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Isolated Nonsyndromic Congenital Heart Defects via the NKX2-5 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
NKX2-5 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9115NKX2-581479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Fang Xu, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Congenital heart defects (CHDs) are the most common birth defect, occurring in 6-10 of every 1000 live births and are a major cause of infant morbidity and mortality (Hoffman et al. 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 in 1000 live births (Wessels et al. Clin Genet 78:103-123, 2010). Roughly 10% of patients with CHDs have conotruncal heart defects, which include tetralogy of Fallot (TOF), double outlet right ventricle (DORV), truncus arteriosus (TA), interrupted aortic arch (IAA), and transposition of the great arteries (TGA) (Oyen et al. Circulation 120:295-301, 2009).


CHDs have genetic and non-genetic causes. The majority of patients with CHDs are thought to have a complex, multifactorial etiology. CHDs are caused by single gene or chromosomal abnormalities, exposure to teratogens, and other unknown mechanisms. Non-cardiac malformations are found in roughly 20% of patients with CHDs 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 variants in regulators of heart development (reviewed by Bruneau Nature 451:943-948, 2008). Autosomal dominant nonsyndromic CHDs can occur due to variants in the homeobox transcription factor NKX2-5 (OMIM 600584). Causative variants in NKX2-5 have been reported in patients with CHDs such as septal defects, AV conduction defects, conotrunctal defects, pulmonary stenosis and hypoplastic left heart (McElhinney et al. J Am Coll Cardiol 42:1650-1655, 2003; Stallmeyer et al. Clin Genet 78:533-540, 2010). The majority of documented causative variants in NKX2-5 are missense variants; however, nonsense, small insertions, and small deletions have also been reported. In addition to CHDs, missense variants in NKX2-5 have also been found in patients with congenital nongoitrous hypothyroidism (Dentice et al. J Clin Endocr Metab 91:1428-1433, 2006).

Clinical Sensitivity - Sequencing with CNV PGxome

Variants in the NKX2-5 gene have been reported in up to 4% of sporadic cases of CHDs (Goldmuntz et al. Circulation 104:2565-2568, 2001; McElhinney et al. J Am Coll Cardiol 42:1650-1655, 2003). One study found 7 variants in 26 probands with AV block and cardiac septal defects with and without conotruncal defects (Benson et al. J Clin Invest 104:1567-1573, 1999).

Testing Strategy

This test provides full coverage of all coding exons of the NKX2-5 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Patients with non-syndromic CHD, including cardiac septal defects (ASD, VSD, AVSD), conotruncal defects (TOF, DORV, IAA, TGA), AV conduction defects, and pulmonary valve stenosis are candidates for this test.


Official Gene Symbol OMIM ID
NKX2-5 600584
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


  • Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD. (1999) Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J Clin Invest 104(11):1567-73. PubMed ID: 10587520
  • Bruneau. (2008) The developmental genetics of congenital heart disease. Nature 451(7181):943-948. PubMed ID: 18288184
  • Dentice M, Cordeddu V, Rosica A, Ferrara AM, Santarpia L, Salvatore D, Chiovato L, Perri A, Moschini L, Fazzini C, Olivieri A, Costa P, Stoppioni V, Baserga M, De Felice M, Sorcini M, Fenzi G, Di Lauro R, Tartaglia M, Macchia PE. (2006) Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocr Metab 91(4):1428-1433. PubMed ID: 16418214
  • 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
  • Goldmuntz E, Geiger E, Benson DW. (2001) NKX2.5 mutations in patients with tetralogy of fallot. Circulation 104(21):2565-8. PubMed ID: 11714651
  • Hoffman JI, Kaplan S. (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890-900. PubMed ID: 12084585
  • McElhinney DB, Geiger E, Blinder J, Benson DW, Goldmuntz E. (2003) NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 42(9):1650-1655. PubMed ID: 14607454
  • Stallmeyer B, Fenge H, Nowak-Göttl U, Schulze-Bahr E. (2010) Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease. Clin Genet 78(6):533-540. PubMed ID: 20456451
  • Wessels MW, Willems PJ. (2010) Genetic factors in non-syndromic congenital heart malformations. Clin Genet 78(2):103-23. PubMed ID: 20497191
  • Řyen 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


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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