BlueCross BlueShield of Tennessee Medical Policy Manual

Genetic Testing for Congenital Cardiac Channelopathies

DESCRIPTION

Congenital long QT syndrome (LQTS) is an inherited disorder characterized by the lengthening of the repolarization phase of the ventricular action potential, increasing the risk for arrhythmic events, such as torsades de pointes, which may in turn result in syncope and sudden cardiac death. Management has focused on the use of beta blockers as first-line treatment, with pacemakers or implantable cardiac defibrillators (ICD) as second-line therapy.

Congenital LQTS usually manifests itself before the age of 40 years, and may be suspected when there is a history of seizure, syncope, or sudden death in a child or young adult; this history may prompt additional testing in family members. It is estimated that more than one half of the 8,000 sudden unexpected deaths in children may be related to LQTS. The mortality of untreated patients with LQTS is estimated at 1%–2% per year, although this figure will vary with the genotype.

Frequently, syncope or sudden death occurs during physical exertion or emotional excitement, and thus LQTS has received some publicity regarding evaluation of adolescents for participation in sports. In addition, LQTS may be considered when a long QT interval is incidentally observed on an EKG. Diagnostic criteria for LQTS have been established, which focus on EKG findings and clinical and family history (i.e., Schwartz criteria). However, measurement of the QT interval is not well standardized, and in some cases, patients may be considered borderline cases.

In recent years, LQTS has been characterized as an “ion channel disease,” with abnormalities in the sodium and potassium channels that control the excitability of the cardiac myocytes. A genetic basis for LQTS has also emerged with 7 different variants recognized, each corresponding to mutations in different genes. In addition, typical ST-T-wave patterns are also suggestive of specific subtypes.

• LQT1 is associated with mutations in the gene KNQ1 located on chromosome 11. LQT1 is responsible for about 50% of all LQTS, and arrhythmic events prompted by exercise may occur most commonly in this subtype. Therefore, patients with LQT1 may be advised to minimize exercise.

• LQT2 is associated with mutations in the gene KCNH2 located on chromosome 7 and is seen in 45% of patients with LQTS. Arrhythmic events appear to be precipitated by auditory stimuli, and these patients may be advised to avoid clock alarms, etc.

• LQT3 is associated with mutations in the gene SCN5A located on chromosome 3. This subtype is seen in 3%–4% of patients with LQTS. In this subtype, the majority of cardiac events occur during sleep. LQT3 variant is also known as the Brugada syndrome.

• LQT 4-7 involve KCN genes located on chromosomes 21 and 17. These variants each account for less than 1% of LQTS.

A genetic blood test (e.g., FAMILION™) is intended to identify mutations in the genes of individuals and family members with suspected or confirmed channelopathies.

Note: This policy does not address genetic testing for individuals who meet the Schwartz criteria for long QT syndrome (LQTS). (See Additional Information).

POLICY

• Genetic testing for individuals with suspected congenital long QT syndrome (LQTS) is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)

• Genetic testing for long QT syndrome (LQTS) to determine prognosis and/or direct therapy in patients with known long QT syndrome is considered investigational.

MEDICAL APPROPRIATENESS

• Genetic testing for individuals with suspected congenital long QT syndrome (LQTS) is considered medically appropriate if ANY ONE of the following criteria are met:

• Individual has a close relative (i.e., first-, second-, or third-degree relative) with a known LQTS mutation

• Individual has close relative diagnosed with LQTS by clinical means whose genetic status is unavailable

• Individual has signs and/or symptoms indicating an intermediate-to-high pretest probability of LQTS (e.g., score of 2 to 3 or higher using Schwartz criteria [See Additional Information])

IMPORTANT REMINDER

We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the Medical Policy and a health plan, the express terms of the health plan will govern.

ADDITIONAL INFORMATION

Determining the pretest probability for long QT syndrome (LQTS) is not standardized. The Schwartz criteria are commonly used as a diagnostic scoring system for LQTS. The most recent version of this scoring system is shown below. A score of 4 or greater indicates a high probability that LQTS is present; a score of 2-3 an intermediate probability; and a score of 1 or less indicates a low probability of the disorder. Prior to the availability of genetic testing, it was not possible to test the sensitivity and specificity of this scoring system; therefore, the accuracy of this scoring system is ill-defined.

SOURCES

American College of Cardiology. American Heart Association Task Force and the European Sociaety of Cardiology Committee for Practice Guidelines. (2006). Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Retrieved February 5, 2010 from http://circ.ahajournals.org.

American Heart Association. (2009). Genetic testing for long-QT syndrome: Distinguishing pathogenic mutations from benign variants. Retrieved October 28, 2011 from http://circ.ahajournals.org/content/120/18/1752.

BlueCross BlueShield Association, Medical Policy Reference Manual. (7:2011). Genetic testing for congenital long QT syndrome. (2.04.43). Retrieved October 28, 2011 from BlueWeb. (23 articles and/or guidelines reviewed)

Heart Rhythm Society. European Heart Rhythm Association. (2011). Expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Eurospace, 13, 1077-1109.

Hofman, N., Wilde, A. A. M., Kaab, S., van Langen, I. M., Tanck, M. W. T., Mannens, M. M. A. M., et al. (2007). Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: Do we need a scoring system? European Heart Journal, 28, 575-580. (Level 3 Evidence)

Lau, J.F. & Smith, D.A. (2009). Advanced lipoprotein testing: recommendations based on current evidence. Endocrinology and Metabolism Clinics of North America, 38 (1), 1-31. (Level 2 Evidence)

Lehnart, S. E., Ackerman, M. J., Benson, D. W., Brugada, R., Clancy, C. E., Donahue, J. K., et al. (2007) 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, 116 (20), 2325-2345.

Libby, P., Bonow., R.O., Mann, D.L. & Zipes, D.P. (2007). Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. (8th ed., Chapter 39). Philadelphia: Saunders Elsevier.

Robin, N. H., Tabereaux, P. B., Benze, R., & Korf, B. R. (2007). Genetic testing in cardiovascular disease. Journal of the American College of Cardiology, 50 (8), 727-737. (Level 5 Evidence)

U. S. Food and Drug Administration. (2007, February) Center for Devices and Radiological Health. Pre-market approval K063608. Retrieved October 27, 2009 from http://www.accessdata.fda.gov/cdrh_docs/pdf6/K063608.pdf.

U. S. Food and Drug Administration. (2008, March). Center for Devices and Radiological Health. Pre-market approval K0073488. Retrieved October 27, 2009 from http://www.accessdata.fda.gov/cdrh_docs/pdf7/K073488.pdf.

U. S. Food and Drug Administration. (2009, September). Center for Devices and Radiological Health. Pre-market approval K092051. Retrieved October 27, 2009 from http://www.accessdata.fda.gov/cdrh_docs/pdf9/K092051.pdf.

ORIGINAL EFFECTIVE DATE:  5/13/2006

MOST RECENT REVIEW DATE:  12/8/2011

ID_BT

Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

This document has been classified as public information.