Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy
Executive Summary
Background
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular condition in the U.S., and the most common cause of sudden cardiac death in adults younger than 35 years of age. For the purpose of this Assessment, HCM will refer to inherited HCM that is not associated with other congenital abnormalities and arises from a mutation in one of the cardiac sarcomere or related genes. This excludes left-ventricular hypertrophy (LVH) that is due to secondary causes, such as hypertension and/or valvular disease, and also excludes increased cardiac mass that is associated with systemic syndromes such as infiltrative disorders (e.g., amyloidosis, sarcoid), glycogen storage diseases (e.g., Fabry disease, Pompe disease), and neuromuscular disorders (e.g., Noonan’s syndrome, Friederich’s ataxia).
The clinical diagnosis of HCM depends on the presence of LVH, in the absence of other known causative factors such as valvular disease, long-standing hypertension, or other myocardial disease. As this definition implies, the diagnosis of HCM is largely one of exclusion. Both cardiac causes and noncardiac causes of increased cardiac mass or LVH need to be excluded prior to a diagnosis of HCM.
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. Mutations in the genes coding for these proteins can result in HCM. The genetics of HCM is complicated by the convergence of several factors, as follows:
* Several genes, many mutations. Several hundred distinct mutations in at least 12 different genes have been related to HCM cases. Despite this, known genes and mutations do not yet account for all cases of HCM.
* Penetrance. Genetic mutations for HCM may not ever result in clinical disease; the probability that a specific mutation will result in disease is called its penetrance. The penetrance for different HCM mutations is variable, but there are insufficient data to characterize the penetrance of every mutation.
* Variable expressivity. Patients with identical mutations may have widely differing clinical phenotypes. This may be the result of other modifying factors that affect disease expression, for example, hypertension or obesity.
Commercial testing for mutations in the cardiac sarcomere genes is currently available. In the case of predispositional testing (i.e., individual is currently without signs or symptoms), if there is a known mutation in the family, targeted testing of the specific familial mutation can be performed, which examines whether the familial mutation is present or absent in the tested at-risk individual. If there is no known mutation in the family, comprehensive testing can be performed, which examines the relevant known genes in their entirety for sequence variations that may be causative of HCM. Genetic testing for HCM may improve outcomes for the at-risk individual by providing information on the likelihood of future disease, which may lead to changes in screening and management and/or may aid individuals in making informed choices regarding decisions on reproduction, employment, or strenuous activities.
Objective
To determine whether genetic testing for predisposition to inherited HCM improves health outcomes in patients at risk for HCM.
Search Strategy
MEDLINE® was searched (via PubMed) using the terms “hypertrophic cardiomyopathy” and “HCM,” cross-referenced with the terms “genetics,” “genomics,” and “cardiogenomics” for the period of 1990 through November 2009; focused searches were completed in March 2010. Electronic search was supplemented with the “related articles” function in PubMed and with manual review of recent relevant review articles.
Selection Criteria
Studies were selected that included primary evidence on genetic testing in a population of patients with HCM and that assessed the performance characteristics of genetic testing. Studies were selected that: 1) included a cohort of unrelated index patients with HCM; 2) included at least 100 patients with HCM; and 3) performed testing for multiple HCM mutations, including at minimum, the 5 most common genes. Evidence was also sought on whether genetic testing impacted management decisions for at-risk individuals. Studies were selected that: 1) were cohort studies, case-control studies, or controlled clinical trials; 2) used information from genetic testing in determining individual treatment decisions; and 3) applied one of the accepted treatments for HCM, either medical therapy, surgical therapy, implantation of a cardioverter-defibrillator (ICD), or cardiac transplantation.
Main Results
Seven studies were identified that met the inclusion criteria for review and contained relevant evidence on testing for HCM. No studies met the inclusion criteria for evaluating the impact of genetic testing on treatment decisions. These peer-reviewed articles were supplemented by data on analytic validity available through the manufacturers’ websites or personal communications.
For predispositional genetic testing, the clinical validity (ability to detect a mutation in a patient with HCM and exclude a mutation in a patient without HCM) is more relevant when there is not a known mutation in the family, whereas the analytic validity, rather than the clinical validity, is more relevant for individuals with a known mutation in the family.
Evidence on clinical validity consists of several case series of patients with established HCM. An important component of clinical validity in considering predisposition testing for HCM is the clinical sensitivity, also called the mutation detection rate. To date, the published mutation detection rate ranges from 33–63%. 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.
The analytic validity of sequence analysis for detecting mutations that cause HCM (ability to identify small nucleotide changes that result in abnormal sarcomere protein products) 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 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, but that the rate of false-positives is likely to be higher for classification of previously unknown variants.
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. The negative predictive value for targeted familial mutation analysis is substantially higher than for comprehensive testing performed when there is not a known mutation in the family.
For patients without a known mutation in the family, genetic testing is not sufficient to rule out HCM. A positive genetic test in a patient without a known family history of disease increases the likelihood that an individual carries a pathologic mutation. In most cases, a positive genetic test is not sufficient to establish clinical disease, since not all patients with a genetic mutation will develop HCM, so the ultimate diagnosis depends on clinical criteria.
The other important component to clinical validity in the context of predisposition testing 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). In addition, penetrance varies among different mutations and may even vary among different families with an identical pathologic mutation. As a result, it is not possible to estimate accurately the penetrance for any given mutation in a specific family.
Author’s Conclusions and Comments
There are limitations in the strength of the evidence on genetic testing for predisposition to HCM. The published evidence on diagnostic accuracy is primarily limited to a small number of studies on mutation detection rate (clinical sensitivity) in individuals with HCM. There is scant published evidence on the analytic sensitivity of testing, and there is also scant published evidence on the specificity (analytic and clinical) of test results. Despite the limitations in the evidence, some conclusions can be drawn on the utility of genetic testing.
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 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 recommended surveillance for HCM manifestations will be essentially no different than those based on family history alone.
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 with established HCM will improve outcomes for close relatives by informing and directing the subsequent testing of these 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 can be excluded 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, employment, and participating in strenuous activities (e.g., sports) 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.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether the use of predispositional genetic testing for inherited hypertrophic cardiomyopathy meets the Blue Cross and Blue Shield Association’s Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
There are no assay kits approved by the U.S. Food and Drug Administration (FDA) for genetic testing for HCM, nor are any kits being actively manufactured and marketed for distribution. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing. While the FDA has technical authority to regulate home-brew tests, there is currently no active oversight nor any known plans to begin oversight. Home-brew tests may be developed using reagents prepared in-house or, if available, commercially manufactured analyte-specific reagents (ASRs). ASRs are single reagents “intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens” and must meet certain FDA criteria but are not subject to premarket review.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
For individuals at risk for HCM and with a known mutation in the family, genetic testing will establish the presence or absence of the same genetic 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. Identifying the familial mutation will confirm the inheritance of the familial predisposition to HCM and will increase the likelihood of developing clinical disease, but the diagnosis of HCM will still depend on the demonstration of clinical signs of the disorder.
For at-risk individuals without a known mutation in the family, there is little to no impact of genetic testing on clinical outcomes. In this situation, the negative predictive value of testing is not high enough to rule out the possibility of the presence of a pathologic genetic mutation that has gone undetected given the limitations of current technology. Therefore, a negative test is not likely to be helpful in refining risk estimates for development of HCM and in changing clinical surveillance for signs relating to HCM. A positive test result would confirm the predisposition, and could be helpful in reproductive and personal decision making, but it would not alter clinical decision making—that is similar, surveillance/management would be recommended.
3. The technology must improve the net health outcome.
For the at-risk individual with a known mutation in the family who does not have the familial predisposition (i.e., tests negative), there is a net improvement in health outcome. These patients no longer need ongoing surveillance for the presence of clinical signs of HCM and can be reassured that they need not consider changes in employment, avoid activities involving physical exertion, or change decisions about reproduction. For the index patient with established HCM, testing improves outcomes for at-risk relatives. By testing a patient with established disease, the predictive value of testing at-risk relatives is improved if a genetic mutation is found in the index patient. The improved predictive value leads to the ability to rule out inherited predisposition to HCM with near certainty in relatives who test negative, which in turn, allows the relative to discontinue screening and not have to consider modifying employment, avoiding activities involving physical exertion, or changing decisions about reproduction.
For at-risk individuals without a known mutation in the family, there is not an improvement in health outcomes since the evidence does not permit conclusions of the effect of genetic testing on outcomes.
4. The technology must be as beneficial as any established alternatives.
The alternative to genetic testing is periodic clinical follow-up to monitor the development of signs or symptoms of HCM informed by personal and family history risk factors. Therefore, for patients in whom health outcomes are improved, testing is more beneficial than alternatives.
5. The improvement must be attainable outside the investigational settings.
Genetic testing for HCM is commercially available in the U.S. For those indications meeting TEC criteria, improvement in health outcomes is based on results of commercial testing, and therefore is attainable outside the investigational setting. For those indications not meeting TEC criteria, improvement in health outcomes was not shown in the investigational setting.
For the above reasons, the use of genetic testing for inherited hypertrophic cardiomyopathy meets the TEC criteria for the following indications:
* Individuals who are at-risk for development of HCM, defined as having a close relative with established HCM, when there is a known pathogenic gene mutation present in an affected relative.
In order to inform and direct genetic testing for at-risk individuals, genetic testing should be initially performed in at least one close relative with definite HCM (index case) if possible. 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.
Due to the complexity of genetic testing for HCM and the potential for misinterpretation of results, the decision to test and the interpretation of test results should be performed by, or in consultation with an expert in the area of medical genetics and/or hypertrophic cardiomyopathy.
Genetic testing for inherited hypertrophic cardiomyopathy does not meet the TEC criteria for predisposition testing in other situations, including the following:
* Individuals who are at-risk for development of HCM, defined as having a close relative with established HCM, when there is no known pathogenic gene mutation present in an affected relative. This includes:
- Patients with a family history of HCM, with unknown genetic status of affected relatives.
- Patients with a family history of HCM, when a pathogenic mutation has not been identified in affected relatives.
Full Study
Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy
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ACC; AICD; ataxia; beta-myosin; cardiac hypertrophy; cardioverter; defibrillator; Fabry; familial; GeneDX; genetic determinants; genetic testing; genotype; genotypic; Harvard Cardiogenomics; HCM; hypertrophic cardiomyopathy; ICD; implantable; infiltrative; inherited; monitoring; mutation; MYH7; myofilament; myosin; Noonan; penetrance; penetrant; PGxHealth; phenotype; phenotypic; Pompe; predictive screening; predisposition; protein; risk stratification; sarcomere; thin filament; TNNT2; tropomyosin; troponin T; ultrasound;
