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Genetic Test: Hypertrophic Cardiomyopathy, Predisposition | |
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Description: |
Familial hypertrophic cardiomyopathy (HCM) is an inherited condition that is caused by a disease associated variant 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 variants is 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%) (Semsarian, 2015). It is the most common cause of sudden cardiac death (SCD) in adults younger than 35 years of age and is probably the most common cause of death in young athletes (Alcalai, 2008). The overall mortality rate for patients with HCM is estimated to be 1% per year in the adult population (Spirito, 2014).
The genetic basis for HCM is a defect in the cardiac sarcomere, which is the basic contractile unit of cardiac myocytes composed of different protein structures (Keren, 2008). Around 1400 disease-associated variants in at least 18 different genes have been identified (Maron, 2012; Crino, 2014; Ghosh, 2011; Teo, 2015). About 90% of pathogenic variants are missense (i.e., 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 (Keren, 2008). In patients with clinically documented hypertrophic cardiomyopathy, genetic abnormalities can be identified in approximately 60% (Cirino, 2014; Elliott, 2004). Most patients with clinically documented disease are demonstrated to have a familial pattern, although some exceptions are found presumably due to de novo variants (Elliot, 2004).
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 (Cirino, 2009). 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’s syndrome and Friederich’s ataxia (Elliott, 2004). 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 variant is present, including among affected family members (Alcalai, 2008). This variability in clinical expression may be related to environmental factors and modifier genes (Maron, 2003). A large percentage of patients with HCM, perhaps the majority of all HCM patients, are asymptomatic or have minimal symptoms (Elliott, 2004; Maron, 2003). 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 sudden cardiac death due to unpredictable ventricular tachyarrhythmias, heart failure, or atrial fibrillation, or some combination (Gersh, 2011).
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 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 (Maron, 2003). Additional screening is recommended for any change in symptoms that might indicate the development of HCM (Maron, 2003).
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. However, the likelihood of obtaining a positive genetic test in the proband is only about 50% 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 (Maron, 2012; Arya, 2010). 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 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 MolecularMedicine) is a next-generation sequencing panel of 62 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 (Pan Cardiomyopathy Panel, 2022).
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 (Das, 2014; Andreasen, 2013). 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 1 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 (Zou, 2013).
Regulatory Status
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 Act (CLIA). Sequencing tests for hypertrophic cardiomyopathy (HCM) are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by 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.
There are no assay kits approved by the U.S. Food and Drug Administration (FDA) for genetic testing for HCM.
Coding
Effective in 2013, there are CPT codes that can be used to report this testing.
Code 81405 includes:
ACTC1 (actin, alpha, cardiac muscle 1) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
MYL2 (myosin, light chain 2, regulatory, cardiac, slow) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
MYL3 (myosin, light chain 3, alkali, ventricular, skeletal, slow) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
TNNC1 (troponin C type 1 [slow]) (e.g., hypertrophic cardiomyopathy or dilated cardiomyopathy), full gene sequence
TNNI3 (troponin I, type 3 [cardiac]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
TPM1 (tropomyosin 1 [alpha]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
Code 81406 includes:
TNNT2 (troponin T, type 2 [cardiac]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
Code 81407 includes:
MYBPC3 (myosin binding protein C, cardiac) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
MYH7 (myosin, heavy chain 7, cardiac muscle, beta) (e.g., familial hypertrophic cardiomyopathy, Liang distal myopathy), full gene sequence
Code 81479 (unlisted molecular pathology procedure) would be used to report ACTN2 and MYOZ2 testing.
Prior to 2013, there was no specific CPT code for this type of testing. Multiple codes that describe genetic analysis would likely have been used (e.g., 83890-83912). An example of coding for this testing in a new patient from one laboratory found on the internet included 83891x 1, 83900x1, 83901x51, 83904x51, 83909x3 and 83912x1.
There are specific HCPCS “S” codes for this testing:
S3865: Comprehensive gene sequence analysis for hypertrophic cardiomyopathy
S3866: Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family
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Policy/ Coverage: |
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for predisposition to hypertrophic cardiomyopathy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes 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 mutation present in that affected relative.
Note: 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, and expert in the area of medical genetics and/or hypertrophic cardiomyopathy.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for predisposition to hypertrophic cardiomyopathy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients with a family history of hypertrophic cardiomyopathy in which a first-degree relative has tested negative for pathologic mutations.
For members with contracts without primary coverage criteria, genetic testing for predisposition to hypertrophic cardiomyopathy 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. Services that are considered not medically necessary are specific contract exclusions in most member benefit certificates of coverage.
Genetic testing for predisposition to hypertrophic cardiomyopathy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all other patient populations, including but not limited to individuals who have a first-degree relative with clinical hypertrophic cardiomyopathy, but in whom genetic testing is unavailable.
For members with contracts without primary coverage criteria, genetic testing for predisposition to hypertrophic cardiomyopathy is considered investigational for all other patient populations, including but not limited to individuals who have a first-degree relative with clinical hypertrophic cardiomyopathy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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Rationale: |
Commercial testing has been available since May 2008, and there are numerous commercial companies that currently offer genetic testing for hypertrophic cardiomyopathy (HCM) (Arya, 2010) (GeneDx, 2010) (Correlagan, 2010) (PGxHealth, 2010). 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. 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.
The rationale for this policy statement is based primarily on a 2009 TEC Assessment that considered whether genetic testing for patients at risk for HCM improves outcomes. This Assessment reviewed the evidence on the accuracy of genetic testing in identifying patients who will subsequently develop HCM. Seven studies were identified that met the inclusion criteria for review. These peer-reviewed articles were supplemented by data on analytic validity available through the manufacturers’ websites or personal communication (Arya, 2010) (GeneDx, 2010) (Correlagan, 2010) (PGxHealth, 2010) (Watkins, 1995).
Analytic and Clinical Validity:
For predispositional genetic testing, the analytic validity (ability to detect or exclude a specific mutation identified in another family member) and clinical validity (ability to detect any pathologic mutation in a patient with HCM and exclude a mutation in a patient without HCM) were evaluated. The analytic validity is more relevant when there is a known mutation in the family, whereas the clinical validity is more relevant for individuals without a known mutation in the family.
The analytic sensitivity (ability to detect a specific mutation that is present) of sequence analysis for detecting mutations that cause HCM is likely to be very high based on what is known about the types of mutations that cause HCM and the limited empiric data provided by the manufacturer and detailed description of the testing methodology (PGxHealth, 2009). There are scant data available on the analytic specificity of HCM testing. The available information on specificity, mainly from series of patients without a personal or family history of HCM, suggests that false-positive results for known pathologic mutations are uncommon (Niimura, 1998) (Watkins, 1995). However, the rate of false-positive results is likely to be higher for classification of previously unknown variants.
Therefore, for a patient with a known mutation in the family, the high analytic validity means that targeted genetic testing for a familial mutation has high predictive value for both a positive (mutation detected) and a negative (mutation not detected) test result. A negative test indicates that the individual is free of the mutation, while a positive test indicates that the patient has the mutation and is at risk for developing HCM in the future.
Multiple pathologic mutations are found in 1-5% of patients with HCM and are associated with more severe disease and a worse prognosis (Cirino, 2008). For these patients, targeted mutation analysis may miss mutations other than the one tested for. Some experts recommend comprehensive testing of all individuals for this reason; however, the number of patients with multiple pathologic mutations that will be missed through targeted testing is small.
However, a positive genetic test result does not indicate that the individual has clinical HCM. The other important component to clinical validity in this context is penetrance, or the probability that an individual with a pathogenic mutation will eventually develop the condition of concern. There is reduced penetrance in HCM (i.e., not everyone with a deleterious mutation will develop manifestations of HCM) (Charron, 1997). In addition, penetrance varies among different mutations and may even vary among different families with an identical pathologic mutation (Fananapazir, 1994). As a result, it is not possible to estimate accurately the penetrance for any given mutation in a specific family.
The clinical validity of genetic testing for HCM is considerably lower than the analytic validity. Evidence on clinical sensitivity, also called the mutation detection rate, consists of several case series of patients with established HCM. To date, the published mutation detection rate ranges from 33–63% (Harvard CardioGenomics website, 2010) (Erdmann, 2003) (Olivotto, 2008) (Richard, 2003) (Van Driest, 2003). The less-than-perfect mutation detection rate is due in part to the published studies having investigated some, but not all, of the known genes that underlie HCM, and investigators in these studies using mutation scanning methods such as single-strand conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE) that will miss certain deleterious mutations. Presumably more comprehensive mutation analysis methods (e.g., sequence analysis with or without deletion duplication analysis) could identify additional mutations. Another reason for the less-than-perfect mutation detection rate is that other, as yet unidentified, genes may be responsible for HCM. Finally, there may be unknown, nongenetic factors that mimic HCM.
Therefore, for patients without a known mutation in the family, a negative test is not sufficient to rule out HCM because of the suboptimal clinical sensitivity. A positive genetic test in a patient without a known family history of disease increases the likelihood that an individual carries a pathologic mutation but is not sufficient for establishing the presence of clinical disease.
Clinical Utility:
There are benefits to predisposition genetic testing for at-risk individuals when there is a known mutation in the family. Inheritance of the predisposition to HCM can be ruled out with near certainty when the genetic test is negative (mutation not detected) in this circumstance. A positive test result (mutation detected) is less useful. It confirms the presence of a pathologic mutation and an inherited predisposition to HCM but does not establish the presence of the disease. It is possible that surveillance for HCM may be increased after a positive test, but the changes in management are not standardized, and it is also possible that surveillance will be essentially the same following a positive test.
Because of the suboptimal clinical sensitivity relating to less-than-perfect mutation detection, the best genetic testing strategy for predisposition testing for HCM begins with comprehensive testing (e.g., sequence analysis) of a DNA sample from an affected family member. Comprehensive mutation analysis in an index patient is of importance by informing and directing the subsequent testing of at-risk relatives. If the same mutation is identified in an at-risk relative, then it confirms the inheritance of the predisposition to HCM and the person is at risk for developing the manifestations of the disease. However, if the familial mutation is not identified in an at-risk relative, then this confirms that the mutation has not been inherited, and there is a very low likelihood (probably similar to or less than the population risk) that the individual will develop signs or symptoms of HCM. Therefore, clinical surveillance for signs of the disorder can be discontinued, and they can be reassured that their risk of developing the disease is no greater than the general population.
If a familial mutation is not known and an at-risk individual undergoes testing, a positive result (mutation detected) would confirm an inherited predisposition to HCM and an increased risk for clinical manifestations in the future. However, a negative result (no mutation detected) could not exclude the possibility that a mutation was inherited. In this case, risk assessment and surveillance for HCM would depend on the family history and other personal risk factors. Thus, in this situation, testing has limited utility in decision making. Moreover, if a familial mutation is not known, comprehensive mutation analysis would be the method of choice, and in addition to a positive or negative result, there is the possibility of detecting a variant of uncertain significance––a variant for which the association with clinical disease is not known.
Knowledge of the results of genetic testing may aid in decision making on such issues as reproduction by providing information on the susceptibility to develop future disease. Direct evidence on the impact of genetic information on this type of decision making is lacking, and the effect of such decisions on health outcomes is uncertain.
Summary
For individuals at risk for HCM (first-degree relatives), genetic testing is most useful when there is a known mutation in the family. In this situation, genetic testing will establish the presence or absence of the same mutation in a close relative with a high degree of certainty. Absence of this mutation will establish that the individual has not inherited the familial predisposition to HCM and thus has a similar risk of developing HCM as the general population. These patients no longer need ongoing surveillance for the presence of clinical signs of HCM. Therefore, genetic testing meets primary coverage criteria that there be scientific evidence of effectiveness for first-degree relatives of individuals with a known pathologic mutation.
For at-risk individuals without a known mutation in the family, the evidence does not permit conclusions of the effect of genetic testing on outcomes, since there is not a clear relationship between testing and improved outcomes.
Practice Guidelines and Position Statements
The ACC Foundation and the AHA issued joint guidelines on the diagnosis and treatment of hypertrophic cardiomyopathy in 2011 (Gersh, 2011). The following recommendations were issued concerning genetic testing:
Class I indications
Class IIa indications
Class IIb indications
Class III indications, No Benefit
The Heart Rhythm Society and the European Heart Rhythm Association published recommendations for genetic testing for cardiac channelopathies and cardiomyopathies in 2011 (Ackerman, 2011). For hypertrophic cardiomyopathy, the following recommendations were made:
2012 Update
A search of the MEDLINE database through September 2012 did not reveal any new information that would prompt a change in the coverage statement.
2013 Update
A literature search was conducted using the MEDLINE database through September 2013. There was no new information identified that would prompt a change in the coverage statement.
2014 Update
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
HCM is a very heterogeneous disorder. Symptoms and presentation may include SCD due to unpredictable ventricular tachyarrhythmias, heart failure, or atrial fibrillation, or some combination (Gersh, 2011). Management of patients with HCM involves treating cardiac comorbidities, avoiding therapies that may worsen obstructive symptoms, treating obstructive symptoms with beta-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.
Genetic Testing for Familial Hypertrophic Cardiomyopathy
Characteristics of Commercial Testing for HCM
The above listed characteristics of commercial testing for HCM were adapted from Maron et al and GeneTests.org.
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 non-compaction syndrome, Danon syndrome, Fabry disease, Barth syndrome, and transthyretin amyloidosis.
Clinical Validity
Given the large size of many of the genes associated with HCM, particularly MYBPC3 and MYH7, the use of next generation sequencing (NGS) methods has been investigated as a more efficient way to evaluate for genetic mutations in HCM. Next generation sequencing refers to 1 of several methods that use massively parallel platforms to allow the sequencing of large stretches of DNA. The use of NGS and whole-exome sequencing has the potential to substantially increase the sensitivity of genetic testing for HCM. Small studies have demonstrated the potential role of NGS in detected recognized and novel mutations. Gomez et al reported the yield of a 2-step NGS process in a cohort of 136 patients with clinically-diagnosed HCM (Gomez, 2014). In a validation cohort of 60 patients with both NGS results and prior results identification of a mutation in MYH7, MYBPC3, TNNT2, TNNI3, ACTC1,TNNC1, MYL2, MYL3, or TPM1, sensitivity of NGS was 100% and specificity was 97% for single nucleotide variants and 80% for insertion or deletion variants. Among 76 clinically-diagnosed cases without previous genetic mutation testing, NGS identified 19 mutations. Millat et al developed a NGS platform to evaluate the most common genetic mutations in a cohort of 75 patients with HCM and dilated cardiomyopathy (Millat, 2014). The authors report very high analytic sensitivity (98.9%) for previously-detected mutations in the covered regions
Several studies that evaluated clinical predictors of detecting a mutation have been.
Bos et al conducted a retrospective evaluation of 1053 patients with a clinical diagnosis of HCM and available HCM genetic testing for 9 HCM-associated myofilament genes to develop a phenotype-based genetic test prediction score (Bos, 2014). Of 1053 tested from 1997 to 2007, 359 patients (34%) were found to have a mutation in 1 or more HCM-associated genes on testing with PCR, high performance liquid chromatography, and direct DNA sequencing. Factors that were associated with a positive genetic test result in multivariate analyses were used to generate a predictive model to estimate the likelihood of a positive genetic test result, with each predictor assigned equipotent positive or negative weights. The most commonly-identified variants were in MYBPC3 (N=96; 46%), and MYH7 (N=74; 36%). Compared with genotype-negative patients, genotype positive patients were younger at diagnosis (mean 36.4 years vs 48.5 years; P<0.001), had more hypertrophy (mean 22.6 mm vs 20.1 mm; P<0.001), were more likely to have a family history of HCM (505 vs 23%; P<0.001), and were more likely to have a family history of SCD (27% vs 15%; P<0.001). Independent predictors of a positive genetic test were reverse curve HCM, age at diagnosis, maximum left ventricular wall thickness, family history of HCM, family history of SCD, and presence of mild hypertension (negative association). When all 5 positive markers were present, the likelihood of a positive genetic test was 80%.
Marsiglia et al evaluated predictors of a positive genetic test among 268 index patients with clinically-diagnosed HCM (Marsiglia, 2014). Pathogenic mutations were found in 131 subjects (48.8%), 79 (59.9%) in the MYH7 gene, 50 (38.2%) in the MYBPC3 gene, and 3 (2.3%) in the TNNT2 gene. Factors significantly associated with a positive genetic test in univariate models were entered into a multivariable regression model to predict the likelihood of a positive genetic test, which demonstrated that a family history of confirmed HCM, average heart frequency, history of nonsustained ventricular tachycardia, and age were significantly associated with genetic test results. The authors postulate that parameters from the multivariable model be used to predict genetic test results; however, the validity of the predictive equation was not evaluated in populations other than the derivation group.
Clinical Utility
Genetic testing for HCM may potentially play a role in several clinical situations. Situations considered here are genetic testing for disease prediction in at-risk individuals; genetic testing for diagnosis or prognosis in patients with HCM; and genetic testing for reproductive decision-making.
Predictive Testing: Mutation Detection in At-Risk Individuals
Michels et al attempted to risk-stratify asymptomatic patients with a positive genetic test for HCM. The authors reported cardiac evaluation outcomes and risk stratification for SCD in 76 asymptomatic HCM mutation carriers identified from 32 families (Michels, 2009). Between 2007 and 2008, 76 asymptomatic family members of 32 probands with HCM and known mutations were found to have mutations in one or more of the following genes: MYBPC3, MYH7, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC, TNNC1, CSRP3, and TCAP. HCM was diagnosed in 31 (41%) asymptomatic family members. The authors attempted to risk stratify patients for SCD, and found that none of the screened carriers were symptomatic, had a history of syncope, or had severe hypertrophy (≥30 mm). Four carriers were found to have an abnormal blood pressure response during exercise, which is associated with worse prognosis; of those, 3 were diagnosed with HCM. Three carriers were found to have nonsustained ventricular tachycardia, which is also associated with worse prognosis in HCM; of those, 2 were diagnosed with HCM. The study does not have long enough follow up to determine whether these risk factors were associated with differences in SCD rates.
Ongoing and Unpublished Clinical Trials
A search of the online database ClinicalTrials.gov in October 2014 identified several ongoing trials evaluating genetic testing for HCM:
2015 Update
A literature search conducted through November 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Analytic and Clinical Validity
For predispositional genetic testing, the analytic validity (ability to detect or exclude a specific mutation; in this case, the specific mutation of interest is a mutation identified in another family member) and clinical validity (ability to detect any pathologic mutation in a patient with HCM and to exclude a mutation in a patient without HCM) were evaluated. The analytic validity is more relevant when there is a known mutation in the family, whereas the clinical validity is more relevant for individuals without a known mutation in the family.
Analytic Validity
The analytic sensitivity (probability that a test will detect a specific mutation that is present) of sequence analysis for detecting mutations that cause HCM is likely to be very high based on what is known about the types of mutations that cause HCM and the limited empiric data provided by the manufacturer and detailed description of the testing methodology. There are fewer data available on the analytic specificity (probability that a test will be negative when a specific mutation is absent) of HCM testing. The available information on specificity, mainly from series of patients without a personal or family history of HCM, suggests that false-positive results for known pathologic mutations are uncommon (Niimura, 1998; Watkins, 1995).
However, the rate of false-positive results is likely to be higher for classification of previously unknown variants. There is some published evidence available on the analytic validity of next-generation sequencing (NGS) panels for genes associated with cardiomyopathies, including HCM. For example, one 17-gene panel was reported to have a maximum 96.7% sensitivity for single-nucleotide variants, with positive predictive values above 95%, compared with Sanger sequencing (Oliveira, 2015).
Genotype-Phenotype Correlations
Given the variability in penetrance and expressivity in HCM-related gene mutations, a number of studies have evaluated the association between specific mutations and clinical features. Studies identified that evaluate the association between HCM-related phenotypes and the presence of any disease-causing mutation, compared with negative testing, or the presence of specific types of mutations, are described next.
A number of studies have focused specifically on mutations that lead to the presence or absence of sarcomere protein. Lopes and colleagues evaluated the effect of mutations leading to sarcomere protein-related variants in a cohort of 874 individuals with HCM (Lopes, 2015). All subjects underwent evaluation with high throughput sequencing of genes associated with HCM, and 383 subjects were found to mutations in the 8 sarcomere protein genes most commonly associated with HCM (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, ACTC1, and TPM1). Patients with SP-related mutations tended to be younger, more likely to have a family history of HCM and sudden cardiac death, more likely to have asymmetric septal hypertrophy, had a greater maximum left ventricular wall thickness, and had an increased incidence of sudden cardiac death.
In an evaluation of NGS testing of the MYBPC3 gene in a cohort of 114 patients with clinically-defined HCM, Liu and coleagues evaluated genotype-phenotype correlations (Liu, 2015). Among the 20 patients with novel or known mutations detected, those with double mutations (n=2) or premature stop codon mutations (n=12) were more likely to have severe manifestations requiring invasive therapies (eg, septal myomectomy), compared with those with missense mutations (n=11). However, the small study population limits generalizability.
In a cohort of 137 patients with HCM diagnosed before age 21, 71 of whom (52%) were genotype positive, those who were genotype-positive had more cardiac hypertrophy and earlier myomectomies (Loar, 2015). However, there were no differences in overall survival between genotype-positive and –negative groups, and there were no significant differences in outcomes between the 2 major genotypes among genotype-positive subjects (those with MYH7 and MYBPC3 mutations).
Ellims and colleagues evaluated cardiac fibrosis in 139 patients with HCM, 56 of whom underwent NGS for cardiomyopathy genes, using magnetic resonance imaging (MRI) to evaluate regional myocardial fibrosis with late gadolinium enhancement (LGD) and diffuse myocardial fibrosis (Ellims, 2014). Among those who underwent NGS testing, 36 (64%) had a likely causative mutation detected, most commonly in the MYBPC3 gene (n=17). Compared with genotype-negative patients, those with a causative mutation detected had more focal myocardial fibrosis (higher LGE; 7.9 vs 3.1, p=0.03), but less diffuse myocardial fibrosis (measured by post-contrast T1 time: 498 vs 451, p=0.03).
Coppini and colleagues reported differences in phenotype among patients with HCM (n=230) with mutations associated with thick-filament (n=150) or thin-filament (n=80) abnormalities (Coppini, 2014). Thin-filament mutations are generally less commonly identified than thick-filament mutations and include TNNT2, TNNI3, TPN1, and ACTC. Patients with thin-filament mutations were less likely to have dynamic outflow tract obstruction (19% vs 34% among those with thick-filament mutations, p=0.015).Over a mean follow up of 4.7 years, patients with thin-filament mutations were more likely to progress to stage III/IV heart failure (15% vs 5%, p=0.013) and more likely to have left ventricular ejection fraction (LVEF) under 50% (18% vs 8%, p=0.031), have a restrictive left ventricular filling pattern (16% vs 5%, p=0.003).
Section Summary: Analytic and Clinical Validity
The available evidence on testing for mutations related to HCM indicates a high analytic sensitivity and specificity. This indicates that in cases where there is interest in identifying a specific mutation (ie, when there is a known mutation in an affected family member), testing can rule in or rule out the presence of a mutation with high certainty. In contrast, given the wide genetic variation in HCM and the likelihood that not all causative mutations have been identified, there is imperfect clinical sensitivity. Therefore, a negative test is not sufficient to rule out a mutation in patients without a known family mutation. On the other hand, variability in clinical penetrance means that a positive genetic test does not “rule in” clinical HCM, although it makes HCM more likely. A number of studies have investigated models for predicting clinical a positive genetic test among patients with clinical HCM, but the clinical use of these models is not well-established. The available evidence has not demonstrated that specific genetic testing results are associated with HCM-related phenotype or disease penetrance.
Clinical Utility
Genetic testing for HCM may potentially play a role in several clinical situations. Situations considered here are genetic testing for disease prediction in at-risk individuals and genetic testing for reproductive decision making.
Predictive Testing: Mutation Detection in At-Risk Individuals
At present, management of patients with HCM is not dependent on the identification of a specific mutation or any positive mutation testing results. There is active investigation into treatments that may slow disease progression before the development of overt echocardiographic signs of HCM.
Axelsson and colleagues reported results of the INHERIT trial, a randomized, double-blind, placebo-controlled trial evaluating the use of losartan among 133 patients with HCM (Axelsson, 2015). Patients with a diagnosis of HCM were eligible if they had unexplained LV hypertrophy with either a maximum wall thickness of 15 mm or more on echocardiography or borderline hypertrophy (maximum wall thickness 13-14 mm) and at least one 1st degree relative with HCM. For the study’s primary endpoint, change in LV mass at 12 months, there were no significant differences between the placebo and losartan groups (mean difference 1 g/m2, 95% CI -3 to 6, P=0.60). In post hoc subgroup analyses based on genotype, there was no significant interaction between the treatment group and genotype.
Ho and colleagues reported results of a small (n=38), double-blind, placebo-controlled pilot trial of the use of diltiazem in patients with a known sarcomere mutation (mutations in MYBPC3, MYH7, or TNNT2) but without septal hypertrophy (Ho, 2015). Over 2 years of follow up, patients in the diltiazem group (n=18) had improvement in mean left ventricular end-diastolic diameter (LVEDD), while controls (n=20) had decreased LVEDD (change in Z score, 0.5 vs -0.5, p<0.001). The mean LV thickness-to-dimension ratio was stable in the diltiazem group but worsened in controls (-0.02 vs 0.15, p=0.04).
The evidence for testing for specific hypertrophic cardiomyopathy (HCM)-related mutation identified in affected family member(s) in individuals who are asymptomatic with risk for HCM because of a positive family history includes studies reporting on the analytic and clinical validity of testing. Relevant outcomes include overall survival, test accuracy and validity, other test performance measures, changes in reproductive decision making, symptoms, change in disease status, and morbid events. For individuals at risk for HCM (first-degree relatives), genetic testing is most useful when there is a known mutation in the family. In this situation, genetic testing will establish the presence or absence of the same mutation in a close relative with a high degree of certainty. Absence of this mutation will establish that the individual has not inherited the familial predisposition to HCM and thus has a similar risk of developing HCM as the general population. These patients no longer need ongoing surveillance for the presence of clinical signs of HCM. Although no direct evidence comparing outcomes for at-risk individuals managed with and without genetic testing was identified, there is a strong indirect chain of evidence that there are management changes that improve outcomes with genetic testing when there is a known familial mutation.
The evidence for nonspecific testing for HCM-related mutation(s) in individuals who are asymptomatic with risk for HCM because of a positive family history includes studies reporting on the analytic and clinical validity of testing. Relevant outcomes include overall survival, test accuracy and validity, other test performance measures, changes in reproductive decision making, symptoms, change in disease status, and morbid events. Given the wide genetic variation in HCM and the likelihood that not all causative mutations have been identified, there is imperfect clinical sensitivity. Therefore, a negative test is not sufficient to rule out a mutation in patients without a known family mutation. On the other hand, variability in clinical penetrance means that a positive genetic test does not always “rule in” clinical HCM. For at-risk individuals without a known mutation in the family, the evidence does not permit conclusions of the effect of genetic testing on outcomes, since there is not a clear relationship between testing and improved outcomes.
2018 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage status.
2019 Update
A literature search was conducted through December 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
When a patient tests positive for a specific HCM-related variant, the clinical validity of a test to detect that specific variant in an asymptomatic first-degree relative relies on 2 factors: the analytic validity of the test itself and the penetrance (the probability that an individual with an identified pathogenic variant already has HCM or will develop HCM in the near future). A negative test indicates that the individual is free of the variant, while a positive test indicates that the patient has the variant and is at higher risk for developing HCM in the future.
Multiple studies have been published on the phenotypic penetrance of HCM, which ranges from 50% to 100% and is briefly summarized below.
Studies relating to clinical validity are summarized below.
2020 Update
A literature search was conducted through December 2019. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Data from patients diagnosed with hypertrophic cardiomyopathy in the Sarcomeric Human Cardiomyopathy Registry (SHaRe) (n=4591; 12% with affected relatives; 35% with family history of hypertrophic cardiomyopathy) indicates that for patients harboring 1 or more sarcomeric pathogenic/likely pathogenic variants, median age at diagnosis was 13.6 years younger than in those with no pathogenic variants (median [37.5 years; interquartile range, 23.6 to 49.8 years] vs. [51.1 years; interquartile range, 38.3 to 61.8 years]; p<0.001) (Ho, 2018). Furthermore, patients with pathogenic/likely pathogenic sarcomere mutations had a 2-fold greater risk for adverse outcomes compared with patients without these mutations and a higher rate of hypertrophic cardiomyopathy family history (58% vs. 25%; p<0.001).
Maurizi et al assessed long-term outcomes of pediatric-onset hypertrophic cardiomyopathy and age-specific risk factors for lethal arrhythmic events (Maurizi, 2018). Of 1,644 patients with hypertrophic cardiomyopathy at 2 national referral centers for cardiomyopathies in Italy, 100 (6.1%) were aged 1 to 16 years at diagnosis. Forty-two of the 100 patients were symptomatic (42%) according to New York Heart Association classification >1 or Ross score >2. The yield of sarcomere gene testing was 55 of 70 patients (79%). During a median follow-up period of 9.2 years, 24 of 100 patients (24.0%) experienced cardiac events (1.9% per year), which included 19 lethal arrhythmic events and 5 heart failure-related events. Risk of lethal arrhythmic event was associated with symptoms at onset (hazard ratio 8.2; 95% CI, 1.5 to 68.4; p=0.02). A trend toward an association between lethal arrhythmic event and Troponin I or Troponin T gene mutations was also detected (hazard ratio 4.1; 95% CI, 0.9 to 36.5; p=0.06) but did not reach statistical significance.
Robyns et al conducted genotype-phenotype analyses of hypertrophic cardiomyopathy patients to construct a score to predict the genetic yield and improve counseling (Robyns, 2019). Unrelated patients with hypertrophic cardiomyopathy (n=378) underwent genetic testing for a panel of genes including at minimum MYBPC3, MYH7, and TNNT2. Multivariate logistic regression was utilized to identify clinical and electrocardiogram variables that predicted a positive genetic test. In total, 141 patients carried a mutation (global yield 37%), 181 were variant-negative, and 56 carried a variant of uncertain significance. MYBPC3 variants accounted for 21.6% of the genetic yield. Age at diagnosis <45 years, familial hypertrophic cardiomyopathy, familial sudden death, arrhythmic syncope, maximal wall thickness ≥20 mm, asymmetrical hypertrophy and the absence of negative T waves on lateral electrocardiogram were significant predictors of a positive genetic test. MYBPC3 mutation carriers more frequently suffered sudden cardiac death compared to troponin complex mutation carriers (p=0.01). Limitations of this study included heterogeneity in usage of baseline versus extended gene panels administered to patients.
A study conducted by Restrepo-Cardoba et al assessed the utility of genetic testing in patients with diagnosed hypertrophic cardiomyopathy classified with poor (Group A) or favorable (Group B) clinical course (Restrepo-Cardoba, 2017). Poor clinical course was defined as occurrence of a sudden cardiac death event, an appropriate implantable cardioverter-defibrillator discharge, and/or a required heart transplant for end-stage heart failure. Forty-five pathogenic mutations were identified in 28 (56%) patients in Group A and in 23 (46%) from Group B (p=0.317). Only 40 patients (40%) demonstrated pathogenic mutations that were previously reported in the literature and only 15 (15%) had pathogenic mutations that were reported in ≥10 individuals. Four out of the 46 pathogenic mutations identified (8%) could have been considered as associated with poor prognosis based on published information. Pathogenic mutations associated with poor prognosis were detected in only 5 patients in Group A (10%). Additionally, mutations considered to confer a benign prognosis were detected in 3 patients (6%). By contrast, pathogenic mutations were identified in 3 patients (6%) and mutations considered to confer a benign prognosis were detected in 4 patients (8%) with a favorable clinical course in Group B. Therefore, study authors concluded that genetic findings were not useful to predict prognosis in most hypertrophic cardiomyopathy patients.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Lorenzini et al evaluated the incidence of new hypertrophic cardiomyopathy diagnoses in sarcomere protein mutation carriers in a retrospective analysis (Lorenzini, 2020). A total of 583 pathogenic/likely pathogenic variant carriers from 307 families were evaluated, with 267 (45.8%) diagnosed with hypertrophic cardiomyopathy at the initial evaluation and thereby excluded from the remainder of the study. An additional 31 subjects underwent a screening visit and were also excluded. This left a final study cohort of 285 subjects (median age: 14.2 years; 49.5% male). The frequency of causal genes was: MYBPC3 (43.2%), MYH7 (24.2%), TNNI3 (13.7%), TNNT2 (11.9%), TPM1 (3.2%), MYL2 (2.1%), ACTC1 (0.4%), and multiple mutations (1.4%). At a median follow-up of 8 years, 86 (30.2%) subjects developed hypertrophic cardiomyopathy and the estimated penetrance at 15 years of follow-up was 46%.
In 2020 , the American College of Cardiology Foundation and the American Heart Association issued updated joint guidelines on the diagnosis and treatment of hypertrophic cardiomyopathy (Ommen, 2020):
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2023, the Heart Rhythm Society and the European Heart Rhythm Association, along with the Asian Pacific and Latin America Heart Rhythm Societies published an expert consensus statement focused on the state of genetic testing for cardiac diseases (Wilde, 2022). The following recommendations were made regarding genetic testing of family members of individuals with hypertrophic cardiomyopathy:
A 2023 systematic review characterized the prevalence and penetrance of genetic variants causing hypertrophic cardiomyopathy (Topriceanu, 2024). The prevalence of pathogenic/likely pathogenic variants in sarcomere or sarcomere-related genes was 50-fold higher, and the penetrance was 5-fold higher in patients with hypertrophic cardiomyopathy and their relatives compared to sarcomere variant carriers incidentally identified in the general population. Data from studies involving approximately 21,000genotyped patients with hypertrophic cardiomyopathy found a 34% occurrence rate of pathogenic/likely pathogenic sarcomere variants using the American College of Medical Genetics and Genomics criteria. The most common pathogenic/likely pathogenic variants associated with hypertrophic cardiomyopathy were MYBPC3 (30% to 40%), MYH7 (10% to 30%), and TNNT2 andTNNI3 (3% to 10%). The penetrance across all genes in non-proband relatives carrying a pathogenic/likely pathogenic variant was 57%, ranging from approximately 32% for MYL3 to 55% for MYBPC3, 60% for TNNT2 and TNNI3, and 65% for MYH7.
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