BlueCross BlueShield of Tennessee Medical Policy Manual

Genetic Testing for Congenital Cardiac Channelopathies

DESCRIPTION

Congenital cardiac channelopathies are autosomal dominant disorders that affect the flow of potassium and sodium ions and electrical activity of the heart, leading to irregular heartbeats. Conditions related to cardiac channelopathies may include congenital long QT syndrome (LQTS) and Brugada syndrome, among others. Possible external causes of QT prolongation or other electrical abnormalities can include heart disease, electrolyte imbalance, and hypothyroidism. Certain medications, such as antiarrhythmics, antidepressants and antibiotics can also contribute to prolongation of the QT interval.

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. However, measurement of the QT interval is not well standardized, and in some cases, patients may be considered borderline cases.

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.

POLICY

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

Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is considered investigational.

MEDICAL APPROPRIATENESS

Genetic testing Individuals who do not meet the clinical criteria for long QT syndrome is considered medically appropriate if any of the following criteria are met:

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

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

• The individual has signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS

ADDITIONAL INFORMATION

Determining the pretest probability of 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

Ackerman, M. J. (2005). Genetic testing for risk stratification in hypertrophic cardiomyopathy and long QT syndrome: Fact or fiction? Current Opinion in Cardiology, 20 (3), 175-181. Abstract retrieved September 6, 2007 form PubMed database.

BlueCross BlueShield Association. Medical Policy Reference Manual. (6:2007). Genetic testing for congenital long QT syndrome. (2.04.43). Retrieved February 14, 2008 from BlueWeb. (20 articles and/or guidelines reviewed)  

BlueCross BlueShield of Tennessee network physicians. September 2005.

Clancy, C. E., & Kass, R. S. (2005). Inherited and acquired vulnerability to ventricular arrhythmias: Cardiac Na+ and K+ channels. Physiological Reviews, 85 (1), 33-47.

ECRI Institute. Health Technology Information Service. TARGET database. (2006, July). Genetic testing for inherited cardiac channelopathies. Retrieved September 6, 2007 from ECRI Institute. (22 articles and/or guidelines reviewed)

Hayes. Brief. (2007, October). Genetic testing using the familion® test (PGxHealth™) for diagnosis of inherited channelopathies. Retrieved February 14, 2008 from http://www.Hayesinc.com/subscribers. (48 articles and/or guidelines reviewed)

Kannankeril, P. J., Roden, D. M., Norris, K. J., Whallen, S. P., George, A. L., Jr., & Murray, K. T. (2005). Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives. Heart rhythm, 2 (2), 134-140. Abstract retrieved August 8, 2005 from PubMed database.

Kass, R. S. (2005). The channelopathies: Novel insights into molecular and genetic mechanisms of human disease. Journal of Clinical Investigation, 115 (8), 1986-1989.

Kaufman, E. S., Gorodeski, E. Z., Dettmer, M. M., & Dikshteyn, M. (2005). Use of autonomic maneuvers to probe phenotype/genotype discordance in congenital long QT syndrome. American Journal of Cardiology, 96 (10), 1425-1430.

Maron, B. J., Chaitman, B. R., Ackerman, M. J., Bayés de Luna, A., Corrado, D., Crosson, J. E. et al. (2004). Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation; 109 (22), 2807-2816.

Martin, J. R., & Wilikofsky, A. S. (2004). Genetic counseling in primary care: Longitudinal, psychosocial issues in genetic diagnosis and counseling. Primary Care: Clinics in Office Practice, 31 (3), 509-524.

Mayo Clinic Medical Services. (2006, March). Long QT syndrome. Retrieved September 17, 2007 from http://www.mayoclinic.com/invoke.cfm?id=DS00434.

Mayo Clinic Medical Services. (2007). Diagnosis of long QT syndrome. Retrieved September 17, 2007 from http://www.mayoclinic.org/long-qt-syndrome/diagnosis.html.

Mayo Clinic Medical Services. (2007). Types of long QT syndrome. Retrieved September 17, 2007 from http://www.mayoclinic.org/long-qt-syndrome/types.html.

Meyer, J. S., Mehdirad, A., Salem, B. I., Kulikowska, A., & Kulikowski, P. (2003). Sudden arrhythmia death syndrome: Importance of the long QT syndrome. American Family Physician, 68 (3), 483-488.

Moss, A. J., & Kass, R. S. (2005). Long QT syndrome: From channels to cardiac arrhythmias. Journal of Clinical Investigation, 115 (8), 2018-2024.

Napolitano, C., Priori, S. G., Schwartz, P. J., Bloise, R., Ronchetti, E., Nastoli, J., et al. (2005). Genetic testing in the long QT syndrome. Journal of the American Medical Association, 294 (23) 2975-2983.

Orphanet Encyclopedia. (2004). Brugada syndrome. Retrieved September 28, 2005 from http://www.orpha.net/data/patho/GB/uk-BrugadaSyndrome.pdf.

Pellegrino, P. L., Bafunno, V., Ieva, R., Brunetti, N. D., Mavilio, G., Sessa, F., et al. (2007). A novel mutation in human ether-a-go-go-related gene, alanine to proline at position 490, found in a large family with autosomal dominant long QT syndrome. American Journal of Cardiology, 99 (12), 1737-1740.

Priori, S. G., & Napolitano, C. (2005). Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels. Journal of Clinical Investigation, 115 (8), 2033-2038.

Priori, S. G., Schwartz, P J., Napolitano, C., Bloise, R., Ronchetti, E., Grillo, M., et al. (2003). Risk stratification in the long-QT syndrome. New England Journal of Medicine, 348 (19), 1866-1874.

Roden, D. M. (2008). Long-QT syndrome. The New England Journal of Medicine, 358 (2), 169-176.

Roden, D. M., & Viswanathan, P. C. (2005). Genetics of acquired long QT syndrome. Journal of Clinical Investigation, 115 (8), 2025-2032.

Shimizu, W., Horie, M., Ohno, S., Takenaka, K., Yamaguchi, M., Shimuzi, M., et al. (2004). Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: Multicenter study in Japan. Journal of the American College of Cardiology, 44 (1), 117-125. Abstract retrieved October 17, 2005 from PubMed database.

Sudden Arrhythmia Death Syndromes Foundation. (2005, August). Genetic testing for the congenital long QT syndrome. Retrieved August 8, 2005 from http://www.sads.org/Clinical%20Testing.htm.

Sudden Arrhythmia Death Syndromes Foundation. (2005, August). Long QT syndrome (LQTS). Retrieved August 24, 2005 from http://www.sads.org/LQT%20facts%202003.htm.

Sudden Arrhythmia Death Syndromes Foundation. (2005, August). Testing: How to navigate the maze. Retrieved August 8, 2005 from http://www.sads.org/genetics.html.

Sudden Arrhythmia Death Syndromes Foundation. (2005, August). Who should be screened? Retrieved August 8, 2005 from http://www.sads.org/Screen%202003.htm.

Tan, H. L., Hofman, N., van Langen, I. M., van der Wal, A. C., & Wilde, A.M. (2005). Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation, 112 (2), 207-213.

The Technology Evaluation Center. (2008, February). Genetic testing for long QT syndrome (Vol. 22, No. 9). Chicago: BlueCross BlueShield Association. (39 articles and/or guidelines reviewed)

Towbin, J. A. (2004). Molecular genetic basis of sudden cardiac death. Pediatric Clinics of North America, 51 (5), 1229-55.

Vincent, M. G. (2003). The long-QT syndrome - Bedside to bench to bedside. New England Journal of Medicine, 348 (19), 1837-1838.

Wilde, A. A. M., & Bezzina, C. R. (2005). Genetics of cardiac arrhythmias. Heart, 91, 1352-1358.

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