Hereditary Cardiomyopathies (Including ARVD/C)

10/5/2017 GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C)

Medical Policy

Subject: Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C) Policy #: GENE.00017 Current Effective Date: 06/28/2017 Status: Revised Last Review Date: 05/04/2017

Description/Scope

This document addresses genetic testing for the hereditary cardiomyopathies which includes hypertrophic (HCM), dilated (DCM), restrictive (RCM), arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and left ventricular noncompaction (LVNC).

Note: This document addresses genetic testing for hereditary cardiomyopathies only. For information about genetic testing for other hereditary cardiac conditions, see:

GENE.00007 Cardiac Ion Channel Genetic Testing

Position Statement

Medically Necessary:

Genetic testing for hereditary hypertrophic cardiomyopathies (HCM) is considered medically necessary when all of the following criteria are met:

A. The individual to be tested has a first degree family member with a documented HCM and the first degree relative also has a genetic mutation with strong evidence for pathogenicity; and B. The individual to be tested has been clinically screened (for example, with EKG, echocardiogram, or cardiac magnetic resonance imaging [MRI]) and does not have a diagnosis of HCM; and C. Genetic counseling, which encompasses all of the following components, has been performed: 1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and 2. Education about inheritance, genetic testing, disease management, prevention and resources; and 3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and 4. Counseling for the psychological aspects of genetic testing.

Investigational and Not Medically Necessary:

Genetic testing for determining the diagnosis and for management of hereditary HCM is considered investigational and not medically necessary when the above criteria are not met.

Genetic testing for determining the diagnosis and for management of all other hereditary cardiomyopathies, including but not limited to, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), dilated, restrictive, and left ventricular noncompaction cardiomyopathies, is considered investigational and not medically necessary for all indications.

Rationale

Genetic testing has been proposed to determine an individual's predisposition to hypertrophic cardiomyopathy (HCM) among those persons considered to be at risk, due to confirmed HCM in a close family member. Familial HCM is the most common hereditary cardiac condition in the U.S. and is thought to be the most common cause of sudden cardiac death (SCD) in young athletes and others 35 years of age and younger. Developments in the field of genetic testing have led to identification of specific genetic mutations that are associated with high risk for HCM. Proponents of this testing suggest that identification of these mutations in at risk individuals may lead to improved clinical outcomes.

According to the HFSA practice guideline on genetic testing:

The available clinical genetics data for each of the cardiomyopathies varies greatly in content and quality, and thus, the quality and certainty of genetic counseling information is also variable. So too, the evidence that supports clinical genetic testing varies greatly. Although analytic validity (the ability of the test to detect a mutation) is attainable with current methods, evidence to support clinical validity (the ability of the test to detect the condition) remains quite limited for most cardiomyopathies, the exception being HCM. A separate measurement, clinical utility, defines the global risks and benefits of any test, asking the all-important question: how will the genetic information, whether positive or negative, affect clinical decision-making…Clinical utility remains to be defined for all genetic testing of cardiomyopathies (Hershberger, 2009). https://www.anthem.com/medicalpolicies/policies/mp_pw_c132947.htm 1/8 10/5/2017 GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C) This information was updated in 2011 in a Heart Failure Society of America/European Heart Rhythm Association (HRS/EHRA) Consensus Statement on the State of Genetic Testing for Channelopathies and Cardiomyopathies (Ackerman, 2011) 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, 2011) 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).

In 2011, the American College of Cardiology Foundation and the American Heart Association (ACCF/AHA) Task Force on Practice Guidelines issued a Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy (Gersh, 2011) which included the following recommendations:

Evaluation of familial inheritance and genetic counseling is recommended as part of the assessment of patients with HCM; (Class I; Level of Evidence: B) Screening (clinical, with or without genetic testing) is recommended in first-degree relatives of patients with HCM; (Class I; Level of Evidence: B) Genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause; (Class I; Level of Evidence: B) Genetic testing is reasonable in the index patient to facilitate the identification of first-degree family members at risk for developing HCM. (Class IIa; Level of Evidence: B)

According to a recent review paper on the current knowledge base for the genetics of HCM testing (Maron, 2012), the following genetic mutations have strong evidence for pathogenicity in HCM:

Thick filament:

β-myosin heavy chain -- MYH7 Regulatory myosin light chain -- MYL2 Essential myosin light chain -- MYL3

Thin filament:

Cardiac troponin T -- TNNT2 Cardiac troponin I -- TNNI3 Cardiac troponin C -- TNNC1 α-tropomyosin -- TPM1 α-cardiac actin -- ACTC

Intermediate filament:

Cardiac myosin-binding protein C -- MYBPC3 https://www.anthem.com/medicalpolicies/policies/mp_pw_c132947.htm 2/8 10/5/2017 GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C) Z-disc:

α-actinin 2 -- ACTN2 Myozenin 2 -- MYOZ2

The high negative predictive value of genetic testing for HCM can be used to reduce follow-up screening in individuals who have a first degree relative with clinical findings of HCM and a genetic test which has strong evidence for pathogenicity when the individual being tested has no evidence of HCM. However, even an individual with a negative test can develop clinical disease due to, as yet, unidentified gene mutations and de novo mutations. For this reason, genetic counseling is necessary to make sure any individual to be tested understands the implications of the test and the uncertainty which often remains after the results are known. The positive predictive value of genetic testing for HCM remains of uncertain clinical value and the diagnostic utility of a positive result remains uncertain. More comprehensive evidence across different population groups and in larger numbers of individuals will continue to inform the practice community about the role of genetic testing, particularly in the heritable cardiomyopathies (Maron, 2012).

Background/Overview

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 U.S. Food and Drug Administration (FDA) regulates tests sold as "diagnostic devices," that is, tests manufactured by one company and then sold as a kit to a laboratory for genetic testing. However, the FDA does not regulate these tests that are both manufactured and performed by the same laboratory (the FAMILION test falls into this category). Because of this regulatory exception, genetic testing services for these laboratory-based tests can be marketed directly to the medical community and the public without FDA regulation or oversight.

Another genetic test for cardiomyopathy, the HCM CardioChip™ test, is exclusively available at the Laboratory for Molecular Medicine at Harvard Medical School, Boston MA.

Genetic Counseling According to the National Society of Genetic Counselors (NSGC), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease. This process typically includes the guidance of a specially trained professional who:

1. Integrates the interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and 2. Provides education about inheritance, genetic testing, disease management, prevention and resources; and 3. Provides counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and 4. Provides counseling for the psychological aspects of genetic testing (NSGC, 2006).

Definitions

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C): This is a myocardial disorder that predominantly affects the right ventricle. ARVD/C is a progressive disorder characterized by fibro-fatty replacement of the myocardium (heart muscle), which predisposes affected individuals to ventricular tachycardia and sudden death commonly in young persons and athletes. The pathology in ARVD/C may also extend to involve the left ventricle.

Familial dilated cardiomyopathy (FDC): A form of dilated cardiomyopathy (DCM) which is associated with specific genetic mutations and is characterized by an enlargement of the left ventricle (i.e., hypertrophy) with systolic dysfunction and a reduction in the force of contraction. Symptoms at initial presentation of DCM often include heart failure, arrhythmias and/or conduction system disease, and/or thromboembolic disease.

Familial hypertrophic cardiomyopathy (FHCM): A form of HCM (see below) which is associated with specific genetic mutations and is characterized by left ventricular hypertrophy (enlargement/thickening of the ventricle wall and/or interventricular septum), in the absence of another cardiac condition or systemic disease capable of producing significant hypertrophy. It is the most common inherited cardiac disorder, affecting 1 in 500 adults.

Hypertrophic cardiomyopathy (HCM): This myocardial disorder is caused by mutation in one of the genes currently known to encode different components of the sarcomere. The disorder is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiac conditions, (e.g., aortic stenosis) or cardiovascular conditions, (e.g., long- standing hypertension). The clinical manifestations of HCM range from asymptomatic to progressive heart failure to sudden cardiac death and vary from individual to individual even within the same family. Common symptoms include shortness of breath (particularly with exertion), chest pain, palpitations, orthostasis, presyncope, and syncope. Most often the LVH of HCM becomes apparent during adolescence or young adulthood, although it may also develop late in life, in infancy, or in childhood. https://www.anthem.com/medicalpolicies/policies/mp_pw_c132947.htm 3/8 10/5/2017 GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C) Sudden cardiac death (also called sudden death [SCD]): This term refers to death resulting from an abrupt loss of heart function (cardiac arrest).

Coding

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 for HCM:

CPT 81403 Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) [when specified as the following]:

PLN (phospholamban) (eg, dilated cardiomyopathy, hypertrophic cardiomyopathy), full gene sequence

81405 Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) [when specified as the following]:

ACTC1 (actin, alpha, cardiac muscle 1) (eg, familial hypertrophic cardiomyopathy), full gene sequence MYL2 (myosin, light chain 2, regulatory, cardiac, slow) (eg, familial hypertrophic cardiomyopathy), full gene sequence MYL3 (myosin, light chain 3, alkali, ventricular, skeletal, slow) (eg, familial hypertrophic cardiomyopathy), full gene sequence TNNC1 (troponin C type 1 [slow]) (eg, hypertrophic cardiomyopathy or dilated cardiomyopathy), full gene sequence TNNI3 (troponin I, type 3 [cardiac]) (eg, familial hypertrophic cardiomyopathy), full gene sequence TPM1 (tropomyosin 1 [alpha]) (eg, familial hypertrophic cardiomyopathy), full gene sequence

81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

PRKAG2 (protein kinase, AMP-activated, gamma 2 non-catalytic subunit) (eg, familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome, lethal congenital glycogen storage disease of heart), full gene sequence TNNT2 (troponin T, type 2 [cardiac]) (eg, familial hypertrophic cardiomyopathy), full gene sequence

81407 Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform) [when specified as the following]:

MYBPC3 (myosin binding protein C, cardiac) (eg, familial hypertrophic cardiomyopathy), full gene sequence MYH7 (myosin, heavy chain 7, cardiac muscle, beta) (eg, familial hypertrophic cardiomyopathy, Liang distal myopathy), full gene sequence

81479 Unlisted molecular pathology procedure [when specified as a gene panel for hereditary hypertrophic cardiomyopathy]

HCPCS S3866 Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family

ICD-10 Diagnosis I42.0-I42.9 Cardiomyopathy [when specified for hereditary hypertrophic cardiomyopathy] Z82.41-Z82.49 Family history of ischemic heart disease and other diseases of the circulatory system [when specified as hereditary hypertrophic cardiomyopathy]

https://www.anthem.com/medicalpolicies/policies/mp_pw_c132947.htm 4/8 10/5/2017 GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C) When services are Investigational and Not Medically Necessary: For the procedure codes listed above, when criteria are not met for hereditary hypertrophic cardiomyopathy.

When services are Investigational and Not Medically Necessary:

CPT 81405 Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons), regionally targeted cytogenomic array analysis [when specified as the following]:

ANKRD1 (ankyrin repeat domain 1) (eg, dilated cardiomyopathy), full gene sequence

DSC2 (desmocollin) (eg, arrhythmogenic right ventricular dysplasia/ cardiomyopathy 11), full gene sequence DSG2 (desmoglein 2) (eg, arrhythmogenic right ventricular dysplasia/ cardiomyopathy 10), full gene sequence DSP (desmoplakin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 8), full gene sequence JUP (junction plakoglobin) (eg, arrhythmogenic right ventricular dysplasia/ cardiomyopathy 11), full gene sequence LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy, myofibrillar myopathy), full gene sequence PKP2 (plakophilin 2) (eg, arrhythmogenic right ventricular dysplasia/ cardiomyopathy 9), full gene sequence TMEM43 (transmembrane protein 43) (eg, arrhythmogenic right ventricular cardiomyopathy), full gene sequence

MYH6 (myosin, heavy chain 6, cardiac muscle, alpha) (eg, familial dilated cardiomyopathy), full gene sequence SCN5A (sodium channel, voltage-gated, type V, alpha subunit) (eg, familial dilated cardiomyopathy), full gene sequence

81408 Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis) [when specified as the following]:

RYR2 (ryanodine receptor 2 [cardiac]) (eg, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia), full gene sequence or targeted sequence analysis of >50 exons

81479 Unlisted molecular pathology procedure [when specified as a gene panel for other than hereditary hypertrophic cardiomyopathy, such as ARVC test, DCM test, CD-DCM test]

ICD-10 Diagnosis I42.0-I42.9 Cardiomyopathy [when specified for cardiomyopathy other than hereditary HCM] Z82.41-Z82.49 Family history of ischemic heart disease and other diseases of the circulatory system [when specified as cardiomyopathy other than hereditary HCM]

When services are also Investigational and Not Medically Necessary:

CPT 81439 Inherited cardiomyopathy (eg, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy) genomic sequence analysis panel, must include sequencing of at least 5 genes, including DSG2, MYBPC3, MYH7, PKP2 and TTN [Note: code effective 01/01/2017]

HCPCS S3865 Comprehensive gene sequence analysis for hypertrophic cardiomyopathy

ICD-10 Diagnosis All diagnoses https://www.anthem.com/medicalpolicies/policies/mp_pw_c132947.htm 5/8 10/5/2017 GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C) References

Peer Reviewed Publications:

1. Asimaki A, Tandri H, Huang H, et al. A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med. 2009; 360(11):1075-1084. 2. Awad MM, Calkins H, Judge DP. Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Prac Cardiovasc Med. 2008; 5(5):258-267. 3. Barahona-Dussault C, Benito B, Campuzano O, et al. Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Clin Genet. 2010; 77(1):37-48. 4. Bos JM, Will ML, Gersh BJ, et al. Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. Mayo Clin Proc. 2014; 89(6):727-737. 5. Cox MG, van der Zwaag PA, van der Werf C, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study. Circ. 2011; 123(23):2690-2700. 6. Fowler SJ, Cerrone M, Napolitano C, Priori SG. Genetic testing for inherited cardiac arrhythmias. Hellenic J Cardiol. 2010; 51(2):92-103. 7. Fowler SJ, Napolitano C, Priori SG. When is genetic testing useful in patients suspected to have inherited cardiac arrhythmias? Curr Opin Cardiol. 2010; 25(1):37-45. 8. Fressart V, Duthoit G, Donal E, et al. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace. 2010; 12(6):861- 868. 9. Gomez J, Reguero JR, Moris C, et al. Mutation Analysis of the Main Hypertrophic Cardiomyopathy Genes Using Multiplex Amplification and Semiconductor Next-Generation Sequencing. Circ J. 2014; 78(12):2963-2971. 10. Haas J, Frese KS, Peil B, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. 2015; 36(18):1123-1135. 11. Hodgkinson K, Dicks E, Connors S, et al. Translation of research discoveries to clinical care in arrhythmogenic right ventricular cardiomyopathy in Newfoundland and Labrador: lessons for health policy in genetic disease. Genet Med. 2009; 11(12):859-865. 12. Junttila MJ, Castellanos A, Huikuri HV, Myerburg RJ. Risk markers of sudden cardiac death in standard 12-lead electrocardiograms. Ann Med. 2012; 44(7):717-732. 13. Kapplinger JD, Landstrom AP, Salisbury BA, et al. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J Am Coll Cardiol. 2011; 57(23):2317-2327. 14. Keren A, Syrris P, McKenna WJ. Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nat Clin Pract Cardiovasc Med. 2008; 5(3):158-168. 15. Kramer CM, Appelbaum E, Desai MY, et al. Hypertrophic Cardiomyopathy Registry: The rationale and design of an international, observational study of hypertrophic cardiomyopathy. Am Heart J. 2015; 170(2):223-230. 16. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years -- clinical perspectives. J Am Coll Cardiol. 2012; 60(8):705–715. 17. Merner ND, Hodgkinson KA, Haywood AF, et al. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008; 82(4):809-821. 18. Quarta G, Muir A, Pantazis A, et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011; 123(23):2701-2709. 19. Rodday AM, Triedman JK, Alexander ME, et al. Electrocardiogram screening for disorders that cause sudden cardiac death in asymptomatic children: a meta-analysis. Pediatrics. 2012; 129(4):e999-e1010. 20. Sen-Chowdhry S, Syrris P, McKenna WJ. Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Col Card. 2007; 50(19):1813-1821.

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(8):1308-1339. 2. American Academy of Pediatrics (AAP). Policy statement: Pediatric Sudden Cardiac Arrest. Pediatrics. 2012 April; 129(4). Available at: http://pediatrics.aappublications.org/content/129/4/e1094.full.pdf. Accessed on April 6, 2017. 3. American Board of Genetic Counselors (ABGC). Genetic Counselors' Scope of Practice. Available at: http://www.abgc.net/docs/GC_Scope_of_prractice_final.pdf. Accessed on April 6, 2017. 4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Genetic testing for predisposition to inherited hypertrophic cardiomyopathy. TEC Assessment. 2010; 24(11). 5. Cirino AL, Ho C. Familial hypertrophic cardiomyopathy overview. Gene Reviews. Last updated January 16, 2014. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hyper-card. Accessed on April 6, 2017. 6. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014; 35(39):2733-2779. 7. 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 https://www.anthem.com/medicalpolicies/policies/mp_pw_c132947.htm 6/8 10/5/2017 GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C) 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(21):1- 62. 8. Gersh BJ, Maron BJ, Bonow RO, et al. American College of Cardiology/American Heart Association (ACCF/AHA) Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011; 58(25):e121-e260. 9. Gollob MH, Blier L, Brugada R, et al. Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position paper. Can J Cardiol. 2011; 27(2):232-245. 10. Heart Rhythm UK Familial Sudden Death Syndromes Statement Development Group (HRUK). Clinical indications for genetic testing in familial sudden cardiac death syndromes: an HRUK position statement. Heart. 2008; 94(4):502-507. 11. 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://www.onlinejcf.com/article/S1071-9164(09)00028-1/fulltext?mobileUi=0. Accessed on April 6, 2017. 12. Hershberger RE, Morales A. Dilated Cardiomyopathy Overview. Gene Reviews. Last updated September 24, 2015. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1309/. Accessed on April 6, 2017. 13. Holtzman NE, Watson MS, editors. National Human Genome Research Institute. Final Report of the Task Force on Genetic Testing: Promoting safe and effective genetic testing in the United States. 1997. Last reviewed April 2006. Available at: http://www.genome.gov/page.cfm?pageID=10001733. Accessed on April 6, 2017. 14. 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. 15. Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation. 2009; 119(8):1085–1092. 16. Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. Eur Heart J. 2003; 24(21):1965-1991. 17. 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(14):1460-1471. 18. McNally E, MacLeod H, Dellefave L. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant. National Center for Biotechnology Information (NCBI). Gene Reviews. Last updated January 9, 2014. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1131/. Accessed on April 6, 2017. 19. National Society of Genetic Counselors' (NSGC) Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83. 20. 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. 21. Raman G, Chang LKW, Gaylor JM, et al. Tufts Medical Center. Update on Mapping the Landscape of Genetic Tests for Non-cancer Diseases/Conditions. Agency for Healthcare Research and Quality (AHRQ). Technology Assessment Report: GEND0511. May 22, 2012. Available at: http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id86TA.pdf. Accessed on April 6, 2017. 22. University of Virginia, National Heart, Lung and Blood Institute. HCMR - Novel Markers of Prognosis in Hypertrophic Cardiomyopathy (HCMR). NLM Identifier: NCT01915615. Last updated on May 11, 2016. Available at: https://clinicaltrials.gov/ct2/show/NCT01915615?term=NCT01915615&rank=1. Accessed on April 6, 2017. 23. van der Zwaag PA, Jongbloed JD, van den Berg MP, et al. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat. 2009; 30(9):1278-1283. 24. Walsh R, Thomson KL, Ware KS, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genetics Med. 2017; 19:192-203. Available at: http://www.nature.com/gim/journal/vaop/ncurrent/full/gim201690a.html. Accessed on April 6, 2017. 25. 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(10):e385-484.

Websites for Additional Information

1. National Institutes of Health (NIH). National Heart, Lung and Blood Institute (NHLBI). Cardiomyopathy. Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/cm/cm_what.html. Accessed on April 6, 2017.

https://www.anthem.com/medicalpolicies/policies/mp_pw_c132947.htm 7/8 10/5/2017 GENE.00017 Genetic Testing for Diagnosis and Management of Hereditary Cardiomyopathies (including ARVD/C) Index

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Cardiomyopathy, Hypertrophic (HCM) Familial Dilated Cardiomyopathy (FDC) Familial Hypertrophic Cardiomyopathy (FHCM) FAMILION Genetic Testing

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Document History Status Date Action Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated the medically necessary statements to include criteria for genetic counseling. Updated Background/Overview, Definitions, References and History sections. Reviewed 11/03/2016 MPTAC review. References were updated. Updated Coding section with 01/01/2017 CPT changes. Reviewed 11/05/2015 MPTAC review. References were updated. Removed ICD-9 codes from Coding section. Reviewed 11/13/2014 MPTAC review. Updated Reference section. Reviewed 11/14/2013 MPTAC review. Updated Rationale and Reference sections. Updated Coding section with 01/01/2014 CPT descriptor changes for 81405. 07/01/2013 Updated Coding section with 07/01/2013 CPT changes. 01/01/2013 Updated Coding section with 01/01/2013 CPT changes; removed 83890-83914 deleted 12/31/2012. Revised 11/08/2012 MPTAC review. A new position statement has been added which considers genetic testing for HCM medically necessary when criteria are met. The Rationale, Coding and Reference sections were updated. Reviewed 05/10/2012 MPTAC review. The Definitions and References were updated. Reviewed 02/16/2012 MPTAC review. Consultant input reviewed, along with the recommendations of the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy (Gersh, 2011). Reviewed 11/17/2011 MPTAC review. The Rationale, Definitions and References were updated. New 11/18/2010 MPTAC review. Initial document development.

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