This document addresses genetic testing of cardiac ion channel mutations in persons with suspected channelopathies, such as long QT syndrome (LQTS), in order to determine the risk for sudden cardiac death (SCD).  Congenital LQTS is an inherited disorder characterized by the lengthening of the repolarization phase of the ventricular action potential (an abnormally long QT interval seen on electrocardiographic [EKG] tracings).  This increases the risk for arrhythmic events, such as torsades de pointes, and may result in syncope (fainting episodes) and SCD.  It is estimated that more than half of the 8,000 sudden unexpected deaths in children per year may be related to LQTS, many of which occur during strenuous physical exertion or emotional excitement, (e.g., adolescents while participating in sports activities).  Diagnostic criteria for LQTS have been established which focus on EKG findings, as well as clinical and family history.

Voltage-gated sodium channels are transmembranous proteins that play an important role in the initiation, propagation and maintenance of normal cardiac rhythm.  In recent years, inherited mutations in the sodium channel genes have emerged as a genetic basis for LQTS with seven variants identified, each corresponding to mutations in different genes.  The FAMILION^® Test (Transgenomic^® Inc., New Haven, CT formerly manufactured by PGx Health^™ a division of Clinical Data^® Inc.) is a genetic test designed to identify mutations in inherited cardiac channelopathies, such as LQTS.  It is proposed for use in determining the diagnosis of, and for counseling of individuals with, LQTS.  The test involves examination of the DNA taken from a blood sample for identification of mutations in five cardiac ion channel genes that have been associated with cardiac channel disorders (channelopathies), such as LQTS. 

Medically Necessary: 

Genetic testing for LQTS is considered medically necessary in a potentially at-risk individual, to rule out significant increased risk of LQTS and sudden death, when ALL of the following are present:

• Individual to be tested has a first-degree relative (proband) with a clinical diagnosis of LQTS;  AND
• That proband has sustained ONE of the following:
  • Sudden death, OR
  • Unexplained syncopal episode, OR
  • Ventricular fibrillation with successful resuscitation;
    AND

• A mutation confirmatory for LQTS has been identified in the proband that will be specifically tested for in this potentially at-risk individual;  AND
• The individual will also undergo genetic counseling.

Investigational and Not Medically Necessary:

Genetic testing for cardiac ion channel mutations is considered investigational and not medically necessary for all other indications not meeting the criteria above.

The LQTS is a familial disease characterized by an abnormally prolonged QT interval, seen on EKG, and also by stress-mediated life-threatening ventricular arrhythmias (Priori, 2001).  Congenital LQTS usually manifests before the age of 40 and may be suspected when there is a history of seizure, syncope, or sudden death in a child or young adult.  A history of these occurrences in a first-degree relative may prompt diagnostic scrutiny of other family members.  While current diagnostic criteria for LQTS focus on typical ST-T wave patterns on EKG findings, in correlation with the individual's clinical and family history, recently testing for the presence of genetic variants in specific genes has been associated with a predisposition to LQTS.   

The FAMILION^® test is a genetic test that analyzes a blood sample for the specific cardiac ion mutations currently associated with cardiac channelopathies, such as LQTS and Brugada syndrome.  According to the manufacturer, this test can confirm the presence or absence of genetic mutations in five specific cardiac ion channel genes.  This information is potentially helpful in risk stratification for SCD in carriers of LQTS and in treatment planning for the individual and other family members.  However, the study evidence currently available has indicated the propensity for differing mutations all along the length of these large cardiac ion channel genes, making the clinical significance of each of these discrete mutations difficult to determine with current study evidence.  Another factor confounding interpretation of this genetic analysis is the penetrance of a given mutation or the presence of multiple phenotypic expressions.  This explains why many carriers of genetic mutations never exhibit actual symptoms of the disease process, themselves.

The European Society of Cardiology Task Force on Sudden Cardiac Death published a guidance document in 2001 (Priori, et al) which refers to genetic defects on one specific cardiac sodium channel gene (LQT3), as being associated with higher risk for SCD in LQTS.  However, this document focuses more on primary and secondary prevention strategies for SCD with established treatment modalities, (e.g., anti-arrhythmic agents, implantable cardioverter-defibrillator [ICD]).   The Task Force acknowledged that much work is needed in larger population groups with less known or apparent heart disease (than those reviewed for this paper), in order to achieve effective identification and risk stratification of at-risk population groups for the ultimate goal of substantial reductions in the rates of SCD in the general population (Priori, 2001).

In one study of asymptomatic family members with a relative with known LQTS and a known genotype, although the genotypes of 580 subjects were studied, along with the history of syncope, arrest or SCD, several subjects considered to be at low risk (based on these findings) still died suddenly.  The authors concluded that, based on their findings regarding risk stratification, it is uncertain whether information obtained from LQTS genetic subtypes can be used to defer prophylactic treatment in any at-risk groups (Vincent, 2003). 

According to the American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities, "The clinical manifestations of a long-QT mutation may be influenced by the specific gene involved and the functional consequences of the mutation in that gene. Risk stratification for LQTS continues to evolve, with data from genetic analysis becoming increasingly useful for clinical decision making" (Epstein, 2008). 

In 2011, a Heart Failure Society of America/European Heart Rhythm Association (HRS/EHRA) Consensus Statement on the State of Genetic Testing for Channelopathies and Cardiomyopathies was issued which included the following guidance:

• A Class I recommendation ("is recommended") was applied for genetic testing in index cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a genetic test is high (likelihood of positive result > 40% and signal/noise ratio > 10 AND/OR when the genetic test result provides either diagnostic or prognostic information, or when the genetic test result influences therapeutic choices;
• Screening of family members for the mutation identified in the proband of the family is recommended as a Class I when genetic testing leads to the adoption of therapy/protective measures/lifestyle adaptations;
• Conversely, the authors have assigned a Class IIa recommendation when results of genetic testing are not associated with the use of therapeutic or protective measures but the results may be useful for reproductive counseling or instances in which genetic testing is requested by the patient who wants to know his/her mutation status.

Regarding the strength of the evidence currently available for genetic testing, this HRS/EHRA Consensus Statement provided the following additional information: 

Documents produced by other scientific societies have acknowledged the need to define the criteria used to rank the strength of recommendation for genetic diseases.  The most obvious difference is that randomized and/or blinded studies do not exist. Instead, most of the available data are derived from registries that have followed patients and recorded outcome information…Contrary to common misperception, genetic tests are probabilistic tests, not deterministic tests. Many positive test results contain the index case's and his/her family's definitive disease-causing mutation, the proverbial pathogenic "smoking gun."  However, many so-called "positive" test results are represented by less informative DNA variants currently annotated with the expression, "Variants of Uncertain Significance" (VUS).  Only recently is the frequency of rare VUS among otherwise healthy volunteers across the exomes of various disease-causing genes being identified…Regardless of the disease in question or the specific genetic test pursued, treatment decisions should not rely solely on the patient's genetic test result but should be based on results from his/her comprehensive clinical evaluation. 

Ackerman (HRS/EHRA Consensus Statement) also noted, "When using or considering the guidance from this document, it is important to remember that there are no absolutes governing many clinical situations. The final judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all relevant circumstances" (Ackerman, 2011).

The medical necessity criteria in this document have been formulated based on the evidence currently available demonstrating clinical benefit to testing for a select population group.  Further studies are expected to further elucidate the impact of this genetic testing technology on risk stratification, preventative treatment management, and clinical outcomes.

The FAMILION^® test is currently performed exclusively at designated laboratory facilities provided by Transgenomics, Inc. (New Haven, CT) which purchased all rights to the genetic testing products under the FAMILION brand of PGx Health™ in December, 2010.  According to information available online at the manufacturer's web site, "FDA approval is not currently required for clinical use of this test.  This test meets the requirements for high complexity tests under the Clinical Laboratory Improvement Amendments Act (CLIA) and its implementing regulations. The test may use some reagents produced for research purposes only."  The test can be performed in three different configurations:

• Comprehensive Cardiac Ion Channel Analysis:  provides analysis for variants in five cardiac ion genes and is considered appropriate (by the manufacturer's information) when there is a high index of suspicion of disease, such as stress-induced syncope, prolonged QT interval, family history of SCD and/or unexplained ventricular rhythms;
• Sodium Channel Analysis:  provides analysis for variants only for the SCN5A gene and is appropriate (according to the manufacturer) in cases of suspected Brugada syndrome;
• Family Specific Analysis:  provides analysis of one or more mutations found in an index case using either one of the above test configurations or confirmed results from another laboratory and is appropriate (according to the manufacturer) for testing blood relatives.

Brugada Syndrome (also known as Sudden Unexpected Death Syndrome [SUDS]):  A genetic cardiac disease manifested by abnormal EKG findings and an increased risk of sudden cardiac death.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT):  An inherited cardiac channelopathy characterized by irregular heart rhythms brought on by physical exertion or intense emotion. CPVT may cause syncope (fainting), cardiac arrest, or sudden cardiac death in affected individuals.

Ion Channel:  This term refers to pore-forming proteins that help to establish and control the small voltage gradient that exists across the plasma membranes of all living cells by allowing the flow of ions down their electrochemical gradient.  These channels play an integral role in the repolarization during the heartbeat cycle and thus, enable the regular contractions of the healthy pumping heart.

Long QT Syndrome (also referred to as a cardiac channelopathy):  An inherited congenital cardiac disorder which is characterized as an "ion channel disease."  This refers to abnormalities in the sodium and potassium channels that control the excitability of the cardiac cells (myocytes), which can lead to episodes of syncope (dizziness/fainting) and sudden cardiac death in affected individuals.

Sudden Cardiac Death (also called sudden death [SCD]):  Death resulting from an abrupt loss of heart function (cardiac arrest).

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage or these services as it applies to an individual member.

When Services may be Medically Necessary when criteria are met:

When Services may also be Medically Necessary when criteria are met:

When Services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Albert CM, MacRae CA, Chasman DI, et al.  Common variants in cardiac ion channel genes are associated with sudden cardiac death.  Circ Arrhythm Electrophysiol. 2010; 3(3):222-229.
2. Crotti L, Monti MC, Insolia R, et al. NOS1AP is a genetic modifier of the long-QT syndrome. Circulation. 2009; 120(17):1657-1663.
3. Hoffman N, Wilde AA, Kaab S, et al. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? Eur Heart J. 2007; 28(5):575-580.
4. Imboden M, Swan H, Denjoy I, et al. Female predominance and transmission distortion in the long-QT syndrome. N Engl J Med. 2006; 355(26):2744-2751.
5. Jons C, Moss AJ, Lopes CM, et al. Mutations in conserved amino acids in the KCNQ1 channel and risk of cardiac events in type-1 long-QT syndrome. J Cardiovasc Electrophysiol. 2009; 20(8):859-865.
6. Kapa S, Tester DJ, Salisbury BA, et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009; 120(18):1752-1760.
7. Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation. 2001; 104(5):557-562.
8. Migdalovich D, Moss AJ, Lopes CM, et al.  Mutation and gender-specific risk in type 2 long QT syndrome: Implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome.  Heart Rhythm. 2011 Mar 25. [Epub ahead of print]
9. Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007; 115:2481-2489.
10. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long QT syndrome. Circulation. 2000; 101(6):616-623.
11. Napolitano C, Priori SG, Schwartz PJ, et al.  Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005; 294(23):2975-2980.
12. Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA. 2004; 292(11):1341-1344.
13. Priori S, Schwartz PJ, Napolitano C, et al. Risk stratification in the long QT syndrome. N Engl J Med. 2003; 348(19):1866-1874.
14. Robin NH, Tabereaux PB, Benza R, Korf BR. Genetic testing in cardiovascular disease. J Am Coll Cardiol. 2007; 50(8):727-737.
15. Roden DM. Long QT Syndrome. N Engl J Med. 2008; 358(20:169-176.
16. Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol. 2007; 49(3):329-337.
17. Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: clinical implications. J Intern Med. 2006; 259(1):39-47.
18. Schwartz PJ, Priori SG, Spazzolini C, et al.  Genotype-phenotype correlation in the long QT syndrome gene-specific triggers for life-threatening arrhythmias. Circulation. 2001; 103(1):89-95.
19. Shimizu W, Moss AJ, Wilde AA, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009; 54(22):2052-2062.
20. Sy RW, Chattha IS, Klein GJ, et al. Repolarization dynamics during exercise discriminate between LQT1 and LQT2 genotypes. J Cardiovasc Electrophysiol. 2010; Apr 29 [epub ahead of print].
21. Tester DJ, Salisbury BA, Carr JL, et al. The effect of mutation class on QTc in unrelated patients referred for the Familion™ genetic test for long QT syndrome. Abstract presented at Heart Rhythm Society Meeting, May 11, 2007, Denver, CO.
22. Tester DJ, Will ML, Haglund CM, Ackerman MJ.  Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005; 2(5):507-517.
23. Tester DJ, Will ML, Haglund CM, et al. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol. 2006; 47(4):764-768.
24. Vincent GM.  The long QT syndrome: bedside to bench to bedside.  N Engl J Med. 2003; 348(19):1837-1838.
25. Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol. 2003; 14(4):337-341.
26. Zareba W, Moss AJ, Locati EH, et al.  International Long QT Syndrome Registry. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol. 2003; 42(1):103-109.
27. Zareba W, Moss AJ, Schwartz PJ, et al.  Influence of the genotype on the clinical course of the long QT syndrome.  N Engl J Med. 1998; 339(14):960-965.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Ackerman MJ, Priori SG, Willems S, et al.  Heart Rhythm Society/European Heart Rhythm Association (HRS/EHRA) Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies.  Heart Rhythm. 2011; 8:1308-1339.
2. Adelaide Health Technology Assessment (AHTA). Genetic testing for long QT syndrome; Horizon scanning prioritising summary - Volume 13(5). Adelaide, SA: Adelaide Health Technology Assessment (AHTA) on behalf of National Horizon Scanning Unit (HealthPACT and MSAC); June 2006. Available at: http://www.horizonscanning.gov.au/internet/horizon/publishing.nsf/Content/84C1091198F8C1CFCA2575AD0080F357/$File/Genetic%20testing%20for%20Long%20QT%20syndrome%20to%20identify%20individuals%20at%20high-risk%20of%20sudden%20cardiac%20death%20June2006.pdf.  Accessed on September 23, 2011.
3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Genetic testing for long QT syndrome. TEC Assessment, 2008; 22(9).
4. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008; 51:1-62. Available at: http://content.onlinejacc.org/cgi/content/full/51/21/e1#SEC6.  Accessed on September 23, 2011.
5. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic Evaluation of Cardiomyopathy. A Heart Failure Society of America Practice Guideline. J Card Failure. 2009; 15(2):83-97.  Available at:   http://download.journals.elsevierhealth.com/pdfs/journals/1071-9164/PIIS1071916409000281.pdf. Accessed on September 23, 2011.
6. Lehnart SE, Ackerman MJ, Benson DW Jr, et al. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation. 2007; 116(20):2325-2345.
7. Maron BJ, Moller JH, Seidman CE, et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: Hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association. Circulation. 1998; 98:1460-1471.
8. National Heart Lung and Blood Institute (NHLBI). Long QT Syndrome-Population Genetics and Cardiac Studies.  NCT00005176.  Last updated July 23, 2008.  Available at:
9. http://www.clinicaltrials.gov/ct2/show/NCT00005176?term=long+QT&rank=2.  Accessed on September 23, 2011.  
10. Priori SG, Aliot E, Blomstrom-Lundqvist C, et al.  The European Society of Cardiology. Task Force on Sudden Cardiac Death.  Eur Heart J. 2001; 22(16):1374-1450.
11. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death).  Circulation. 2006; 114:1088-1132.  Available at:  http://circ.ahajournals.org/cgi/reprint/114/10/e385.  Accessed on September 23, 2011.

1. American Heart Association.  Information on long QT syndrome. Last updated July 28, 2011. Available at:   http://www.heart.org/HEARTORG/Conditions/Arrhythmia/AboutArrhythmia/Conduction-Disorders_UCM_302046_Article.jsp.  Accessed on September 23, 2011.
2. Consumer information available at the manufacturer's web site.  Transgenomics Inc.  Available at: http://www.familion.com/familion/.  Accessed on September23, 2011.
3. Gene Reviews. Information on genetic testing and genetic disorders. Funded by the NIH. Developed at the University of Washington. (Seattle, WA). Available at:  http://www.geneclinics.org/servlet/access?id=8888892&key=rMRN7lC0V-9ix&gry=INSERTGRY&fcn=y&fw=NdTJ&filename=/reviewsearch/searchdz.html. Accessed on September 23, 2011.
4. National Institutes of Health (NIH). National Heart, Lung and Blood Institute (NHLBI). Long QT Syndrome. July 2007. Available at URL address: http://www.nhlbi.nih.gov/health/dci/Diseases/qt/qt_all.html.  Accessed on September 23, 2011.

Brugada Syndrome
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Cardiac Ion Channel Genetic Testing
Channelopathies
FAMILION^®
Genetic Testing
Long QT Syndrome, LQTS
Therapeutic Diagnostics^™ 

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.