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Familial hypertrophic cardiomyopathy (HCM) is an inherited condition that is caused by a mutation in one or more of the cardiac sarcomere genes. HCM is associated with numerous cardiac abnormalities, the most serious of which is sudden cardiac death (SCD). Genetic testing for HCM-associated mutations is currently available through a number of commercial laboratories.
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular condition, with a phenotypic prevalence of approximately 1 in 500 adults (0.2%). It is the most common cause of sudden cardiac death (SCD) in adults younger than 35 years of age and is probably also the most the most common cause of death in young athletes. The overall death rate for patients with HCM is estimated to be 1% per year in the adult population.
The genetic basis for HCM is a defect in the cardiac sarcomere, which is the basic contractile unit of cardiac myocytes and is composed of a number of different protein structures. Nearly 1,400 individual mutations in at least 18 different genes have been identified to date. Approximately 90% of pathogenic mutations 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). Mutations in myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3) are the most common and account for roughly 80% of sarcomeric HCM. These genetic defects are inherited in an autosomal dominant pattern with rare exceptions. In patients with clinically documented HCM, genetic abnormalities can be identified in approximately 60%. Most patients with clinically documented disease are demonstrated to have a familial pattern, although some exceptions are found presumably due to de novo mutations.
The clinical diagnosis of HCM depends on the presence of left ventricular hypertrophy (LVH), measured by echocardiography or magnetic resonance imaging (MRI), in the absence of other known causative factors such as valvular disease, long-standing hypertension, or other myocardial disease. In addition to primary cardiac disorders, there are systemic diseases that can lead to LVH and thus “mimic” HCM. These include infiltrative diseases such as amyloidosis, glycogen storage diseases such as Fabry disease and Pompe disease, and neuromuscular disorders such as Noonan syndrome and Friederich ataxia. These disorders need to be excluded before a diagnosis of familial HCM is made.
HCM 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 mutation 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 HCM, perhaps the majority of all HCM patients, are asymptomatic or have minimal symptoms. These patients do not require treatment and are not generally at high risk for SCD. 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 HCM, including heart failure and malignant ventricular arrhythmias. Symptoms and presentation may include SCD due to unpredictable ventricular tachyarrhythmias, heart failure, or atrial fibrillation, or some combination. Management of patients with HCM 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 SCD risk stratification.
Diagnostic screening of first-degree relatives and other family members is an important component of HCM management. Guidelines have been established for clinically unaffected relatives of affected individuals. Screening with physical examination, electrocardiography, and echocardiography is recommended every 12-18 months for individuals between the ages of 12 to 18 years and every 3 to 5 years for adults. Additional screening is recommended for any change in symptoms that might indicate the development of HCM.
Genetic Testing for Familial Hypertrophic Cardiomyopathy
Genetic testing has been proposed as a component of screening at-risk individuals to determine predisposition to HCM among those patients at risk. Patients at risk for HCM are defined as individuals who have a close family member with established HCM. Results of genetic testing may influence 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.
Commercial testing has been available since May 2003, and there are numerous commercial companies that currently offer genetic testing for HCM. Testing is performed either as comprehensive testing or targeted gene testing. Comprehensive testing, which is done for an individual without a known genetic mutation in the family, analyzes the genes that are most commonly associated with genetic mutations for HCM and evaluates whether any potentially pathogenic mutations are present. The number of HCM genes in the testing panel ranges between 12 and 18, and additional testing characteristics of some of the commercially available panels are presented in the table below. For a patient with a known mutation in the family, targeted testing is performed. Targeted mutation testing evaluates the presence or absence of a single mutation known to exist in a close relative.
There can be difficulties in determining the pathogenicity of genetic variants associated with HCM. Some studies have reported that assignment of pathogenicity has a relatively high error rate and that classification changes over time. With next generation 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 unknown significance is also increased with next generation sequencing (NGS). Also, the percent of individuals who have more than 1 mutation that is thought to be pathogenic is increasing. A study in 2013 reported that 9.5% (19/200) patients from China with HCM had multiple pathogenic mutations and that the number of mutations correlated with severity of disease.
Characteristics of Commercial Testing for HCM
Some of these panels include testing for multisystem storage diseases that may include cardiac hypertrophy, such as Fabry disease (GLA), familial transthyretin amyloidosis (TTR), X-linked Danon disease (LAMP2). Several academic centers, including Emory University School of Medicine and Washington University in St. Louis, also offer HCM genetic panels.
Other panels include testing for genes that are related to HCM but also those associated with other cardiac disorders. For example, the Comprehensive Cardiomyopathy panel (ApolloGen, Irvine, CA) is a next-generation sequencing panel of 44 genes that are associated with HCM, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, left ventricular noncompaction syndrome, Danon syndrome, Fabry disease, Barth syndrome, and transthyretin amyloidosis.
There are no assay kits approved by the U.S. Food and Drug Administration (FDA) for genetic testing for HCM, nor are any kits being actively manufactured and marketed for distribution. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing. While the FDA has technical authority to regulate home-brew tests, there is currently no active oversight nor any known plans to begin oversight. Home-brew tests may be developed using reagents prepared in-house or, if available, commercially manufactured analyte-specific reagents (ASRs). ASRs are single reagents “intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens” and must meet certain FDA criteria but are not subject to premarket review.
Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) may be considered medically necessary for individuals who are at risk for development of HCM, defined as having a first-degree relative with established HCM, when there is a known pathogenic gene mutation present in that affected relative. (See Policy Guidelines section)
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.
Genetic testing for predisposition to HCM is considered investigational for all other patient populations, including but not limited to individuals who have a first-degree relative with clinical HCM, but in whom genetic testing is unavailable.
Due to the complexity of genetic testing for HCM 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.
In order to inform and direct genetic testing for at-risk individuals, genetic testing should be initially performed in at least one close relative with definite HCM (index case), if possible.
Because there are varying degrees of penetrance for different HCM mutations, 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 HCM, in conjunction with a detailed pedigree analysis, is appropriate when testing of second- or third- degree relatives is considered.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY03/22/2012: 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.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.02.28
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.