Clinical Policy Title: Genetic testing for long QT syndrome (LQTS)

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1 Clinical Policy Title: Genetic testing for long QT syndrome (LQTS) Clinical Policy Number: Effective Date: Dec. 1, 2013 Initial Review Date: June 19, 2013 Most Recent Review Date: July 20, 2016 Next Review Date: July 2017 Policy contains: Familion testing. Long QT syndrome subtypes. RELATED POLICIES: CP# Molecular targeted therapy ABOUT THIS POLICY: AmeriHealth Caritas Pennsylvania has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas Pennsylvania s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (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, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by AmeriHealth Caritas Pennsylvania when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas Pennsylvania s 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. AmeriHealth Caritas Pennsylvania s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas Pennsylvania will update its clinical policies as necessary. AmeriHealth Caritas Pennsylvania s clinical policies are not guarantees of payment. Coverage Policy AmeriHealth Caritas Pennsylvania considers the use of genetic testing for long QT syndrome (LQTS), also known as Familion testing, to be clinically proven and therefore medically necessary when the following criteria are met: The individual has a close relative (first-, second- or third-degree) with a known LQTS mutation. The individual has a close relative (first-, second- or third-degree) diagnosed with LQTS by clinical means and whose genetic status is unavailable. The individual has palpitations, syncope and/or dizziness with a history of a close relative (first-, second-, or third-degree) 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.) 1

2 The individual has signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS using the Schwartz criteria (score of 2 3). Limitations All other uses of genetic testing for long QT syndrome/familion testing are not medically necessary. 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: The following CPT/HCPCS code is not listed in the Pennsylvania Medicaid fee schedule: S Genetic counseling, under physician supervision, each 15 minutes Alternative covered services Physical examination. Electric conductivity tests: electrocardiogram (ECG), echocardiography. Genetic counseling. 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 Q T 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. Normal Long QT LQTS genetic mutations may lead to an increase in the Q T Interval on an electrocardiogram. 2

3 In medical genetics, testing is done to diagnose 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 percent 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 through medical therapy, to counsel the individual and their family, and to assist with lifestyle 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 States 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). Practice guideline statements from the American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and European Society of Cardiology (ESC) have noted an evolving role for genetic testing of LQTS in risk stratification and clinical decision-making (Zipes, et al., 2006). This stance pertaining to the use of risk stratification and data from genetic analysis becoming of increasing import to meaningful clinical decisionmaking was further addressed in the 2012 American College of Cardiology, American Heart Association Task Force, and European Society of Cardiology (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 and Cerrone, 2005). 3

4 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+, α1-syntrophin LQT13 KCNJ5 Rare potassium channel Searches: AmeriHealth Caritas Pennsylvania searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality Guideline Clearinghouse and evidence-based practice centers. The Centers for Medicare & Medicaid Services. Searches were conducted in June 13, 2016 using the terms cardiac, genetic testing, Familion and long QT syndrome. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings 4

5 The genetics of cardiac ion channelopathies are extremely varied. The number of genes that have been associated with causing long-qt syndrome has risen to 10, and there are hundreds of possible mutations in these genes that appear to be harmful. The Familion genetic test includes just 5 of the genes that are known to be associated with cardiac ion channelopathies and therefore, the number of symptomatic first-degree relatives of those with known LQTS mutations is high. The use of the Familion genetic test may potentially have clinical utility in patients with LQTS. For firstdegree relatives with known LQTS mutations in 1 of 5 genes included in the test, the Familion genetic test can confirm the presence of the familial mutation. A negative result is also instructive, as with the high analytical sensitivity and low probability of a sporadic mutation, a negative result would indicate a low probability of the patient having LQTS. Thus, use of the Familion genetic test in first-degree relatives of those with a known LQTS mutation may allow better use of prophylactic treatment for payers and avoidance of unnecessary restrictive activity for patients. Genetic tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA) Act of Premarketed approval from FDA is not required as long as the assay is performed in a laboratory facility that observes the CLIA regulations. The provider of the Familion genetic test has a current CLIA license. Policy updates: None. Summary of Clinical Evidence Citation Taggart NW, et. al. (2007) Content Key Points: Diagnostic miscues in congenital long-qt syndrome: BACKGROUND: Long-QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that can be mistaken for palpitations, neurocardiogenic syncope and epilepsy. Because of increased physician and public awareness of warning signs suggestive of LQTS, there is the potential for LQTS to be overdiagnosed. The authors sought to determine the agreement between the dismissal diagnosis from an LQTS subspecialty clinic and the original referral diagnosis. METHODS AND RESULTS: Data from the medical record were compared with data from the outside evaluation for 176 consecutive patients (121 females, median age 16 years, average referral corrected QT interval [QTc] of 481 ms) referred with a diagnosis of LQTS. After evaluation at Mayo Clinic's LQTS Clinic, patients were categorized as having definite LQTS (D- LQTS), possible LQTS (P-LQTS), or no LQTS (No-LQTS). Seventy-three patients (41%) were categorized as No-LQTS, 56 (32%) as P-LQTS, and only 47 (27%) as D-LQTS. The yield of genetic testing among D-LQTS patients was 78% compared with 34% for P-LQTS and 0% among No-LQTS patients (P<0.0001). The average QTc was greater in either D-LQTS or P- LQTS than in No-LQTS (461 versus 424 ms, P<0.0001). Vasovagal syncope was more common among the No-LQTS subset (28%) than the P-LQTS/D-LQTS group (8%; P=0.04). Determinants for discordance (i.e., positive outside diagnosis versus No-LQTS) included overestimation of QTc, diagnosing LQTS on the basis of "borderline" QTc values and interpretation of a vasovagal fainting episode as an LQTS-precipitated cardiac event. CONCLUSIONS: Diagnostic concordance was present for less than one-third of the patients 5

6 who sought a second opinion. Two of every 5 patients referred with the diagnosis of LQTS departed without such a diagnosis. Miscalculation of the QTc, misinterpretation of the normal distribution of QTc values and misinterpretation of symptoms appear to be responsible for most of the diagnostic miscues. Moss et. al. (2007) Key Points: The effects of 77 different KCNQ1 mutations on phenotype in 600 patients from 101 families from the United States, Japan and the Netherlands were investigated: Mutations were classified according to their location in the KCNQ1, potassium channel position protein, i.e., N-terminus, transmembrane or C-terminus. Transmembrane mutations accounted for 66% of the mutations. In patients with transmembrane mutations, their QTc interval was longer, there was a higher incidence of cardiac events (syncope, aborted cardiac arrest or death) and the use of betablockers was more common. The QTc interval was also significantly longer in 19 patients who had 2 SCN5A mutations compared with those with a single mutation. In patients with KCNQ1 mutations that cause a > 50% increase in ion channel repolarizing current, the risk of cardiac events was approximately twice that of patients with mutations that cause a < 50% reduction in ion channel repolarizing current. The QTc was also significantly longer in patients with the worst impairment in ion channel function. Glossary 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. Gene An integral part of a chromosome that determines an individual organism s hereditary physical characteristics. KCNQ1 Approved symbol. Approved name potassium voltage-gated channel subfamily Q member 1. Mutation Any change in the inherited genetic structure. Relatives, first-, second-, and third-degree An individual s close blood family members: First-degree relative Parents, full siblings or children. Second-degree relative Aunts, uncles, grandparents, grandchildren, nieces, nephews or half-siblings. 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. 6

7 References Professional society guidelines/other: Ackerman MJ, Priori SG, Williams S, Berul C, 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). Heart Rhythm Aug;8(8): [Agency for Healthcare Research and Quality (ARHQ) Web site]. Available at:. Accessed June 13, 2016 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 June 13, 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 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: E. Epstein AE, et. al.,acc/aha/hrs 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities, J Am Coll Cardiol. 2008;51(21):e1-e62. doi: /j.jacc , Accessed June 13,

8 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, et al. 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, et al. American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. 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. Peer-reviewed 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. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115(4):

9 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 June 13, Brenyo, A., Huang, D., Aktas. M. Congenital Long and Short QT Syndromes. Carfdiology, May 8, 2012;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 genotypeconfirmed 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): 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 June 13, 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

10 Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 lone-qt syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulations. 2007;115(19): 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 June 13, 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. 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): Taggart NW 1, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in cogenital long-qt syndrome.2007 May 22; 115(20): Epub 2007 May 14. Transgenomic, Inc. FAMILION Comprehensive Genetic Tests for Cardiac Syndromes. [Transgenomic, Inc. Web site]. Available at: Accessed. June 13, Vetter VL, Clues or miscues? How to make the right interpretation and correctly diagnose long-qt syndrome. Circualtin. 2007:115(20):

11 Clinical trials Searched clinicaltrials.gov on June 13,2016 using termslong QT syndrome (LQTS), genetic testing Open Studies. 22 studies found, onerelevant. Massachusetts General Hospital.Boston, Massachusetts. Long QT syndrome (LQTS), and the subsequent fatal arrhythmia torsade de pointes (TdP), Published May 2015Updated March Accessed June 13, CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations MolecularPathologyProcedures.(L34519). Updated: 01/01/ Accessed June 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 accordingly. 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. ICD-9 Code Description Comment Long QT syndrome Syncope and collapse 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. Symptoms of long QT syndrome. 11

12 V82.71 Screening for genetic disease carrier status. Genetic testing. V82.79 Other genetic screening. ICD-10 Code Description Comment I45.81 Long QT syndrome. R55 Syncope and collapse. Symptoms of syndrome. R42 Dizziness and giddiness. R00.2 Palpitations. R94.31 Abnormal electrocardiogram [ECG] [EKG]. Z82.41 Family history of sudden cardiac death. Z84.81 Family history of carrier of genetic disease. Z13.89 Encounter for screening for other disorder Z13.71 Encounter for nonprocreative screening for genetic disease carrier status. Genetic test screening. Z13.79 Encounter for other screening for genetic and chromosomal anomalies. HCPCS Level II S0265 Description Genetic counseling, under physician supervision, each 15 minutes. Comment 12