Medical Policy: 02.04.37
Original Effective Date: October 2012
Reviewed: June 2018
Revised: June 2018
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
There are currently genetic tests available for multiple cardiac conditions. This includes various channelopathies and other systemic conditions effecting cardiac health. With the multitude of genetic tests commercially available, there is great importance in choosing the most appropriate test. Confining your analysis to a smaller number of genes (ie, targeted panels over more broad approaches such as clinical exome/genome sequencing) will reduce the number of uncertain and incidental variants.
Currently, interpretation of cardiac ion channelopathy variation testing is complicated by several factors. The pathophysiologic significance of each of the discrete variations is an important part of the interpretation of genetic analysis. Laboratories that test for cardiac ion channelopathies keep a database of known pathologic mutations; however, these are mainly proprietary and may vary among different laboratories. In addition, the probability that a specific variation is pathophysiologically significant is greatly increased if the same variation has been reported in other cases. However, a variation may also be found that has not definitely been associated with a disorder and therefore may or may not be pathologic.
As the prevalence of genetic testing has increased, the limitations become more important to the practicing physician. Testing may reveal a change in the patient’s genome from the typical sequence, but certifying a variation as the clinical cause of a patient’s disease remains a challenge.
The expression levels of various genes in circulating white blood cell or whole blood samples have been reported to discriminate between cases of obstructive coronary artery disease (CAD) and healthy controls. Multiplex gene expression testing can be combined with other risk factors to predict the likelihood of obstructive CAD in patients who present with chest pain or other suggestive symptoms, or in asymptomatic patients who are at high risk of CAD.
Heart disease is the leading cause of mortality in the U.S. and, together with cerebrovascular disease, accounted for 31% of deaths in 2007. Individuals with signs and symptoms of obstructive coronary artery disease (CAD), the result of a chronic inflammatory process that ultimately results in progressive luminal narrowing and acute coronary syndromes, may be evaluated with a variety of tests according to prior risk. Coronary angiography is the gold standard for diagnosing obstructive CAD, but it is invasive and associated with a low but finite risk of harm. Thus, coronary angiography is recommended for patients at a high prior risk of CAD according to history, physical findings, electrocardiogram, and biomarkers of cardiac injury. For patients initially assessed at low-to-intermediate risk, observation and noninvasive diagnostic methods, which may include imaging methods such as coronary computed tomographic angiography, may be recommended. Nevertheless, even noninvasive imaging methods have potential risks of exposure to radiation and contrast material. In addition, coronary angiography has a relatively low yield despite risk stratification recommendations. In one study of nearly 400,000 patients without known CAD undergoing elective coronary angiography, approximately 38% were positive for obstructive CAD (using the CAD definition, stenosis of 50% or more of the diameter of the left main coronary artery or stenosis of 70% or more of the diameter of a major epicardial or branch vessel that was more than 2.0 mm in diameter; result was 41% if using the broader definition, stenosis of 50% or more in any coronary vessel). Thus, methods of improving patient risk prediction prior to diagnostic testing are needed.
A CAD classifier has been developed based on the expression levels, in whole blood samples, of 23 genes plus patient age and sex. This information is combined in an algorithm to produce a score from 1 to 40, with higher values associated with a higher likelihood of obstructive CAD. The test is marketed as Corus CAD™ (CardioDx, Inc.). The intended population is stable, nondiabetic patients suspected of CAD either because of symptoms, a high-risk history, or a recent positive or inconclusive test result by conventional methods.
The Corus CAD™ test is not a manufactured test kit and has not been reviewed by the U.S. Food and Drug Administration (FDA). Rather, it is a laboratory-developed test (LDT), offered by the Clinical Laboratory Improvement Act (CLIA)-licensed CardioDx Commercial Laboratory.
Brugada Syndrome is characterized by cardiac conduction abnormalities which increase the risk of syncope, ventricular arrhythmia, and sudden cardiac death. Inheritance occurs in an autosomal dominant manner with patients typically having an affected parent. Children of affected parents have a 50% chance of inheriting the variation. The instance of de novo variations is very low and is estimated to be only 1% of cases.
The disorder primarily manifests during adulthood although ages between two days and 85 years have been reported. Geno typical males are more likely to be affected than geno typical females (approximately an 8:1 ratio). Brugada syndrome is estimated to be responsible for 12% of SCD cases For both genders there is an equally high risk of ventricular arrhythmias or sudden death. Penetrance is highly variable, with phenotypes ranging from asymptomatic expression to death within the first year of life. Management has focused on the use of implantable cardiac defibrillators (ICD) in patients with syncope or cardiac arrest and isoproterenol for electrical storms. Patients who are asymptomatic can be closely followed to determine if ICD implantation is necessary.
The diagnosis of Brugada Syndrome is considered definite when the characteristic EKG pattern is present with at least one of the following clinical features: documented ventricular arrhythmia, sudden cardiac death in a family member <45 years old, characteristic EKG pattern in a family member, inducible ventricular arrhythmias on EP studies, syncope, or nocturnal agonal respirations.
Congenital long QT syndrome (LQTS) is an inherited disorder characterized by the lengthening of the repolarization phase of the ventricular action potential, increasing the risk of arrhythmic events, such as torsades de pointes, which may in turn result in syncope and sudden cardiac death. Management has focused on the use of beta blockers as first-line treatment, with pacemakers or implantation cardioverter defibrillators (ICD) as second-line therapy.
Currently, there are three major LQTS genes (KCNQ1, KCNH2, and SCN5A) that account for approximately 75% of the disorder. The 10 minor LQTS-susceptibility genes collectively account for less than 5% of LQTS cases.
Congenital LQTS usually manifests itself before the age of 40 years. Frequently, syncope or sudden death occurs during physical exertion or emotional excitement. LQTS may be considered when a long QT interval is incidentally observed on an ECG. Diagnostic criteria for LQTS have been established, which focus on ECG findings and clinical and family history (i.e., Schwartz criteria, see following table). The Schwartz criteria are commonly used as a diagnostic scoring system for LQTS. The most recent version of this scoring system is shown below. A score of 4 or greater indicates a high probability that LQTS is present; a score of 2 to 3, a moderate-to-high probability; and a score of 1 or less indicates a low probability of the disorder. Prior to the availability of genetic testing, it was not possible to test the sensitivity and specificity of this scoring system; and since there is still no perfect gold standard for diagnosing LQTS.
LQTS is a disorder that may lead to catastrophic outcomes, ie, sudden cardiac death in otherwise healthy individuals. Diagnosis using clinical methods alone may lead to underdiagnosis of LQTS, thus exposing undiagnosed patients to the risk of sudden cardiac arrest. For patients in whom the clinical diagnosis of LQTS is uncertain, genetic testing may be the only way to further clarify whether LQTS is present. Patients who are identified as genetic carriers of LQTS variations have a non-negligible risk of adverse cardiac events even in the absence of clinical signs and symptoms of the disorder. Therefore, treatment is likely indicated for patients found to have a LQTS variation, with or without other signs or symptoms.
There is not sufficient evidence to conclude that the information obtained from genetic testing on risk assessment leads to important changes in clinical management. Most patients will be treated with betablocker therapy and lifestyle modifications, and it has not been possible to identify a group with low enough risk to forego this conservative treatment. Conversely, for high-risk patients, there is no evidence suggesting that genetic testing influences the decision to insert an ICD and/or otherwise intensify treatment.
|History of torsades de pointes||2|
|Notched T-waves in three leads||1|
|Low heart rate for age||0.5|
|Syncope brought on by stress||2|
|Syncope without stress||1|
|Family members with definite LQTS||1|
|Unexplained sudden death in immediate family members younger than 30 years of age||0.5|
Short QT syndrome is a condition that can cause a disruption of the heart's normal rhythm (arrhythmia). In people with this condition, the heart (cardiac) muscle takes less time than usual to recharge between beats. The term "short QT" refers to a specific pattern of heart activity that is detected with an electrocardiogram (EKG), which is a test used to measure the electrical activity of the heart. In people with this condition, the part of the heartbeat known as the QT interval is abnormally short.
SQTS has been linked predominantly to variations in 3 genes KCNH2, KCNJ2, and KCNQ1. Some individuals with SQTS do not have a variation in these genes suggesting changes in other genes may also cause this disorder.
No studies were identified that provide evidence for the clinical utility of genetic testing for SQTS. Clinical sensitivity for the test is low with laboratory testing providers estimating a yield as low as 15%.
Mutations in 4 genes are known to cause CPVT, and investigators believe other unidentified loci are involved as well. Currently, only 55% to 65% of patients with CPVT have an identified causative mutation. Mutations to the gene encoding the cardiac ryanodine receptor (RYR2) or to KCNJ2 result in an autosomal dominant form of CPVT. CASQ2 (cardiac calsequestrin) andTRDN-related CPVT exhibit autosomal recessive inheritance. Some authors have reported heterozygotes for CASQ2 and TRDN mutations for rare, benign arrhythmias. RYR2 mutations represent the majority of CPVT cases (50-55%), with CASQ2 accounting for 1% to 2% and TRDN accounting for an unknown proportion of cases.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition characterized by an abnormal heart rhythm (arrhythmia). As the heart rate increases in response to physical activity or emotional stress, it can trigger heartbeat called ventricular tachycardia.
Management of CPVT is primarily with beta-blockers. If protection is incomplete (ie, recurrence of syncope or arrhythmia), then flecainide may be added. If recurrence continues, an ICD may be necessary with optimized pharmacologic management continued postimplantation. Lifestyle modification with the avoidance of strenuous exercise is recommended for all CPVT patients.
Familial TAAD is believed to account for at least 20 percent of thoracic aortic aneurysms and dissections. In the remainder of cases, the abnormalities are thought to be caused by factors that are not inherited, such as damage to the walls of the aorta from aging, tobacco use, injury, or disease.
Ambry Genetics offers “TAADNEXT,” an NGS panel which simultaneously analyzes 20 genes that are associated with TAADs, MFS and related disorders. Published studies on the analytic validity of genetic testing for connective tissue disorders associated with thoracic aortic aneurysms are lacking. The sensitivity of sequence analysis for individual variations for these disorders is generally high for certain disorders, but lower, for others. Conventional testing for these disorders has historically consisted of sequencing for individual variations associated with one suspected disorder, followed by duplication/deletion analysis if sequencing is negative. More recently, panel testing by next-generation sequencing (NGS) tests has been developed to test for multiple syndromes simultaneously.
DCM is defined as the presence of left ventricular enlargement and dilatation in conjunction with significant systolic dysfunction. Dilated cardiomyopathy has an estimated prevalence of 1 in 2700 in the United States. The age of onset for DCM is variable, ranging from infancy to the eighth decade, with most individuals developing symptoms in the fourth through sixth decade. Primary clinical manifestations of DCM are heart failure and arrhythmias. Symptoms of heart failure, such as dyspnea on exertion and peripheral edema, are the most common presentation of DCM. These symptoms are generally gradual in onset and slowly progressive over time. Progressive myocardial dysfunction also may lead to electrical instability and arrhythmias. Symptoms of arrhythmias may include light-headedness, syncope or sudden cardiac arrest.
Many genetic variations on more than 40 different genes have been associated with DCM. This remains an active area of research, and it is likely that many more variations will be identified in the future. Analytic validity of genetic testing for DCM is expected to be high when testing is performed by direct sequencing or next-generation sequencing. In contrast, clinical validity is not high. The percentage of patients with idiopathic DCM who have a genetic variation (clinical sensitivity) is relatively low.
Treatment of DCM is similar to that for other causes of heart failure. This includes medications to reduce fluid overload and relieve strain on the heart, and lifestyle modifications such as salt restriction. Patients with clinically significant arrhythmias also may be treated with antiarrhythmic medications, pacemaker implantation, and/or an automatic implantable cardiac defibrillator (AICD). AICD placement for primary prevention also may be performed if criteria for low ejection fraction and/or other clinical symptoms are present. End-stage DCM can be treated with cardiac transplantation.
Familial hypertrophic cardiomyopathy (HCM) is an inherited condition that is caused by a variation in 1 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 variations is currently available through a number of commercial laboratories.
For individuals at risk for HCM (first-degree relatives), genetic testing is most useful when there is a known variation in the family. In this situation, genetic testing will establish the presence or absence of the same variation in a close relative with a high degree of certainty. Absence of this variation 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 variation.
For at-risk individuals without a known variation 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. For at-risk individuals who have a family member with HCM who tests negative for pathologic variations, genetic testing is not medically necessary.
The primary benefit of identifying genetic abnormality is to ensure family members determine if they also have hypertrophic cardiomyopathy, or the gene responsible for it. If the individual has a gene identified, but the family member does not, that family member will not move to be further screened for hypertrophic cardiomyopathy in the future and no special surveillance would be necessary.
ARVC/ARVD is a rare type of cardiomyopathy that occurs if the muscle tissue in the right ventricle dies and is replaced by fat or scar tissue:
Variations in several genes have been found to cause left ventricular noncompaction. Mutations in the MYH7 and MYBPC3 genes have been estimated to cause up to 30 percent of cases; mutations in other genes are each responsible for a small percentage of cases. However, the cause of the condition is often unknown.
It is unclear how genetic mutations cause left ventricular noncompaction. During normal development before birth, cardiac muscle gets condensed (compacted), becoming smooth and firm. Mutations in certain genes likely lead to changes in this process, resulting in a left ventricular cardiac muscle that is not compacted but is thick and spongy, leading to left ventricular noncompaction.
In cases where the family member’s genetic diagnosis is unavailable, testing is available through either single-gene testing or panel testing. Panels for cardiac ion channelopathies are diagnostic test panels that may fall into one of several categories: panels that include variants for a single condition; panels that include variants for multiple conditions (indicated plus non-indicated conditions); and panels that include variants for multiple conditions (clinical syndrome for which clinical diagnosis not possible).
With the addition of multiple gene panels available for cardiology, the number of panel tests, and number of gene variations examined have continued to expand. The use of panel testing in cardiology includes, but not limited, to the following examples of panel testing:
The FAMILION test is currently performed exclusively at designated laboratory facilities provided by Transgenomics® Inc. (New Haven, CT) The FAMILION family of tests detects genetic variations that can cause cardiac channelopathies, cardiomyopathies, and other cardiopathies. Cardiac channelopathies are rare, potentially lethal inherited heart conditions, including Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Brugada Syndrome (BrS) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Cardiomyopathies are potentially lethal progressive diseases that affect the heart muscle including, Hypertrophic Cardiomyopathy (HCM), Dilated Cardiomyopathy (DCM), Conduction Disease associated with DCM (CD-DCM), and Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Other cardiopathies include Marfan Syndrome and familial Thoracic Aortic Aneurysms and Aortic Dissections (Marfan/TAAD). According to information available online the test “may use some reagents produced for research purposes only."
HCM First, CM Next, DCM Next, RhythmNext, RhythmFirst, CPVTNext, ARVDNext, CardioNext are all multi-gene test panels performed by AmbryGeneticsa (Aliso Viejo, CA).
CardioNext is a next generation sequencing (NGS) and deletion/duplication panel of 84 genes associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular dysplasia (ARVD), left ventricular non-compaction (LVNC), restrictive cardiomyopathy, long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome. This panel also includes genes that cause cardiomyopathy that is associated with inherited muscular dystrophies, as well as some genes associated with congenital heart defects.
RhythmNext is a panel including 34 genes associated with arrhythmogenic right ventricular dysplasia (ARVD), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), short QT syndrome (SQTS), other arrhythmias/channelopathies, as well as sudden cardiac arrest.
The Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) jointly published an expert consensus statement on genetic testing for channelopathies and cardiomyopathies. This document made the following specific recommendations concerning testing for LQTS, CPVT, Brugada Syndrom, and SQTS.
*Class I: “is recommended” when an index case has a sound clinical suspicion for the presence of a channelopathy with a high PPV for the genetic test (>40%) with a signal to noise ratio of >10 AND/OR the test may provide diagnostic or prognostic information or may change therapeutic choices.; Class IIa: “can be useful”; Class IIb: “may be considered”; Class III (“is not recommended”): The test fails to provide any additional benefit or could be harmful in the diagnostic process.
(EWG) found insufficient evidence to recommend testing for the 9p21 genetic variant or 57 other variants in 28 genes to assess risk for cardiovascular disease (CVD) in the general population, specifically heart disease and stroke. The EWG found that the magnitude of net health benefit from use of any of these tests alone or in combination is negligible. The EWG discourages clinical use unless further evidence supports improved clinical outcomes. Based on the available evidence, the overall certainty of net health benefit is deemed “Low.”
They published a joint position paper in 2011.24 Genetic testing was recommended for cardiac arrest survivors with LQTS for the purpose of familial screening as well as those with syncope with QTc prolongation as well as asymptomatic patients with QTc prolongation with a high clinical suspicion of LQTS. For clinically suspect CPVT, testing is recommended for the purpose of familial screening.
The society published guidelines for the management of atrial fibrillation (AF). Regarding genetic testing, the guideline notes while genomic analysis may provide an opportunity to improve the diagnosis and management of AF in the future, routine genetic testing for common gene variants associated with AF cannot be recommended at present. The guideline also notes that monogenic defects only account for 3–5% of all patients with AF, even in younger populations. Furthermore, there is no clear link between detected mutations and specific outcomes or therapeutic needs. Genetic testing is not recommended in the general population.
Multi-gene next generation panels are not medically necessary. This includes panels that test variants for multiple conditions (indicated plus non-indicated conditions); and panels that include variants for multiple non-specific conditions (clinical syndrome for which clinical diagnosis is not possible). The medical necessity of testing is based on medical factors for individual conditions and not panels that test for multiple syndromes or cardiac conditions without clinical cause. Testing for the individual condition will be expected when medically necessary criteria is present. The following is a list of common multi-condition panels (not all inclusive):
Panel testing is considered not medically necessary with any known condition/genetic variation and/or when focused genetic testing for a specific condition is possible.
Genetic testing for Short QT Syndrome is considered medically necessary for the following indications:
Genetic testing in patients with suspected CPTV may be considered medically necessary for the following indications:
Testing for Brugada Syndrome may be considered medically necessary for the following indications:
Genetic testing is not indicated and therefore not medically necessary in the setting of an isolated type 2 or type 3 Brugada ECG pattern
Genetic testing in patients with suspected congenital long QT syndrome may be considered medically necessary for the following indications:
Individuals who do not meet the clinical criteria for LQTS (ie, those with a Schwartz score <4), but who have:
Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is considered medically necessary only when needed to determine index case variation.
Genetic testing for predisposition to LQTS is considered not medically necessary for patients with a family history of LQTS in which an index case has tested negative for mutations.
Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) may be considered medically necessary for individuals who are at risk for development of HCM:
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 variations.
Genetic testing for determining the diagnosis and for management of all other hereditary cardiomyopathies, including but not limited to, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), dilated, restrictive, and left ventricular noncompaction cardiomyopathies, is considered not medically necessary for all indications.
Genetic testing for dilated cardiomyopathy is considered not medically necessary.
Clinical utility of genetic testing for DCM is uncertain. For a patient who is diagnosed with idiopathic DCM, the presence of a genetic variation will not change treatment or prognosis. For an individual at risk due to genetic DCM in the family, genetic testing can identify whether the variation has been inherited. However, it is uncertain how knowledge of a variation will improve outcomes for an asymptomatic individual. Early treatment based on a genetic diagnosis is unproven. Uncertain accuracy of predictive testing makes it uncertain whether changes in management will improve outcomes.
Genetic testing for thoracic aortic aneurysms and dissections (TAAD) medically necessary for:
Genetic testing of gene FBN1for Marfan Syndrome is considered medically necessary for
Genetic testing of genes MYH11, ACTA2, TGFBR1/2 is considered medically necessary for:
Testing for Marfan syndrome is considered not medically necessary in all other clinical scenarios.
Expanded panel testing for Marfan syndrome is considered not medically necessary.
Genetic testing (including but not limited to the following genes (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) may be considered medically necessary to confirm a clinical diagnosis in those with clinical suspicion of ARVC/ARVD.
Genetic testing (including but not limited to the following genes (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) may be considered medically necessary for first degree relatives of persons with genetically confirmed ARVC/ARVD.
Gene expression testing to predict coronary artery disease is considered investigational.
Genetic testing for atrial fibrillation is considered not medically necessary.
Genetic testing to find variants that correlate to cardiac structural genetics, including but not limited to aortic root size, is not proven at this time and is considered not medically necessary.
Genetic testing (including but not limited to the following genes: MYH7 and MYBPC3) is condidered not medically necessary for the diagnosis of left ventricular noncompaction.
Genetic testing panels for syndromes associated with thoracic aortic aneurysms and dissections, and related disorders that are not limited to focused genetic testing are considered not medically necessary.
Clinical utility of gene expression assays/panels has not been demonstrated. There hasn't been convincing evidence that the use of gene expression scores reduce unnecessary clinical evaluations. There is insufficient evidence in the clinical literature demonstrating that these test have a role in clinical decision-making or have a beneficial effect on health outcomes. Further studies are needed to determine the analytic validity, clinical validity and clinical utility of these tests. Testing for multiple conditions without clinical indications for testing has not been proven to change net health outcomes.
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