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Sick Sinus Syndrome and Brugada Syndrome via the HCN4 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
HCN4 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11369HCN481479 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


  • Chun-An Chen, PhD

Clinical Features and Genetics

Clinical Features

Sick sinus syndrome (SSS), also known as atrial fibrillation with bradyarrhythmia, or familial sinus bradycardia, is a class of arrhythmias caused by sinoatrial node dysfunction. Electrocardiography (ECG) may reveal sinus bradycardia, sinus arrest, sinoatrial block, bradycardia-tachycardia syndrome or polymorphic ventricular tachycardia. Clinical symptoms may include bradycardia, palpitations, fatigue, dizziness, presyncope and syncope. Symptomatic patients may require implantation of an artificial pacemaker. Brugada syndrome is a tachyarrhythmia characterized by ST segment elevation in leads V1-V3 on an ECG. Other findings may include right bundle branch block, first degree AV block, SSS, and intraventricular conduction delay. Implantable cardiac defibrillator may be appropriate for patients with a history of syncope or cardiac arrest.


Dysfunction of sinus node automaticity is most common in the elderly with acquired ischemic heart disease, cardiomyopathy, or congestive heart failure and in children after corrective surgery for congenital heart defects. Sinus node dysfunction can also occur due to variants in cardiac ion channels (reviewed by Park et al. Circulation 123:904-915, 2011). Idiopathic, autosomal dominant sick sinus syndrome 2 is caused by variants in the HCN4 gene. HCN4 encodes for the hyperpolarization activated cyclic nucleotide-gated potassium channel 4, which is a voltage-gated ion channel that mediates the pacemaker (If) current in the heart. To date, eight causative variants in HCN4 have been found in patients with sinus node dysfunction (Shulze-Bahr et al. J Clin Invest 111:1537-1545, 2003; Ueda et al. J Biol Chem 279:27194-27198, 2004; Milanesi et al. N Engl J Med 354-151-157, 2006; Nof et al. Circulation 116:463-470, 2007). A possible founder variant, defined as c.1485C>T (p.Ala485Val), was found in three patients with symptomatic sinus bradycardia from Moroccan Jewish decent (Laish-Farkash et al. J Cardiovasc Electrophysiol 21:1365-1372, 2010). In addition to SSS, variants in HCN4 have also been shown to cause Brugada syndrome 8 (Ueda et al. J Hum Genet 54:115-121, 2009). Autosomal recessive sick sinus syndrome can be caused by variants in SCN5A (Benson et al. J Clin Invest 112:1019-1028, 2003).

Clinical Sensitivity - Sequencing with CNV PGxome

Variants in HCN4 have been found in 2-10% of patients with sinus node dysfunction (Schulze-Bahr et al. J Clin Invest 111:1537-1545, 2003; Milanesi et al. N Engl J Med 354-151-157, 2006). Ueda et al. evaluated 33 patients with Brugada syndrome and found one variant predicted to affect splicing in HCN4 (Ueda et al. J Hum Genet 54:115-121, 2009).

Testing Strategy

This test provides full coverage of all coding exons of the HCN4 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 autosomal dominant SSS2 are candidates for this test. Patients with symptoms suggestive of Brugada syndrome and without variants in the genes more frequently mutated in Brugada syndrome are also candidates for this test.


Official Gene Symbol OMIM ID
HCN4 605206
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


  • Benson, D. W., et.al. (2003). "Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)." J Clin Invest 112(7): 1019-28. PubMed ID: 14523039
  • Laish-Farkash A, Glikson M, Brass D, Marek-Yagel D, Pras E, Dascal N, Antzelevitch C, Nof E, Reznik H, Eldar M, Luria D. (2010). "A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews." J Cardiovasc Electrophysiol 21(12):1365-72. PubMed ID: 20662977
  • Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. (2006). "Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel." N Engl J Med 354(2):151-7. PubMed ID: 16407510
  • Nof E, Luria D, Brass D, Marek D, Lahat H, Reznik-Wolf H, Pras E, Dascal N, Eldar M, Glikson M. (2007). "Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia." Circulation 116(5):463-70. PubMed ID: 17646576
  • Park DS, Fishman GI. (2011). "The cardiac conduction system." Circulation 123(8):904-15. PubMed ID: 21357845
  • Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O, Isbrandt D. (2003). "Pacemaker channel dysfunction in a patient with sinus node disease." J Clin Invest 111(10):1537-45. PubMed ID: 12750403
  • Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A. (2009). "Role of HCN4 channel in preventing ventricular arrhythmia." J Hum Genet 54(2):115-21. PubMed ID: 19165230
  • Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesato Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A. (2004). "Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia." J Biol Chem 279(26):27194-8. PubMed ID: 15123648


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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