Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy

POLICY NUMBER

A.2.02.28

DESCRIPTION

Familial hypertrophic cardiomyopathy is an inherited condition caused by a disease associated variant in one or more of the cardiac sarcomere genes. Hypertrophic cardiomyopathy is associated with numerous cardiac abnormalities, the most serious of which is sudden cardiac death. Genetic testing for hypertrophic cardiomyopathy associated variants is available through a number of commercial laboratories.

Familial Hypertrophic Cardiomyopathy

Familial hypertrophic cardiomyopathy is the most common genetic cardiovascular condition, with a phenotypic prevalence of approximately 1 (0.2%) in 500 adults. It is the most common cause of sudden cardiac death in adults younger than 35 years of age and is probably the most common cause of death in young athletes. The overall mortality rate for patients with hypertrophic cardiomyopathy is estimated to be 1% per year in the adult population.

The genetic basis for hypertrophic cardiomyopathy is a defect in the cardiac sarcomere, which is the basic contractile unit of cardiac myocytes and is composed of different protein structures. Around 1,400 disease-associated variants in at least 18 different genes have been identified. About 90% of pathogenic variants are missense (ie, 1 amino acid is replaced for another), and the strongest evidence for pathogenicity is available for 11 genes coding for thick filament proteins (MYH7, MYL2, MYL3), thin filament proteins (TNNT2, TNNI3, TNNC1, TPM1, ACTC), intermediate filament proteins (MYBPC3), and the Z-disc adjoining the sarcomere (ACTN2, MYOZ2). Variants in myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3) are the most common and account for roughly 80% of sarcomeric hypertrophic cardiomyopathy. These genetic defects are inherited in an autosomal dominant pattern with rare exceptions. In patients with clinically documented hypertrophic cardiomyopathy, genetic abnormalities can be identified in approximately 60%. Most patients with the clinically documented disease are demonstrated to have a familial pattern, although some exceptions are found presumably due to de novo variants.

Diagnosis and Management

The clinical diagnosis of hypertrophic cardiomyopathy depends on the presence of left ventricular hypertrophy, measured by echocardiography or magnetic resonance imaging (MRI), in the absence of other known causative factors such as valvular disease, long-standing hypertension, or another myocardial disease. In addition to primary cardiac disorders, there are systemic diseases that can lead to left ventricular hypertrophy and thus mimic hypertrophic cardiomyopathy. These include infiltrative diseases such as amyloidosis, glycogen storage diseases (eg, Fabry disease, Pompe disease), and neuromuscular disorders (eg, Noonan syndrome, Friederich ataxia). These disorders need to be excluded before a diagnosis of familial hypertrophic cardiomyopathy is made.

Hypertrophic cardiomyopathy is a very heterogenous disorder. Manifestations range from subclinical, asymptomatic disease to severe, life-threatening disease. Wide phenotypic variability exists among individuals, even when an identical variant is present, including among affected family members. This variability in clinical expression may be related to environmental factors and modifier genes. A large percentage of patients with hypertrophic cardiomyopathy, perhaps the majority, are asymptomatic or have minimal symptoms. These patients do not require treatment and are not generally at high-risk for sudden cardiac death. A subset of patients has severe disease that causes a major impact on quality of life and life expectancy. Severe disease can lead to disabling symptoms, as well as complications of hypertrophic cardiomyopathy, including heart failure and malignant ventricular arrhythmias. Symptoms and presentation may include sudden cardiac death due to unpredictable ventricular tachyarrhythmias, heart failure, or atrial fibrillation, or some combination.

Management of patients with hypertrophic cardiomyopathy involves treating cardiac comorbidities, avoiding therapies that may worsen obstructive symptoms, treating obstructive symptoms with β-blockers, calcium channel blockers, and (if symptoms persist), invasive therapy with surgical myectomy or alcohol ablation, optimizing treatment for heart failure, if present, and sudden cardiac death risk stratification. Implantable cardioverter-defibrillator implantation may be indicated if there is a family history of sudden cardiac death.

Diagnostic screening of first-degree relatives and other family members is an important component of hypertrophic cardiomyopathy management. Guidelines have been established for screening clinically unaffected relatives of affected individuals. Screening with physical examination, electrocardiography, and echocardiography is recommended every 1 to 2 years in children and adolescents from genotype-positive families and families with early onset disease; every 2 to 3 years in other children after hypertrophic cardiomyopathy in a family member; and every 3 to 5 years for adults with another family member diagnosed with hypertrophic cardiomyopathy.

Genetic Testing

Genetic testing has been proposed as a component of screening at-risk individuals to determine predisposition to hypertrophic cardiomyopathy among those patients at risk. Patients at-risk for hypertrophic cardiomyopathy are defined as individuals who have a close relative with established hypertrophic cardiomyopathy. Results of genetic testing may influence the management of at-risk individuals, which may, in turn, lead to improved outcomes. Furthermore, results of genetic testing may have implications for decision making in the areas of reproduction, employment, and leisure activities. However, the likelihood of obtaining a positive genetic test in the proband is only about 60% because all genes causing hypertrophic cardiomyopathy have not yet been identified or are absent from testing panels. Failure to identify the causative variant in the proband is an indeterminate result that provides no useful information and precludes predictive testing in 33% to 67% of cases.

Commercial testing has been available since 2003, and numerous companies offer genetic testing for hypertrophic cardiomyopathy. Testing is performed either as a comprehensive or targeted gene test. Comprehensive testing, which is done for an individual without a known genetic variant in the family, analyzes the genes that are most commonly associated with genetic variants for hypertrophic cardiomyopathy and evaluates whether any potentially pathogenic variants are present. Some available panels include testing for multisystem storage diseases that may include cardiac hypertrophy, such as Fabry disease (GLA), familial transthyretin amyloidosis (TTR), and X-linked Danon disease (LAMP2).

Other panels include testing for genes related to hypertrophic cardiomyopathy and those associated with other cardiac disorders. For example, the Pan Cardiomyopathy panel (Laboratory for Molecular Medicine) is a next-generation sequencing panel of 61 genes associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, left ventricular noncompaction syndrome, Danon syndrome, Fabry disease, Brugada syndrome, and transthyretin amyloidosis.

For a patient with a known variant in the family, targeted testing is performed. Targeted variant testing evaluates for the presence or absence of a single variant known to exist in a close relative.

It can be difficult to determine the pathogenicity of genetic variants associated with hypertrophic cardiomyopathy. Some studies have reported that assignment of pathogenicity has a relatively high error rate and that classification changes over time. With next-generation sequencing and whole-exome sequencing techniques, the sensitivity of identifying variants on the specified genes has increased substantially. At the same time, the number of variants of uncertain significance is also increased with next-generation sequencing. Also, the percentage of individuals who have more than one variant that is thought to be pathogenic is increasing. A 2013 study reported that 9.5% (19/200) of patients from China with hypertrophic cardiomyopathy had multiple pathogenic variants and that the number of variants correlated with severity of disease.

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 (CLIA).Sequencing tests for hypertrophic cardiomyopathy are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing.To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

No assay kits have been approved by the U.S. Food and Drug Administration (FDA) for genetic testing for hypertrophic cardiomyopathy.

POLICY

Genetic testing for predisposition to hypertrophic cardiomyopathy may be considered medically necessary for individuals who are at risk for development of hypertrophic cardiomyopathy, defined as having a first-degree relative with established hypertrophic cardiomyopathy, when there is a known pathogenic gene variant present in that affected relative (See Policy Guidelines section).

Genetic testing for predisposition to hypertrophic cardiomyopathy is considered investigational for individuals with a family history of hypertrophic cardiomyopathy in which a first-degree relative with established hypertrophic cardiomyopathy has tested negative for pathogenic variants.

Genetic testing for predisposition to hypertrophic cardiomyopathy is considered investigational for all other populations, including but not limited to individuals who have a first-degree relative with clinicalhypertrophic cardiomyopathy, but in whom genetic testing is unavailable.

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.

Due to the complexity of genetic testing for hypertrophic cardiomyopathy and the potential for misinterpretation of results, the decision to test and the interpretation of test results should be performed by, or in consultation with, an expert in the area of medical genetics and/or hypertrophic cardiomyopathy.

To inform and direct genetic testing for at-risk individuals, genetic testing should initially be performed in at least one close relative with definite hypertrophic cardiomyopathy (index case), if possible.

Because there are varying degrees of penetrance for different hypertrophic cardiomyopathy variants, consideration for testing of second- or third-degree relatives may be appropriate in certain circumstances. Some judgment should be allowed for these decisions, for example, in the case of a small family pedigree. Consultation with an expert in medical genetics and/or the genetics of hypertrophic cardiomyopathy, in conjunction with a detailed pedigree analysis, is appropriate when testing of second- or third- degree relatives is considered.

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 is being 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 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 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 individuals 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 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 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

03/22/2012: Approved by Medical Policy Advisory Committee.

04/01/2013: Policy reviewed; no changes to policy statement. Added ICD-9 codes 425.11, 425.18, and V17.49 to the Code Reference section.

03/12/2014: Policy reviewed; no changes.

02/11/2015: Policy description updated regarding familial HCM and genetic testing for familial HCM. Policy statement unchanged.

08/26/2015: Medical policy revised to add ICD-10 codes.

02/11/2016: Policy description updated regarding testing characteristics of some HCM panels. Not medically necessary policy statement updated to clarify that genetic testing for predisposition to HCM is considered not medically necessary for patients with a family history of HCM in which a first-degree relative with established HCM has tested negative for pathologic mutations. It previously stated: Genetic testing for predisposition to HCM is considered not medically necessary for patients with a family history of HCM in which a first-degree relative has tested negative for pathologic mutations. Policy guidelines updated to add genetic counseling information and medically necessary and investigative definitions.

06/06/2016: Policy number A.2.02.28 added.

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

03/24/2017: Policy description and statements updated to change "mutation" to "variant." Policy guidelines updated to add recommended terminology for variant classification.

12/22/2017: Code Reference section updated to revise description for CPT code 81439 effective 01/01/2018.

04/03/2018: Policy description updated regarding genetic testing. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

04/04/2019: Second policy statement updated to change "pathologic variants" to "pathogenic variants."

04/15/2020: Policy reviewed; no changes.

05/25/2021: Policy description updated regarding panel testing. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

05/11/2022: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

04/13/2023: Policy description updated regarding diagnostic screening. Policy statement updated to change "not medically necessary" to "investigational" and "patients" to "individuals."

04/17/2024: Policy reviewed; no changes.

04/16/2025: Policy description updated regarding panels. Second investigational policy statement revised to change "patient populations" to "populations." Policy Guidelines updated.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.02.28

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.

Covered Codes

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