Official Gene Symbol OMIM ID
GATA4 600576
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Genetic Counselors
  • Øyen N, Poulsen G, Boyd HA, Wohlfahrt J, Jensen PK, Melbye M. (2007) Recurrence of congenital heart defects in families. Circulation 120(4):295-301. PubMed ID: 19597048
  • Øyen N, Poulsen G, Boyd HA, Wohlfahrt J, Jensen PK, Melbye M. (2009) Recurrence of congenital heart defects in families. Circulation 120(4):295-301. PubMed ID: 19597048
  • Bruneau. (2008) The developmental genetics of congenital heart disease. Nature 451(7181):943-948. PubMed ID: 18288184
  • Eskedal L, Hagemo P, Eskild A, Aamodt G, Seiler KS, Thaulow E. (2004) A population-based study of extra-cardiac anomalies in children with congenital cardiac malformations. Cardiol Young 14(6):600-607. PubMed ID: 15679995
  • Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D. (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424(6947):443-447. PubMed ID: 12845333
  • Hoffman JI, Kaplan S. (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890-900. PubMed ID: 12084585
  • Lourenço D, Brauner R, Rybczynska M, Nihoul-Fékété C, McElreavey K, Bashamboo A. (2011) Loss-of-function mutation in GATA4 causes anomalies of human testicular development. PNAS 108(4):1597-1602. PubMed ID: 21220346
  • Moskowitz IP, Wang J, Peterson MA, Pu WT, Mackinnon AC, Oxburgh L, Chu GC, Sarkar M, Berul C, Smoot L, Robertson EJ, Schwartz R, Seidman JG, Seidman CE. (2011) Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development.  PNAS 108(10):4006-4011. PubMed ID: 21330551
  • Nemer G, Fadlalah F, Usta J, Nemer M, Dbaibo G, Obeid M, Bitar F. (2006) A novel mutation in the GATA4 gene in patients with Tetralogy of Fallot. Hum Mutat 27(3):293-294. PubMed ID: 16470721
  • Posch MG, Boldt LH, Polotzki M, Richter S, Rolf S, Perrot A, Dietz R, Ozcelik C, Haverkamp W. (2010) Mutations in the cardiac transcription factor GATA4 in patients with lone atrial fibrillation. Eur J Med Genet 53(4):201-203. PubMed ID: 20363377
  • Tomita-Mitchell A, Maslen CL, Morris CD, Garg V, Goldmuntz E. (2007) GATA4 sequence variants in patients with congenital heart disease. J Med Genet 44(12):779-783. PubMed ID: 18055909
  • Wessels MW, Willems PJ. (2010) Genetic factors in non-syndromic congenital heart malformations. Clin Genet 78(2):103-23. PubMed ID: 20497191
  • Zhang W, Li X, Shen A, Jiao W, Guan X, Li Z. (2008) GATA4 mutations in 486 Chinese patients with congenital heart disease. Eur J Med Genet 51(6):527-535. PubMed ID: 18672102
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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