Clinical Policy Title: Genetic Testing for Long QT Syndrome (LQTS)

Transcription

1 Clinical Policy Title: Genetic Testing for Long QT Syndrome (LQTS) Clinical Policy Number: (391) Effective Date: Dec. 1, 2013 Initial Review Date: June 19, 2013 Most Recent Review Date: July 17, 2013 Next Review Date: June 2014 Policy contains: Familion testing. Long QT Syndrome Subtypes. Lines of Business: TrueBlue clinical policies are subject to all applicable laws and government regulatory requirements of the geographical areas served. Refer to the pertinent government and plan documents for each geographical area for guidance. Individual member benefits must be verified. Policy Definition: TrueBlue covers health care service/items when they are a Plan benefit, medically necessary and not prohibited from coverage by state or federal laws and/or regulatory requirements. This TrueBlue clinical policy addresses the medical evidence supporting the use of genetic testing for long QT syndrome (LQST), also known as Familion testing. TrueBlue considers the use of genetic testing for long QT syndrome (LQST), also known as Familion testing, to be clinically proven as the effectiveness of its use has been established in peer reviewed professional literature. These clinical policies, along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any State or plan specific definition of medically necessary, are considered by TrueBlue when making coverage determinations. Coverage Policy: TrueBlue considers the use of genetic testing for long QT syndrome (LQST); also known as Familion testing to be clinically proven; and therefore, a finding of medically necessary is supported when the following criteria are met: The individual has a close relative (first, second, or third-degree relative) with a known LQTS mutation. 1

2 The individual has a close relative (first, second, or third-degree relative) diagnosed with LQTS by clinical means and whose genetic status is unavailable. The individual has palpitations, syncope, dizziness with a history of a close relative (first, second, or third-degree relative) who experienced a sudden cardiac death. The individual has a prolonged QT interval on resting electrocardiogram (a corrected QTc) of greater than 440 msec without an identifiable acquired or external cause for the QTc prolongation (i.e., bradycardia, electrolyte imbalance, or certain medications/drugs). (QTc values of 0.44 sec are treated as suspicious, CSANZ 2011) The individual has signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS using the Schwartz criteria (score of 2-3). A finding of medical necessity is not supported for all other uses of genetic testing for long QT syndrome/familion testing. Limitations: A negative genetic test in a clinically normal individual of a well-characterized family should eliminate the need for future testing (for the same individual), as genetic testing for a particular disease is usually performed once per lifetime. NOTE: Florida Medicaid does not provide coverage for Long QT syndrome gene analyses (CPT code 81280, 81281, or 81282) or for Genetic counseling under physician supervision (CPT S0265). Alternative Covered Services: Physical examination. Electric conductivity tests: electrocardiogram (ECG), echocardiography. Background: Long QT syndrome (LQTS) is caused by mutations in a set of genes that code the protein subunits of cardiac ion channels. These ion channels are important for the electrical conductivity and signals of the heart. The electrical signals may be recorded by an electrocardiogram (ECG) and produce a characteristic waveform. The different components of the waveform are identified by the letters: P, Q, R, S, and T. The distinctive feature of LQTS is the lengthening of the QT interval on an electrocardiogram (ECG). The Q-T interval on the waveform represents the duration of the electrical activation and deactivation of the heart ventricles, which are the lower, main pumping chambers of the heart. With the advent of genetic testing, there is evidence of an overlap of specific genotypes that cause the characteristic T wave shapes. 2

3 Normal al Long QT LQTS Genetic mutations may lead to an increase in the Q-T Interval on an Electrocardiogram. In medical genetics, testing is done to diagnosis individuals who possess chromosomal, genetic variations associated with a high risk of having or transmitting LQTS. The abnormal mutations and variations in DNA sequencing that cause LQTS are represented by abnormal allele configurations that are not found in the otherwise normal, healthy population. Genetic tests may be conducted for individuals who are asymptomatic, or have a family member with this diagnosed genetic disorder. All first-degree relatives (i.e., siblings, parents and children) of an individual with an LQTS gene mutation have up to a 50% risk of harboring the same mutation. Typically, LQTS is inherited in an autosomal dominant pattern, in which a single mutation causes the disease. The genetic material (DNA) used for testing may be obtained from a blood sample, or may be gathered by a mouth swab. Laboratories are able to offer multi-gene cardiomyopathy/cardiac panels that test many genes (may contain 50 or more) in an effort to diagnose several cardiac conditions at one time. The importance of identifying individuals for an inherited cardiac arrhythmia is highlighted by the potential lethality of these syndromes, mostly due to ventricular tachyarrhythmias. LQTS usually affects children or young adults, although it may occur in otherwise healthy individuals of various ages. Most people with LQTS are diagnosed either by family history, an episode of syncope, or by surviving a severe ventricular arrhythmia. For some unfortunate symptomatic individuals, the initial presentation of LQTS symptoms leads to sudden cardiac death. The goal of genetic testing for LQTS is to prevent sudden death though medical therapy, to counsel the individual and their family, and to assist with life style changes (CSANZ, 2011). Literature suggests that LQTS may be responsible for as many as 3,000 unexpected deaths in children and young adults in the United State each year (Model, 2012). Younger individuals have a higher risk of unexpected sudden death than adults with a genetic cardiac disease. A family history of sudden death, possibly with genetic confirmation, may influence treatment decisions for those with suspected and ultimately confirmed LQTS. Because this disease is a primarily an electrical disorder, most individuals have no evidence of structural heart disease or LV dysfunction, making the long-term prognosis excellent if the arrhythmia is controlled. Treatment may involve beta blockers, permanent pacing, or left cervicothoracic sympathectomy (Tracy, et al, 2008). 3

4 Practice guideline statements from the American College of Cardiology (ACC) / American Heart Association (AHA)/European Society of Cardiology (ESC), (Zipes, et al., 2006) have noted an evolving role for genetic testing of LQTS in risk stratification and clinical decision making. This stance pertaining to the use of risk stratification and data from genetic analysis becoming of increasing import to meaningful clinical decision making was further addressed in the 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. Both independent reviews and professional society guidelines agree that genetic testing should not be used alone in making recommendations for a prognosis for LQTS, though testing may be used to support clinical diagnosis, and early detection of at-risk relatives ( Ackerman, et al., 2011; Antzelevitch, et al.,2005; Priori & Cerrone, 2005). Long QT Syndrome subtypes Variant Gene Name Frequency Current Affected LQT1 KCNQ % K+, alpha subunit LQT2 KCNH % K+, alpha subunit LQT3 SCN5A 5 10% Na+,alpha subunit LQT4 ANK2 1 2% Na+,targeting protein LQT5 KCNE1 1% K+, beta subunit LQT6 KCNE2 Rare K+, subunit LQT7 KCNJ2 Rare K+, potassium channel LQT8 CACNA1C Rare Ca++, alpha 1C subunit LQT9 CAV3 Rare Na+, caveolin-3 protein Long QT Syndrome subtypes Variant Gene Name Frequency Function LQT10 SCN4B Rare Na+, beta subunit LQT11 AKAP9 Rare K+, protein kinase LQT12 SNTA1 Rare Na+, syntrophin- α1 LQT13 KCNJ5 Rare potassium channel Glossary of terms Electrocardiogram (ECG, EKG) - A test that records the electrical activity of the heart and displays the results on a visual graph. It is used to evaluate cardiac function, arrhythmias, and the diagnosis of other cardiac disorders. Chromosome Within a single cell, a strand of amino acids that carries genetic information. 4

5 Gene - An integral part of a chromosome that determines individual organism s hereditary, physical characteristics. Mutation Any change in the inherited genetic structure. Relatives: First, Second, and Third Degree - An individual s close blood family members: a. First degree relative - Parents, full siblings or children b. Second degree relative - Aunts, uncles, grandparents, grandchildren, nieces, nephews or half-siblings c. Third degree relative - Great grandparents, great aunts, great uncles or first cousins Subtype - One type or component that is included in the long QT syndrome type. REFERENCES Professional Society Guidelines Ackerman MJ, Priori SG, Williams S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm Aug;8(8): [Agency for Healthcare Research and Quality (ARHQ) Web site]. Available at: Accessed May 22, Ackerman MJ, Priori SG, Williams, S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011; 13(8): American Academy of Pediatrics. Pediatric sudden cardiac arrest, section on cardiology and cardiac surgery. Pediatrics. March 26, American Heart Association (AHA) Website. 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. May 15, Available at: Accessed May 22, American College of Cardiology, American Heart Association Task Force, European Society of Cardiology guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American 5

6 Heart Association Task Force and the European Society of Cardiology committee for practice guidelines. J Am Coll Cardiol. 2006;48(5). Blue Cross Blue Shield Association (BCBSA), Technology Evaluation Center (TEC). Genetic testing for long QT syndrome TEC Assessments 2008;22(9). Chicago, IL. 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: Accessed May 22, Garratt CJ, Elliott P, Behr E, et al. Heart Rhythm UK Familial Sudden Cardiac Death Syndromes Statement Development Group. Heart Rhythm UK position statement on clinical indications for implantable cardioverter defibrillators in adult patients with familial sudden cardiac death syndromes. Europace Aug;12(8): Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm Jan;7(1): Epub 2009 Oct 8. 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 Nov 13;116(20): Erratum in: Circulation Aug 19;118(8):e132. Skinner, J., et al. Guidelines for the diagnosis and management of familial long QT syndrome. The cardiac Society of Australia and New Zealand (CSANZ). August 10, Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL; American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. 6

7 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): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation Sep 5;114(10):e Epub 2006 Aug 25. Evidence Based References Ackerman MJ. Cardiac causes of sudden unexpected death in children and their relationship to seizures and syncope: genetic testing for cardiac electropathies. Semin Pediatr Neurol Mar;12(1):52-8. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation Feb 8;111(5): Epub 2005 Jan 17. Review. Erratum in: Circulation Jul 26;112(4):e74. Barsheshet A, Goldenberg I, O-Uchi J, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-qt syndrome. Circulation 2012; 125(16): Baylor College of Medicine (BCM). John Welsh cardiovascular diagnostic laboratory. [BCM Web site]. 11/29/2011. Available at: Accessed May 22, Brenyo, A., Huang, D., Aktas. M. Congenital Long and Short QT Syndromes. Carfdiology, May 8, 201;122: Brugada R, Campuzano O, Brugada P, Brugada J, Hong K. Brugada Syndrome Mar 31 [updated 2012 Jan 12]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Costa J, Lopes CM, Barsheshet A, et al. Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome. Heart Rhythm. 2012; 9(6): Goldenberg, I., Horr, S., Moss, A., et al. Risk for life-threatening cardiac events in patients with genotype-confirmed long-qt syndrome and normal-range corrected QT intervals. J Am Coll Cardiol. January 4, 2011; 57(1):51-9. Kapa S, Tester DJ, Salisbury BA, et al. Genetic testing for long-qt syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009; 120(18):

8 Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009; 6: Modell SM, Lehmann MH. The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet Med Mar;8(3): Review. PubMed PMID: Accessed May 22, Modell, S., Bradley,D., and Lehmann, M. Genetic testing for long QT syndrome and the category of cardiac ion channelopathies. PLoS Curr. May 3, Moss AJ, Goldenberg I. Importance of Knowing the Genotype and the Specific Mutation When Managing Patients with Long QT Syndrome. Circ Arrhythm Electrophysiol Aug;1(3):213-26; discussion 226. Review. PubMed PMID: ; PubMed Central PMCID: PMC Napolitano, C., Priori, S., Schwartz, P., 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): National Center for Biotechnology Information (NCBI). Long QT syndrome 1: clinical laboratories. Available at: Accessed May 22, Priori SG, Cerrone M. Molecular genetics: is it making an impact in the management of inherited arrhythmogenic syndromes? Hellenic J Cardiol Mar-Apr;46(2):83-7. PubMed PMID: Refsgaard L, Holst AG, Sadjadieh G, et al. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet [Epub ahead of print]. Schwartz PJ, Moss AJ, Vincent GM et al. Diagnostic criteria for the long QT syndrome An update. Circulation;1993;88(2): 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): Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. 8

9 Prevalence of the congenital long-qt syndrome. Circulation Nov 3;120(18): Epub 2009 Oct 19. PubMed PMID: ; PubMed Central PMCID: PMC Sy RW, Chattha IS, Klein GJ, et al. Repolarization dynamics during exercise discriminate between LQT1 and LQT2 genotypes. J Cardiovasc Electrophysiol Nov;21(11): Tester DJ, Ackerman MJ. Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice. Circulation Mar 8;123(9): Transgenomic, Inc. FAMILION Comprehensive Genetic Tests for Cardiac Syndromes. [Transgenomic, Inc. Web site]. Available at: Clinical Trials Moss, A. Long QT Syndrome-Population Genetics and Cardiac Studies (LQTS). Clinitca trials # NCT University of Rochester. Updated: October 2, Available at: Centers for Medicare Services (CMS) National Coverage Determination As of the writing of this policy, there was no National care determination to address genetic testing for LQTS found to search. There is the MEDCAC Meeting of 2/25/2009 on Genetic (Genomic) Testing: nnsylvania&keyword=genetic&keywordlookup=title&keywordsearchtype=and&bc=gaaaab AAAAAAAA%3d%3d& Local Care Determinations As of the writing of this policy, there were no local care determinations found to search that applied to TrueBlue plans. State Mandates & Legislation N/A Commonly Submitted Codes: Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill in accordance with those manuals. 9

10 CPT Code Description Comment Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1, and ANK2) Full sequence analysis Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1, and ANK2) Known familial sequence variant Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1, and ANK2) Duplication/Deletion variants HCPCS Code S0265 Description Genetic counseling, under physician supervision, each 15 minutes Comment ICD-9 Code Description Comment Long QT syndrome Syncope and collapse Symptoms of Long QT Syndrome Dizziness and giddiness Palpitations Nonspecific abnormal electrocardiogram (ECG) (EKG) V17.41 Family history of sudden cardiac death [SCD] V18.9 Family history of genetic disease carrier V82.71 Screening for genetic disease carrier status Genetic testing V82.79 Other genetic screening The following ICD-10 codes are informational until the ICD-10 Compliance date. ICD-10 Code Description Comment I45.81 Long QT syndrome R55 Syncope and collapse R42 Dizziness and giddiness R00.2 Palpitations R94.31 Abnormal electrocardiogram [ECG] [EKG] Z82.41 Family history of sudden cardiac death Symptoms of Syndrome 10

11 Z84.81 Family history of carrier of genetic disease Z13.71 Encounter for nonprocreative screening for genetic disease carrier status Z13.79 Encounter for other screening for genetic and chromosomal anomalies Genetic test screening Disclaimer: TrueBlue has developed clinical policies to assist with making coverage determinations. TrueBlue clinical policies are based on guidelines from established industry sources such as Centers for Medicare and Medicaid (CMS), State regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer reviewed professional literature. These clinical policies, along with other sources, such as plan benefits and state and federal laws and regulatory requirements, are considered by TrueBlue when making coverage determinations. True Blue clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. TrueBlue clinical policies are reflective of evidence based medicine at the time of review. As medical science evolves, TrueBlue will update its clinical policies as necessary. TrueBlue clinical policies are not guarantees of payment. 11