|MP 2.02.28||Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/12:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular condition, with a phenotypic prevalence of approximately 1 in 500 adults (0.2%).(1) 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 (2) The overall death rate for patients with HCM is estimated to be 1% per year in the adult population.(3,4)
The genetic basis for HCM is a defect in the cardiac sarcomere, which is the basic contractile unit of cardiac myocytes composed of a number of different protein structures.(5) Nearly 1400 individual mutations in at least 18 different genes have been identified to date.(6-8) 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.(5) In patients with clinically documented HCM, genetic abnormalities can be identified in approximately 60%.(7,9) Most patients with clinically documented disease are demonstrated to have a familial pattern, although some exceptions are found presumably due to de novo mutations.(9)
The clinical diagnosis of HCM depends on the presence of left ventricular hypertrophy (LVH), measured by echocardiography or magnetic resonance imaging, in the absence of other known causative factors such as valvular disease, long-standing hypertension, or other myocardial disease.(7) 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 Friedreich ataxia.(9) These disorders need to be excluded before a diagnosis of familial HCM is made.
HCM is a very heterogeneous 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.(2) This variability in clinical expression may be related to environmental factors and modifier genes.(10) A large percentage of patients with HCM, perhaps the majority of all HCM patients, are asymptomatic or have minimal symptoms.(9,10) 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.(11) 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 to 18 months for individuals between the ages of 12 to 18 years and every 3 to 5 years for adults.(10) Additional screening is recommended for any change in symptoms that might indicate the development of HCM.(10)
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.(6,12-15) 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 Table 1.(6) 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,(16,17) 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. 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.(18)
Table 1. Characteristics of Commercial Testing for HCM
No. of HCM Genes in Panel
Turnaround Time, wk
No. of Probability Categories
GeneDX (Gaithersburg, MD)
Direct (Sanger) sequencing
4-6 (comprehensive) 2-4 (targeted)
Correlagen Diagnostics (Waltham, MA)
Direct (Sanger) sequencing
Partners (Cambridge, MA)
Next-generation and Sanger sequencing
|ApolloGen (Irvine, CA)||18||Next-generation sequencing||5-6||3|
|Prevention Genetics (Marshfield, WI)||15||Next-generation sequencing and Sanger sequencing||5-7||4|
|Invitae (San Francisco, CA)||16||Next-generation sequencing
copy number variant
Adapted from Maron et al.(6) 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 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 FDA has technical authority to regulate home-brew tests, there is currently no active oversight or 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 hypertrophic cardiomyopathy (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 HCM.
To inform and direct genetic testing for at-risk individuals, genetic testing should be initially performed in at least 1 close relative with definite HCM (index case), if possible. See Benefit Application section for information regarding testing of the index case.
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.
Effective in 2013, there are CPT codes that can be used to report this testing.
Code 81405 includes:
ACTC1 (actin,alpha,cardiac muscle 1) (eg, familial HCM), full gene sequence
MYL2 (myosin,light chain 2,regulatory, cardiac, slow) (eg, familial HCM), full gene sequence
MYL3 (myosin,light chain 3,alkali,ventricular, skeletal, slow) (eg, familial HCM), full gene sequence
TNNI3 (troponin I, type 3 [cardiac]) (eg, familial HCM), full gene sequence
TPM1 (tropomyosin 1 [alpha]) (eg, familial HCM), full gene sequence
Code 81406 includes:
TNNT2 (troponin T, type 2 [cardiac]) (eg, familial HCM), full gene sequence
Code 81407 includes:
MYBPC3 (myosin binding protein C, cardiac) (eg, familial HCM), full gene sequence
MYH7 (myosin,heavy chain 7, cardiac muscle, beta) (eg, familial HCM, Liang distal myopathy), full gene sequence
Code 81479 (unlisted molecular pathology procedure) would be used to report TNNC1, 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 (eg, 83890-83912). An example of coding for this testing in a new patient from 1 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 HCM
S3866: Genetic analysis for a specific gene mutation for HCM in an individual with a known HCM mutation in the family
Bluecard/National Account Issues
Some Plans may have contract or benefit exclusions for genetic testing.
Recommendations indicate that, when possible, genetic testing for hypertrophic cardiomyopathy (HCM) be performed in an affected family member so that testing in unaffected, at-risk family members can focus on the mutation found in the affected family member. This testing is intended to document whether a known pathologic mutation is present in the family and optimize the predictive value of predisposition testing for at-risk relatives. However, coverage for testing of the affected index case is dependent on contract benefit language when there is no conclusive evidence of clinical benefit to the index case from testing.
Specific contract language must be reviewed and considered when determining coverage for testing. In some cases, coverage for testing the index case may be available through the contract that covers the unaffected, at-risk individual who will benefit from knowing the results of the genetic test.
This policy was created in December 2011 and updated periodically with literature review. The most recent update with literature review covered the period through October 29, 2014.
The rationale for this policy statement is based primarily on a 2010 TEC Assessment(19) that considered whether genetic testing for patients at risk for hypertrophic cardiomyopathy (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.(20-26) These peer-reviewed articles were supplemented by data on analytic validity available through the manufacturers’ websites or personal communication.(12-14, 27)
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. 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.(22,26) 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% to 10% of patients with HCM and are associated with more severe disease and a worse prognosis.(7,18) 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, it is not known whether the presence of multiple pathologic mutations influences management decisions such that health outcomes might be improved.
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% to 67%.(20,21,23-25,28,29) 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 or denaturing gradient gel electrophoresis that will miss certain deleterious 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. Mutation detection rates will likely increase over time with recognition of new mutations.
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. NGS 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 detecting recognized and novel mutations.(30,31) Gomez et al reported the yield of a 2-step NGS process in a cohort of 136 patients with clinically diagnosed HCM.(32) In a validation cohort of 60 patients with both NGS results and prior 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 an NGS platform to evaluate the most common genetic mutations in a cohort of 75 patients with HCM and dilated cardiomyopathy.(33) 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 published.(34-36)
A study by Ingles et al included 265 unrelated individuals with HCM, in which a total of 52% (138/265) had a mutation identified.(34) Mutations were more frequent in patients with an established family history of HCM than in those without a family history (72% vs 29%, p<0.001), and in those with a family history of sudden cardiac death (SCD) (89% vs 59%, p<0.001). Other predictors of finding a pathogenic mutation were female gender and increased left ventricular (LV) wall thickness.
A second study by Gruner et al derived a score for predicting the likelihood of finding a mutation, called the Toronto Hypertrophic cardiomyopathy Genotype Score.(35) The score was developed using data from 471 consecutive patients referred for testing, of which 35% (163/471) were found to have a mutation. Independent predictors of a mutation that were incorporated into the model were age at diagnosis, female gender, arterial hypertension, positive family history, LV wall morphology, and LV posterior wall thickness.
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.(36) 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 polymerase chain reaction (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 LV 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 clinicallydiagnosed HCM.(37) 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.
Because of the imperfect clinical sensitivity, a negative test is not sufficient to rule out HCM in patients without a known mutation in the family. 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.
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 (ie, not everyone with a deleterious mutation will develop manifestations of HCM).(38) In addition, penetrance varies among different mutations and may even vary among different families with an identical pathologic mutation.(39) As a result, it is not possible to estimate accurately the penetrance for any given mutation in a specific family.
A study by Page et al attempted to identify the disease expression and penetrance of MYBPC3 mutations in a cohort of HCM patients and their relatives. Their findings support that clinical disease expression among carriers of HCM mutation is heterogeneous with mutation type (eg, missense, nonsense) or specific mutation. In addition, demographic characteristics such as older patient age or male gender resulted in an increased disease penetrance.(40)
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
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.
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.(41) Between 2007 and 2008, 76 asymptomatic family members of 32 probands with HCM and known mutations were found to have mutations in 1 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.
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 (eg, 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 analysiswould 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.
Carrier Testing: Mutation Detection for Reproductive Decision Making
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.
Additionally, rudimentary disease prevention based on assisted reproduction using preimplantation genetic diagnosis (PGD) is possible. PGD uses in vitro fertilization with a single cell removed from earlystage embryos and tested for the familial mutation. Only those embryos without the identified HCM mutation are used to initiate pregnancy. Disease-modifying studies are in development using animal models of HCM. In rodent models, sarcomere mutations have been implicated in early abnormal intracellular calcium handling far in advance of left ventricular hypertrophy (LVH). Treatment of this calcium handling by use of diltiazem appeared to attenuate the development of LVH when started in early life. The feasibility of this strategy in humans is being assessed by an ongoing randomized controlled trial (NCT00319982), which compares diltiazem to placebo in known sarcomere mutation carriers who have yet to develop LVH; this study has completed enrollment, but has not reported results.(42)
Use of genetic testing for HCM has the greatest utility in asymptomatic family members of patients with HCM who have a known genetic mutation. Given the high sensitivity for known mutations, the absence of a mutation in the asymptomatic relatives should rule out the presence of familial HCM and allow reduction in surveillance for complications. In other clinical scenarios, use of genetic testing for HCM has less clinical utility. Detection of mutations in asymptomatic carriers may aid reproductive decision making, although direct evidence is limited about the impact of genetic information in this setting.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in October 2014 identified several ongoing trials evaluating genetic testing for HCM:
Genetic Predictors of Outcome in HCM Patients (NCT00156429): This is a prospective observational study to assess whether genetic polymorphisms affect morphologic features in patients with HCM or the clinical course and outcome. Enrollment is planned for 540 patients; the estimated study completion date is May 2020.
A Pilot Project Exploring the Impact of Whole Genome Sequencing in Healthcare (NCT01736566): This is a randomized, open-label trial to compare outcomes for patients managed with whole genome sequencing with a genome report with those managed with usual care. A subset of the study will include 100 patients with HCM, who will be randomized to care with a whole genome sequencing report or usual care. The estimated study completion date is November 2015.
HCMR - Novel Markers of Prognosis in Hypertrophic Cardiomyopathy (NCT01915615): This is a prospective, observational study to identify novel risk markers that affect the natural history of hypertrophic cardiomyopathy. Enrollment is planned for 2750 patients; the estimated study completion date is November 2018.
Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
Clinical input was solicited in January 2011 on general agreement with the policy. This was followed up by a second round of focused clinical vetting in October 2011 to address specific questions raised after the first round of vetting. The initial vetting indicated uniform agreement with the medically necessary indication for individuals with a first-degree relative who has a known pathologic mutation. This vetting also asked whether testing should be restricted to first-degree relatives. For this question, there was a mixed response, with 2 reviewers indicating that they agree with testing only first-degree relatives, two reviewers indicating that testing should be offered to non-first-degree relatives, and 1 reviewer who was unsure.
The second round of clinical vetting focused on the changes in management that could result from genetic testing. Reviewers were uniform in responding that a positive test will result in heightened surveillance. All but 1 reviewer indicated that a negative test will eliminate the need for future surveillance in all cases. There was general agreement that the surveillance schedule used in clinical practice was that proposed by Maron et al.(10)
Summary of Evidence
For individuals at risk for hypertrophic cardiomyopathy (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 may be considered medically necessary 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, because there is not a clear relationship between testing and improved outcomes. Genetic testing is considered investigational for this purpose. For at-risk individuals who have a family member with HCM who tests negative for pathologic mutations, genetic testing is not
indicated. Genetic testing is considered not medically necessary in this situation.
Practice Guidelines and Position Statements
In 2014, the European Society of Cardiology issued guidelines on the diagnosis and management of HCM, which included the following recommendations related to genetic testing(43):
Class I Recommendations
- Genetic counselling is recommended for all patients with HCM when their disease cannot be explained solely by a non-genetic cause, whether or not clinical or genetic testing will be used to screen family members. (Level of Evidence: B)
- Genetic testing is recommended in patients fulfilling diagnostic criteria for HCM, when it enables cascade genetic screening of their relatives. (Level of Evidence: B)
- It is recommended that genetic testing be performed in certified diagnostic laboratories with expertise in the interpretation of cardiomyopathy-related mutations. (Level of Evidence: C).
- In the presence of symptoms and signs of disease suggestive of specific causes of HCM, genetic testing is recommended to confirm the diagnosis. (Level of Evidence: B).
- Cascade genetic screening, after pre-test counselling, is recommended in first-degree adult relatives of patients with a definite disease-causing mutation. (Level of Evidence: B)
- Clinical evaluation, employing ECG and echocardiography and long-term follow-up, is recommended in first-degree relatives who have the same definite disease-causing mutation as the proband. (Level of Evidence: C).
Class IIa Recommendations
- Genetic counselling should be performed by professionals trained for this specific task working within a multidisciplinary specialist team. (Level of Evidence: C)
- Genetic testing in patients with a borderline diagnosis of HCM should be performed only after detailed assessment by specialist teams. (Level of Evidence: C)
- Post-mortem genetic analysis of stored tissue or DNA should be considered in deceased patients with pathologically confirmed HCM, to enable cascade genetic screening of their relatives. (Level of Evidence: C)
- First-degree relatives who do not have the same definite disease-causing mutation as the proband should be discharged from further follow-up but advised to seek re-assessment if they develop symptoms or when new clinically relevant data emerge in the family. (Level of Evidence: B)
- When no definite genetic mutation is identified in the proband or genetic testing is not performed, clinical evaluation with ECG and echocardiography should be considered in first-degree adult relatives and repeated every 2–5 years (or 6–12 monthly if non-diagnostic abnormalities are present). (Level of Evidence: C).
- The children of patients with a definite disease-causing mutation should be considered for predictive genetic testing—following pre-test family counselling—when they are aged 10 or more years and this should be carried out in accordance with international guidelines for genetic testing
in children. (Level of Evidence: C)
- In first-degree child relatives aged 10 or more years, in whom the genetic status is unknown, clinical assessment with ECG and echocardiography should be considered every 1–2 years between 10 and 20 years of age, and then every 2–5 years thereafter. (Level of Evidence: C).
Class IIb Recommendations
- If requested by the parent(s) or legal representative(s), clinical assessment with ECG and echocardiography may precede or be substituted for genetic evaluation after counselling by experienced physicians and when it is agreed to be in the best interests of the child. (Level of Evidence: C)
- When there is a malignant family history in childhood or early-onset disease or when children have cardiac symptoms or are involved in particularly demanding physical activity, clinical or genetic testing of first-degree child relatives before the age of 10 years may be considered. (Level of Evidence: C)
- In definite mutation carriers who have no evidence of disease expression, sports activity may be allowed after taking into account the underlying mutation and the type of sport activity, and the results of regular and repeated cardiac examinations. (Level of Evidence: C)
The American College of Cardiology Foundation and the American Heart Association issued joint guidelines on the diagnosis and treatment of hypertrophic cardiomyopathy in 2011.(11) The following recommendations were issued concerning genetic testing.
Class I Recommendations
- Evaluation of familial inheritance and genetic counseling is recommended as part of the assessment of patients with HCM (Level of Evidence: B)
- Patients who undergo genetic testing should also undergo counseling by someone knowledgeable in the genetics of cardiovascular disease so that results and their clinical significance can be appropriately reviewed with the patient (Level of Evidence: B)
- Screening (clinical, with or without genetic testing) is recommended in first-degree relatives of patients with HCM (Level of Evidence: B)
- Genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause (Level of Evidence: B)
Class IIa Recommendations
- Genetic testing is reasonable in the index patient to facilitate the identification of first-degree family members at risk for developing HCM (Level of Evidence: B)
Class IIb Recommendations
- The usefulness of genetic testing in the assessment of risk of SCD in HCM is uncertain (Level of Evidence: B)
Class III Indications: No Benefit
- Genetic testing is not indicated in relatives when the index patient does not have a definitive pathogenic mutation (Level of Evidence: B)
- Ongoing clinical screening is not indicated in genotype-negative relatives in families with HCM (Level of Evidence: B)
The Heart Rhythm Society and the European Heart Rhythm Association published recommendations for genetic testing for cardiac channelopathies and cardiomyopathies in 2011.(44) For hypertrophic cardiomyopathy, the following recommendations were made:
- Comprehensive or targeted HCM genetic testing is recommended for any patient in whom a cardiologist has established a clinical diagnosis of HCM based on examination of the patient’s clinical history, family history, and electrocardiographic/echocardiographic phenotype
- Mutation-specific testing is recommended for family members and appropriate relatives following the identification of the HCM-causative mutation in an index case.
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force has not addressed genetic testing for hypertrophic cardiomyopathy.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Ramaraj R. Hypertrophic cardiomyopathy: etiology, diagnosis, and treatment. Cardiol Rev. Jul-Aug 2008;16(4):172-180. PMID 18562807
- Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. J Cardiovasc Electrophysiol. Jan 2008;19(1):104-110. PMID 17916152
- Marian AJ. Genetic determinants of cardiac hypertrophy. Curr Opin Cardiol. May 2008;23(3):199-205. PMID 18382207
- Roberts R, Sigwart U. Current concepts of the pathogenesis and treatment of hypertrophic cardiomyopath. Circulation. Jul 12 2005;112(2):293-296. PMID 16009810
- Keren A, Syrris P, McKenna WJ. Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nat Clin Pract Cardiovasc Med. Mar 2008;5(3):158-168. PMID 18227814
- Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. Aug 21 2012;60(8):705-715. PMID 22796258
- Cirino AL HC. Hypertrophic Cardiomyopathy: the genetic determinants of clinical disease expression. GeneReviews 2008; http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hyper-card. Accessed January 18, 2009.
- Ghosh N, Haddad H. Recent progress in the genetics of cardiomyopathy and its role in the clinical evaluation of patients with cardiomyopathy. Curr Opin Cardiol. Mar 2011;26(2):155-164. PMID 21297463
- Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. Jun 5 2004;363(9424):1881-1891. PMID 15183628
- Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol. Nov 5 2003;42(9):1687-1713. PMID 14607462
- Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. Nov 8 2011;124(24):2761-2796. PMID 22068434
- Arya A, Bode K, Piorkowski C, et al. Catheter ablation of electrical storm due to monomorphic ventricular tachycardia in patients with nonischemic cardiomyopathy: acute results and its effect on long-term survival. Pacing and clinical electrophysiology : PACE. Dec 2010;33(12):1504-1509. PMID 20636312
- GeneDx® Personal Communication. 4/29/2010 2010.
- Correlagan® Personal Communication. 4/27/2010 2010.
- PGxHealth® Personal Communication. 4/22/2010 2010.
- Das KJ, Ingles J, Bagnall RD, et al. Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment. Genet Med. Oct 10 2013. PMID 24113344
- Andreasen C, Nielsen JB, Refsgaard L, et al. New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet. Sep 2013;21(9):918-928. PMID 23299917
- Zou Y, Wang J, Liu X, et al. Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. Mol Biol Rep. Jun 2013;40(6):3969-3976. PMID 23283745
- Center BBATE. Genetic testing for predisposition to inherited hypertrophic cardiomyopathy. TEC Assessment 2009. 2009;24(11).
- Harvard CardioGenomics. 2010; http://cardiogenomics.med.harvard.edu/home. Accessed December 10, 2014.
- Erdmann J, Daehmlow S, Wischke S, et al. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet. Oct 2003;64(4):339-349. PMID 12974739
- Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. Apr 30 1998;338(18):1248-1257. PMID 9562578
- Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc. Jun 2008;83(6):630-638. PMID 18533079
- Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. May 6 2003;107(17):2227-2232. PMID 12707239
- Van Driest SL, Ellsworth EG, Ommen SR, et al. Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. Circulation. Jul 29 2003;108(4):445-451. PMID 12860912
- Watkins H, McKenna WJ, Thierfelder L, et al. Mutations in the genes for cardiac troponin T and alphatropomyosin in hypertrophic cardiomyopathy. N Engl J Med. Apr 20 1995;332(16):1058-1064. PMID 7898523
- Familion™ genetic tests for inherited cardiac syndromes: technical specifications. PGxHealth Website (now Transgenomics Health) 2009;
http://pgxhealth.com/genetictests/familion/pdf.FAMILION_TechSheet_08TS0801_RAC.pdf. Accessed January 25, 2009.
- Chiou KR, Chu CT, Charng MJ. Detection of mutations in symptomatic patients with hypertrophic cardiomyopathy in Taiwan. J Cardiol. Jul 30 2014. PMID 25086479
- Adalsteinsdottir B, Teekakirikul P, Maron BJ, et al. Nationwide Study on Hypertrophic Cardiomyopathy in Iceland: Evidence of a MYBPC3 Founder Mutation. Circulation. Sep 30 2014;130(14):1158-1167. PMID 25078086
- Mook OR, Haagmans MA, Soucy JF, et al. Targeted sequence capture and GS-FLX Titanium sequencing of 23 hypertrophic and dilated cardiomyopathy genes: implementation into diagnostics. J Med Genet. Sep 2013;50(9):614-626. PMID 23785128
- D'Argenio V, Frisso G, Precone V, et al. DNA Sequence Capture and Next-Generation Sequencing for the Molecular Diagnosis of Genetic Cardiomyopathies. J Mol Diagn. Oct 31 2013. PMID 24183960
- Gomez J, Reguero JR, Moris C, et al. Mutation Analysis of the Main Hypertrophic Cardiomyopathy Genes Using Multiplex Amplification and Semiconductor Next-Generation Sequencing. Circ J. Oct 22 2014. PMID 25342278
- Millat G, Chanavat V, Rousson R. Evaluation of a new NGS method based on a custom AmpliSeq library and Ion Torrent PGM sequencing for the fast detection of genetic variations in cardiomyopathies. Clin Chim Acta. Jun 10 2014;433:266-271. PMID 4721642
- Ingles J, Sarina T, Yeates L, et al. Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy. Genet Med. Apr 18 2013. PMID 23598715
- Gruner C, Ivanov J, Care M, et al. Toronto hypertrophic cardiomyopathy genotype score for prediction of a positive genotype in hypertrophic cardiomyopathy. Circ Cardiovasc Genet. Feb 2013;6(1):19-26. PMID 23239831
- Bos JM, Will ML, Gersh BJ, et al. Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. Mayo Clin Proc. Jun 2014;89(6):727-737. PMID 24793961
- Marsiglia JD, Credidio FL, de Oliveira TG, et al. Clinical predictors of a positive genetic test in hypertrophic cardiomyopathy in the Brazilian population. BMC Cardiovasc Disord. 2014;14:36. PMID 24625281
- Charron P, Carrier L, Dubourg O, et al. Penetrance of familial hypertrophic cardiomyopathy. Genet Couns. 1997;8(2):107-114. PMID 9219008
- Fananapazir L, Epstein ND. Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations. Circulation. Jan 1994;89(1):22-32. PMID 8281650
- Page SP, Kounas S, Syrris P, et al. Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circ Cardiovasc Genet. Apr 1 2012;5(2):156-166. PMID 22267749
- Michels M, Soliman OI, Phefferkorn J, et al. Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. Eur Heart J. Nov 2009;30(21):2593-2598. PMID 19666645
- Ho CY. Genetic considerations in hypertrophic cardiomyopathy. Prog Cardiovasc Dis. May 2012;54(6):456-460. PMID 22687586
- Authors/Task Force members, Elliott PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. Oct 14 2014;35(39):2733-2779. PMID 25173338
- Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. Aug 2011;8(8):1308-1339. PMID 21787999
|CPT||See Policy Guidelines|
|ICD-9 Diagnosis||425.1||Hypertrophic obstructive cardiomyopathy|
|425.4||Other primary cardiomyopathies (included familial and hypertrophic cardiomyopathy not otherwise specified)|
|V17.41||Family history of sudden cardiac death (SCD)|
|V17.49||Family history of other cardiovascular diseases|
|HCPCS||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|
|ICD-10-CM (effective 10/1/15)||I42.1||Obstructive hypertrophic cardiomyopathy|
|I42.2||Other hypertrophic cardiomyopathy|
|Z13.71||Encounter for nonprocreative screening for genetic testing disease carrier status|
|Z31.430||Encounter of female for testing for genetic disease carrier status for procreative management|
|Z31.440||Encounter of male for testing for genetic disease carrier status for procreative management|
|Z82.41||Family history of sudden cardiac death|
|Z82.49||Family history of ischemic heart disease and other diseases of the circulatory system|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are only used for inpatient services. There is no ICD-10-PCS code for laboratory tests.|
Cardiomyopathy, Hypertrophic, Genetic Testing
Genetic Testing, Hypertrophic Cardiomyopathy
Hypertrophic Cardiomyopathy, Genetic Testing
|Policy created with literature search/TEC Assessment through October 2011; 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 an affected relative; considered investigational for all other indications|
|12/13/12||Replace Policy||Policy updated with literature search through October 2012. References 6, 26, and 27. No change to policy statement|
|12/12/13||Replace policy||Policy update with literature search through October 31, 2013. References 15-17 and 30-33 added. The policy statements are unchanged.|
|12/11/14||Replace policy||Policy updated with literature review through October 29, 2014. References 11, 28-29, 32-33, 36-37, 41, and 43 added. Policy statements unchanged.|