Genetic Testing for Idiopathic Dilated Cardiomyopathy

POLICY NUMBER

A.2.04.114

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 for confirming a diagnosis of genetic DCM and as a prognostic test in family members when familial DCM is present.

Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is defined as the presence of left ventricular enlargement and dilatation in conjunction with significant systolic dysfunction. Dilated cardiomyopathy has an estimated prevalence of 1 in 2,700 in the United States. The age of onset for DCM varies, ranging from infancy to the eighth decade, with most individuals developing symptoms in the fourth through sixth decades.

Idiopathic Dilated Cardiomyopathy

When a patient presents with DCM, a workup is performed to identify underlying causes, especially those treatable. The standard workup consists of a clinical exam, blood pressure monitoring, electrocardiography, echocardiography, and workup for coronary artery disease as warranted by risk factors. An extensive workup including cardiac magnetic resonance imaging (MRI), exercise testing, right-sided catheterization with biopsy, and 24-hour electrocardiography monitoring will uncover only a small number of additional etiologies for DCM. Approximately 35% to 40% of DCM cases are thus determined to be idiopathic after a negative workup for secondary causes listed above. 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 two closely related family members have IDC in the absence of underlying causes. Penetrance of familial DCM is variable and age-dependent, often leading to a lack of appreciation of the familial component.

Genetic Dilated Cardiomyopathy

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. Expanded numbers of genotyped individuals facilitate genotype-phenotype correlations and studies of natural disease history. Recognition of high-risk variant carriers is important as these individuals would be expected to have the most to gain from pre-emptive interventions.

In general, genotype-phenotype correlations in the inherited cardiomyopathies are either not present or not well characterized. There have been some purported correlations between certain disease-associated variants and 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 lamin A/C (LM), SCN5A, and desmin genes. Kayvanpour and colleagues performed a meta-analysis of genotype-phenotype associations in DCM. The analysis included 48 studies (N=8,097) and found a higher prevalence of sudden cardiac death, cardiac transplantation, and ventricular arrhythmias in the LM and phospholamban (PLN) disease-associated variant carriers and increasing penetrance with age of DCM phenotype in subjects with titin (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. It also has been suggested that DCM genetics may be more complex than 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.

Diagnosis of Dilated Cardiomyopathy

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 presentations 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, including:

• Ischemic coronary artery disease

• Toxins

• Metabolic conditions

• Endocrine disorders

• Inflammatory and infectious diseases

• Infiltrative disorders

• Tachycardia-mediated cardiomyopathy.

Treatment of Dilated Cardiomyopathy

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 may also be treated with antiarrhythmic medications, pacemaker implantation, and/or an automatic implantable cardiac defibrillator. Automatic implantable cardiac defibrillator placement for primary prevention may also 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 Testing for Dilated Cardiomyopathy

Approximately 30% to 40% of patients with DCM referred for genetic testing will have a disease-associated variant identified. 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-tropomysin (TPM1). These four genes account for approximately 30% of disease-associated variants identified in cohorts of patients with DCM. A high proportion of the identified disease-associated variants are rare, or novel, variants, thus creating challenges in assigning the pathogenicity of discovered variants. Some individuals with DCM will have more than one DCM-associated variant. The frequency of multiple disease-associated variants is uncertain, as is the clinical significance.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Comprehensive genetic testing for individuals with signs or symptoms of dilated cardiomyopathy, which is considered idiopathic after a negative workup for secondary causes is considered medically necessary.

Targeted genetic testing for asymptomatic individuals with a first-degree relative who has dilated cardiomyopathy and a known familial variant is considered medically necessary.

Genetic testing for dilated cardiomyopathy is considered investigational in all other situations.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Standard Workup for Patients with Signs or Symptoms of Dilated Cardiomyopathy

The standard workup for patients with signs or symptoms of dilated cardiomyopathy includes a clinical exam, blood pressure monitoring, electrocardiography, echocardiography, and workup for coronary artery disease as warranted by risk factors. An extensive workup including cardiac magnetic resonance imaging, exercise testing, right-sided catheterization with biopsy, and 24-hour electrocardiography monitoring will uncover only a small number of additional etiologies for DCM.

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. It was implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's 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 (ACMG) and the Association for Molecular Pathology (AMP) 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 terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

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

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to the Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

04/01/2014: Approved by Medical Policy Advisory Committee.

12/31/2014: Code Reference section updated to revise the description of the following CPT codes: 81403 and 81405.

02/10/2015: Policy reviewed; description updated regarding genetic tests for DCM. Policy statement unchanged.

07/20/2015: Code Reference section updated for ICD-10.

03/08/2016: Policy description updated regarding tests. Policy statement unchanged. Policy guidelines updated to add genetic counseling information and to update investigative definition.

06/07/2016: Policy number A.2.04.114 added.

12/30/2016: Code Reference section updated to add new 2017 CPT code 81439.

02/24/2017: Policy description updated regarding a study on genotype-phenotype associations in DCM. Policy statement unchanged. Policy guidelines updated regarding standard terminology for variant classification.

06/27/2017: Code Reference section updated to revise code descriptions for CPT codes 81403, 81405, and 81406, effective 07/01/2017.

12/22/2017: Code Reference section updated to revise descriptions for CPT codes 81403, 81405, 81406, and 81439 effective 01/01/2018.

02/28/2018: Policy description updated. Policy statement unchanged. Policy Guidelines updated regarding genetic counseling.

08/01/2019: Policy title updated to add "Idiopathic." Policy description updated with minor changes. Added the following policy statements: 1) Comprehensive genetic testing for individuals with signs or symptoms of dilated cardiomyopathy which is considered idiopathic after a negative workup for secondary causes is considered medically necessary. 2) Targeted genetic testing for asymptomatic individuals with a first-degree relative who has dilated cardiomyopathy and a known familial variant is considered medically necessary. Genetic testing for dilated cardiomyopathy is considered investigational in all other situations. Policy Guidelines updated regarding standard workup for patients with signs or symptoms of dilated cardiomyopathy. Code Reference section updated to change investigational codes to medically necessary codes and add ICD-10 diagnosis code I42.0.

03/09/2020: Policy title changed from "Genetic Testing for Idiopathic Dilated Cardiomyopathy" to "Genetic Testing for Dilated Cardiomyopathy." Policy description updated to remove information regarding idiopathic dilated cardiomyopathy and genetic dilated cardiomyopathy. Policy statements unchanged.

04/02/2021: Policy description updated to add information regarding dilated cardiomyopathy, idiopathic dilated cardiomyopathy, and genetic dilated cardiomyopathy. Policy statements unchanged. Policy Guidelines updated to define medically necessary and medical necessity.

04/07/2022: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

03/14/2023: Policy title changed from "Genetic Testing for Dilated Cardiomyopathy" to "Genetic Testing for Idiopathic Dilated Cardiomyopathy." Policy reviewed. Policy statements unchanged.

03/15/2024: Policy reviewed; no changes.

04/09/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.114

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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