12.04.114 genetic testing for dilated cardiomyopathy | 5 of 15 ∞ description dilated...

MEDICAL POLICY 12.04.114

Genetic Testing for Dilated Cardiomyopathy

BCBSA Ref. Policy: 2.04.114

Effective Date: May 1, 2018

Last Revised: April 3, 2018

Replaces: 2.04.114

RELATED MEDICAL POLICIES:

12.04.28 Genetic Testing for Predisposition to Inherited Hypertrophic

Cardiomyopathy

12.04.43 Genetic Testing for Cardiac Ion Channelopathies

Select a hyperlink below to be directed to that section.

POLICY CRITERIA | CODING | RELATED INFORMATION

EVIDENCE REVIEW | REFERENCES | HISTORY

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Introduction

Dilated cardiomyopathy is a condition in which the left ventricle (the main pumping chamber of

the heart) becomes enlarged and can no longer pump effectively. This can lead to heart failure,

as well as cause an abnormal rhythm of the heart. It has been found that sometimes dilated

cardiomyopathy seems to run in families, and in these cases it may be caused by a genetic

problem. Doing genetic tests to see if a genetic problem has caused a persons dilated

cardiomyopathy is still investigational. Testing people who do not have any known heart

problems to see if they are at risk for developing dilated cardiomyopathy is also investigational.

Medical studies have not shown that this type of testing helps to manage the care of patients.

For this reason, genetic testing for dilated cardiomyopathy is still considered to be unproven

(investigational).

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The

rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for

providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can

be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a

service may be covered.

Policy Coverage Criteria

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Testing Investigational Genetic testing for dilated

cardiomyopathy

Genetic testing for dilated cardiomyopathy is considered

investigational in all situations.

Coding

There are several listings of genetic tests performed for dilated cardiomyopathy in the CPT Tier 2

molecular pathology codes listed below.

Code Description

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)

Includes: PLN (phospholamban) (eg, dilated cardiomyopathy, hypertrophic

cardiomyopathy), full gene sequence

81405 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence

analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or

characterization of a dynamic mutation disorder/triplet repeat by Southern blot

analysis)

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

sequence; TPM1 (tropomyosin 1 [alpha]) (eg, familial hypertrophic cardiomyopathy),

full gene sequence; TNNC1 (troponin C type 1 [slow]) (eg, hypertrophic

cardiomyopathy or dilated cardiomyopathy), full gene sequence


analysis, mutation scanning or duplication/deletion variants of 26-50 exons,

cytogenomic array analysis for neoplasia)

Includes: LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy,

myofibrillar myopathy), full gene sequence; LMNA (lamin A/C) (eg, Emery-Dreifuss

muscular dystrophy; [EDMD1, 2 and 3] limb-girdle muscular dystrophy; [LGMD] type

1B, dilated cardiomyopathy; [CMD1A], familial partial lipodystrophy; [FPLD2]), full gene

sequence; TNNT2 (troponin T, type 2 [cardiac]) (eg, familial hypertrophic

cardiomyopathy), full gene sequence


analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence

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Code Description

analysis of multiple genes on one platform)

Includes: MYH6 (myosin, heavy chain 6, cardiac muscle, alpha) (eg, familial dilated

cardiomyopathy), full gene sequence; MYH7 (myosin, heavy chain 7, cardiac muscle,

beta) (eg, familial hypertrophic cardiomyopathy, Liang distal myopathy), full gene

sequence; SCN5A (sodium channel, voltage-gated, type V, alpha subunit) (eg, familial

dilated cardiomyopathy), full gene sequence

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: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS

codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

If a genetic sequencing panel (GSP) is performed that does not meet the criteria in code 81439,

the relevant tier 2 codes above would be reported for the specific genes tested, and the unlisted

molecular pathology code would be reported 1 time for the remaining genes in the panel that

lack a specific CPT.

Related Information

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants

found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The

Societys nomenclature is recommended by the Human Variome Project, the Human Genome

Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular

Pathology standards and guidelines for interpretation of sequence variants represent expert

opinion from both organizations, in addition to the College of American Pathologists. These

recommendations primarily apply to genetic tests used in clinical laboratories, including

genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended

standard terminologypathogenic, likely pathogenic, uncertain significance, likely

benign, and benignto describe variants identified that cause Mendelian disorders.

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Table 1. Nomenclature to Report on Variants Found in DNA

Previous Updated Definition

Mutation Disease-associated variant Disease-associated change in the DNA sequence

Variant Change in the DNA sequence

Familial variant Disease-associated variant identified in a proband for use in subsequent

targeted genetic testing in first-degree relatives

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification Definition

Pathogenic Disease-causing change in the DNA sequence

Likely pathogenic Likely disease-causing change in the DNA sequence

Variant of uncertain significance Change in DNA sequence with uncertain effects on disease

Likely benign Likely benign change in the DNA sequence

Benign Benign change in the DNA sequence

American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited

disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and

understanding risk factors can be difficult for some patients; genetic counseling helps

individuals understand the impact of genetic testing, including the possible effects the test

results could have on the individual or their family members. It should be noted that genetic

counseling may alter the utilization of genetic testing substantially and may reduce

inappropriate testing; further, genetic counseling should be performed by an individual with

experience and expertise in genetic medicine and genetic testing methods.

Evidence Review

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Description

Dilated cardiomyopathy (DCM) is characterized by progressive left ventricular enlargement and

systolic dysfunction, leading to clinical manifestations of heart failure. There are a variety of

causes of DCM, including genetic and nongenetic conditions. Genetic forms of DCM are

heterogeneous in their molecular basis and clinical expression. Genetic testing for DCM has

potential utility in confirming a diagnosis of genetic DCM, and as a prognostic test in family

members when familial DCM is present.

Background

Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is defined as the presence of left ventricular enlargement and

dilatation in conjunction with significant systolic dysfunction. DCM has an estimated prevalence

of 1 in 2700 in the United States.1 The age of onset for DCM is variable, ranging from infancy to

the eighth decade, with most individuals developing symptoms in the fourth through sixth

decades.2

Diagnosis

Primary clinical manifestations of DCM are heart failure and arrhythmias. Symptoms of heart

failure, such as dyspnea on exertion and peripheral edema, are the most common presentation

of DCM. These symptoms are generally gradual in onset and slowly progressive over time.

Progressive myocardial dysfunction also may lead to electrical instability and arrhythmias.

Symptoms of arrhythmias may include light-headedness, syncope, or sudden cardiac arrest.

Many underlying conditions can cause DCM, including3:

Ischemic coronary artery disease

Toxins

Metabolic conditions

Endocrine disorders

Inflammatory and infectious diseases

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Infiltrative disorders

Tachycardia-mediated cardiomyopathy

Therefore, when a patient presents with DCM, a workup is performed to identify underlying

causes, especially those treatable. The standard workup consists of clinical exam, blood pressure

monitoring, electrocardiography, echocardiography, and workup for coronary artery disease as

warranted by risk factors. Extensive workup including cardiac magnetic resonance imaging,

exercise testing, right-sided catheterization with biopsy, and 24-hour ECG monitoring will

uncover only a small number of additional etiologies for DCM.4 Approximately 35% to 40% of

DCM cases are thus determined to be idiopathic after a negative workup for secondary causes.3

This has traditionally been termed idiopathic dilated cardiomyopathy (IDC).

Clustering of IDC within families has been reported, leading to the conclusion that at least some

cases of DCM have a genetic basis. Familial DCM is diagnosed when 2 closely related family

members have IDC in the absence of underlying causes. Penetrance of familial DCM is variable

and age-dependent, often leading to lack of appreciation of the familial component.

Treatment

Treatment of DCM is similar to that for other causes of heart failure. This includes medications to

reduce fluid overload and relieve strain on the heart, and lifestyle modifications such as salt

restriction. Patients with clinically significant arrhythmias also may be treated with

antiarrhythmic medications, pacemaker implantation, and/or an automatic implantable cardiac

defibrillator. Automatic implantable cardiac defibrillator placement for primary prevention also

may be performed if criteria for low ejection fraction and/or other clinical symptoms are present.

End-stage DCM can be treated with cardiac transplantation.

Genetic DCM

Genetic DCM has been proposed as a newer classification that includes both familial DCM and

some cases of sporadic IDC. The percentage of patients with sporadic DCM that has a genetic

basis is not well characterized. Most disease-associated variants are inherited in an autosomal

dominant fashion, but some autosomal recessive, X-linked, and mitochondrial patterns of

inheritance also are present.5

In general, genotype-phenotype correlations are either not present or not well-characterized.

There have been some purported correlations between certain disease-associated variants and

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the presence of arrhythmias. For example, patients with conduction system disease and/or a

family history of sudden cardiac death may be more likely to have disease-associated variants in

the LMNA, SCN5A, and DES genes.1 Kayvanpour et al (2017) performed a meta-analysis of

genotype-phenotype associations in DCM.6 The analysis included 48 studies (total N=8097

patients) and found a higher prevalence of sudden cardiac death, cardiac transplantation, and

ventricular arrhythmias in LMNA and PLN disease-associated variant carriers and increasing

penetrance with age of DCM phenotype in subjects with TTN-truncating variants.

There may be interactions between genetic and environmental factors that lead to the clinical

manifestations of DCM. A genetic variant may not in itself be sufficient to cause DCM, but may

predispose to developing DCM in the presence of environmental factors such as nutritional

deficiencies or viral infections.2 It also has been suggested that DCM genetics may be more

complex than simply single-gene variants, with low-penetrance variants that are common in the

population contributing to a cumulative risk of DCM that includes both genetic and

environmental factors.

Genetic Testing for DCM

Approximately 30% to 40% of patients referred for genetic testing will have a disease-associated

variant identified.5 Disease-associated variants linked to DCM have been identified in more than

40 genes of various types and locations. The most common genes involved are those that code

for titin (TTN), myosin heavy chain (MYH7), troponin T (TNNT2), and alpha-tropomyosin (TPM1).

These 4 genes account for approximately 30% of disease-associated variants identified in

cohorts of patients with DCM.5 A high proportion of the identified disease-associated variants

are rare, or novel, variants, thus creating challenges in assigning the pathogenicity of discovered

variants.2 Some individuals with DCM will have more than 1 DCM-associated variant.1 The

frequency of multiple disease-associated variants is uncertain, as is the clinical significance.

Summary of Evidence

For individuals who have signs and/or symptoms of dilated cardiomyopathy (DCM) who receive

comprehensive genetic testing, the evidence includes case series reporting clinical validity.

Relevant outcomes are overall survival, test accuracy and validity, symptoms, change in disease

status, functional outcomes, quality of life, and treatment-related morbidity. There is a large

degree of uncertainty with clinical validity. The percentage of patients with idiopathic DCM who

have a genetic variant (clinical sensitivity) is relatively low, in the range of 10% to 50%. Clinical

specificity of DCM-associated variants is unknown, but DCM-associated variants in the same

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genes have been reported in 1% to 3% of patients without DCM. Because of the suboptimal

clinical validity, the accuracy of assigning variants as disease-associated or benign may also be

suboptimal. The clinical usefulness of genetic testing for diagnosing DCM has not been

demonstrated. For a patient who is diagnosed with idiopathic DCM, the presence of a DCM-

associated variant will not change treatment or prognosis. The evidence is insufficient to

determine the effect of the technology on health outcomes.

For individuals who are asymptomatic with a first-degree relative who has DCM and a known

familial variant who receive targeted genetic testing for a known familial variant, the evidence

includes case series reporting test accuracy and clinical value. Relevant outcomes are test

accuracy and validity, symptoms, morbid events, functional outcomes, quality of life, and

treatment-related morbidity. For an individual at risk due to genetic DCM in the family, genetic

testing can identify whether a familial variant has been inherited. However, it is uncertain how

knowledge of a familial variant improves outcomes for an asymptomatic individual. The

uncertain clinical validity of predictive testing makes it unclear whether actions taken as a result

of testing will improve outcomes. Early treatment based on a genetic diagnosis is unproven. The

evidence is insufficient to determine the effect of the technology on health outcomes.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed below.

Table 3. Summary of Key Trials

NCT No. Trial Name Planned

Enrollment

Completion

Date

Ongoing

NCT02148926 Clinical and Genetic Examinations of Dilated

Cardiomyopathy

480 Sep 2017

(ongoing)

NCT01736566 The MedSeq Project Pilot Study: Integrating Whole Genome

Sequencing Into the Practice of Clinical Medicine

220 Aug 2017

(ongoing)

NCT01857856 PHOspholamban RElated CArdiomyopathy STudy -

Intervention (Efficacy Study of Eplerenone in

Presymptomatic PLN-R14del Carriers)

150 Apr 2020

Unpublished

NCT02057341a A Study of ARRY-371797 in Patients With LMNA-Related 12 May 2016

https://www.clinicaltrials.gov/ct2/show/NCT02148926?term=NCT02148926&rank=1https://www.clinicaltrials.gov/ct2/show/NCT01736566?term=NCT01736566&rank=1https://www.clinicaltrials.gov/ct2/show/NCT01857856?term=NCT01857856&rank=1https://www.clinicaltrials.gov/ct2/show/NCT02057341?term=NCT02057341&rank=1

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NCT No. Trial Name Planned

Enrollment

Completion

Date

Dilated Cardiomyopathy (completed)

NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

Practice Guidelines and Position Statements

British Society of Echocardiography

Guidelines from the British Society of Echocardiography (2017) have presented diagnostic

criteria for assessing dilated cardiomyopathy (DCM) with echocardiography, recommending that

caregivers regularly administer echocardiograms to individuals with potential genetic risk,

particularly those related to an individual with idiopathic DCM.53 The guidelines did not address

the use of genetic testing in cases of DCM.

Cardiac Society of Australia and New Zealand

The Cardiac Society of Australia and New Zealand published a 2017 position statement on the

appropriate assessment of and treatment for familial DCM.54 The statement addressed the

growing number of potentially pathogenic novel variants, recommending that any genetic tests

be evaluated by experts in molecular cardiology to prevent unnecessary or inaccurate reporting

to family members should the variant in question not be disease-causing. The authors

recommended genetic testing for individuals related to patients with familial DCM, especially

relatives of young patients. In general, individuals with increased risk of familial DCM (eg,

women of child-bearing age, families with a history of conduction system disease) should be

counseled on lifestyle modification and followed at regular intervals.

Heart Rhythm Society and European Hearth Rhythm Association

The Heart Rhythm Society and European Hearth Rhythm Association issued joint guidelines

(2011) on genetic testing for cardiac channelopathies and cardiomyopathies.55 These guidelines

contained the following recommendations on genetic testing for DCM:

Class I recommendations

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Comprehensive or targeted (LMNA and SCN5A) DCM genetic testing is recommended for

patients with DCM and significant cardiac conduction disease (ie, first-, second-, or third-

degree heart block) and/or with a family history of premature unexpected sudden death.

Mutation-specific testing is recommended for family members and appropriate relatives

following the identification of a DCM-causative mutation [variant] in the index case.

Class IIa recommendations

Genetic testing can be useful for patients with familial DCM to confirm the diagnosis, to

recognize those who are at highest risk of arrhythmia and syndromic features, to facilitate

cascade screening within the family, and to help with family planning.

The Heart Rhythm Society and European Heart Rhythm Association (2011) consensus statement

also noted that prophylactic implantable cardioverter defibrillator can be considered in patients

with known arrhythmia and/or conduction system disease (LMNA or Desmin [DES]).55

Heart Failure Society of America

The Heart Failure Society of America published practice guidelines (2009) on the genetic

evaluation of cardiomyopathy.52 The following recommendations for genetic testing for

cardiomyopathy (including DCM) were made:

Evaluation, genetic counseling, and genetic testing of cardiomyopathy patients are complex

processes. Referral to centers expert in genetic evaluation and family-based management

should be considered (Level of Evidence B).

Genetic testing should be considered for the one most clearly affected person in a family to

facilitate screening and management.

Genetic and family counseling is recommended for all patients and families with

cardiomyopathy (Level of Evidence A).

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for cardiomyopathy have been

identified.

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Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage

decisions are left to the discretion of local Medicare carriers.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory

service; laboratory-developed tests must meet the general regulatory standards of the Clinical

Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must

be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing.

To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review

of this test.

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cardiomyopathy. Medicine (Baltimore). Aug 2017;96(33):e7727. PMID 28816949

49. Petropoulou E, Soltani M, Firoozabadi AD, et al. Digenic inheritance of mutations in the cardiac troponin (TNNT2) and cardiac

beta myosin heavy chain (MYH7) as the cause of severe dilated cardiomyopathy. Eur J Med Genet. Sep 2017;60(9):485-488.

PMID 28642161

50. Rafiq MA, Chaudhry A, Care M, et al. Whole exome sequencing identified 1 base pair novel deletion in BCL2-associated

athanogene 3 (BAG3) gene associated with severe dilated cardiomyopathy (DCM) requiring heart transplant in multiple family

members. Am J Med Genet A. Mar 2017;173(3):699-705. PMID 28211974

51. Liu JS, Fan LL, Zhang H, et al. Whole-exome sequencing identifies two novel TTN mutations in Chinese families with dilated

cardiomyopathy. Cardiology. 2017;136(1):10-14. PMID 27544385

Page | 14 of 15

52. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America

practice guideline. J Card Fail. Mar 2009;15(2):83-97. PMID 19254666

53. Mathew T, Williams L, Navaratnam G, et al. Diagnosis and assessment of dilated cardiomyopathy: a guideline protocol from the

British Society of Echocardiography. Echo Res Pract. Jun 2017;4(2):G1-G13. PMID 28592613

54. Fatkin D, Johnson R, McGaughran J, et al. Position statement on the diagnosis and management of familial dilated

cardiomyopathy. Heart Lung Circ. Nov 2017;26(11):1127-1132. PMID 28655534

55. Ackerman MJ, Priori SG, Willems 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). Heart Rhythm. Aug 2011;8(8):1308-1339. PMID 21787999

History

Date Comments 03/10/14 New Policy. New policy developed with literature review through December 15, 2013.

Genetic testing for dilated cardiomyopathy is considered investigational for all

indications.

07/24/14 Update Related Policies. Remove 12.04.91.

03/10/15 Annual Review. Policy updated with literature review through December 23, 2014;

references 5, 18-19, and 21-25 added. Policy statement unchanged.

04/01/16 Annual Review, approved March 8, 2016. Policy updated with literature review through

November 17, 2015; reference 1 updated; references 4 and 24 added. Policy statement

unchanged.

01/01/17 Coding update; added new CPT code 81439 effective 1/1/17.

05/01/17 Annual review, approved April 11, 2017. Policy updated with literature review through

December 21, 2016; references 6-10, 18-21, 26-27, and 39-43 added. The policy is

revised with updated genetics nomenclature mutation changed to variant when

applicable. Policy statement unchanged.

09/22/17 Policy moved to new format, no changes to policy statement.

05/01/18 Annual Review, approved April 3, 2018. Policy updated with literature review through

December 2017; references 29, 33-34, and 46-54 added. Policy statement unchanged.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The

Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and

local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review

and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit

booklet or contact a member service representative to determine coverage for a specific medical service or supply.

Page | 15 of 15

CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). 2018 Premera

All Rights Reserved.

Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when

determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to

the limits and conditions of the member benefit plan. Members and their providers should consult the member

benefit booklet or contact a customer service representative to determine whether there are any benefit limitations

applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

037336 (07-2016)

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