Medical Policy: 02.04.37 

Original Effective Date: October 2012 

Reviewed: June 2021 

Revised: June 2021 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

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.

 

Description:

Genetic testing of cardiac conditions and coronary artery disease (CAD) can vary. Tests can include, but are not limited to, those that evaluate variations in the genes, such as chromosome microarray and next generation sequencing (NGS), as well as others that assess the gene products, such as gene expression arrays and microRNA analysis. The number of genes evaluated can range from a single gene to a multi-gene panel testing multiple genes. Results of genetic testing may assist healthcare providers with determining a diagnosis, prognosis and identification of appropriate clinical interventions.

 

Coronary Artery Disease

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. 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.

 

Genetic Testing for Cardiac Ion Channelopathies

Genetic testing is available for patients suspected of having cardiac ion channelopathies, including long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), and short QT syndrome (SQTS). These disorders are clinically heterogeneous and may range from asymptomatic to presenting with sudden cardiac death. Testing for variants associated with these channelopathies may assist in diagnosis, risk-stratify prognosis, and/or identify susceptibility for the disorders in asymptomatic family members

 

Brugada Syndrome

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.

 

Long QT Syndrome

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.

 

Major LQTS Genes
  • KCNQ1 (LQT1)
  • KCNH2 (LQT2)
  • SCN5A (LQT3)

 

Minor LQTS Genes
  • AKAP9
  • CACNA1C
  • CALM1
  • CALM2
  • CAV3
  • KCNE1
  • KCNE2
  • KCNJ5
  • SCN4B
  • SNTA1 

 

A genetic basis for LQTS includes seven different variants, each corresponding to mutations in different genes, and has been identified as follows:

  • LQT1 is associated with mutations in the gene KNQ1, located on chromosome 11. LQT1 is responsible for approximately 50 percent of all LQTS. Arrhythmic events prompted by exercise occur most commonly in this subtype.
  • LQT2 is associated with mutations in the gene KCNH2, located on chromosome 7. LQT2 is seen in 45 percent of individuals with LQTS. Arrhythmic events are often precipitated by loud noises.
  • LQT3 is associated with mutations in the gene SCN5A, located on chromosome 3. This subtype is seen in 3 percent to 4 percent of individuals with LQTS.
  • LQT 4 - 7 involve KCN genes, located on chromosomes 21 and 17. These variants each account for less than 1 percent of LQTS.

 

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.

 

Schwartz Score Diagnostic Criteria for LQTS

 

Electrocardiographic findings* (* In the absence of medications or disorders known to affect these electrocardiographic features) Points
  1. QTC
 
    • ≥480 ms
3
    • 460 to 479 ms
2
    • 450 to 459 ms (in males)
1
  1. QTc fourth minute of recovery from exercise stress test > 480 ms
1
  1. Torsades de points
2
  1. T-wave alternans
1
  1. Notched T wave in 3 leads
1
  1. Low heart rate for age (resting heart rate below the second percentile for age)
0.5
Clinical history Points
  1. Syncope
 
    • With stress
2
    • Without stress
1
  1. Congenital deafness
0.5
Family history Points
  1. Family members with definite LQTS (the same family member cannot be counted in A or B)
1
  1. Unexplained sudden cardiac death below age 30 among immediate family members (the same family member cannot be counted in A or B)
0.5

 

SCORE:

  • ≤1 point = low probability of long QT syndrome (LQTS)
  • 5 to 3 points = intermediate probability of LQTS
  • ≥3.5 points = high probability of LQTS

 

Short QT Syndrome

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.

 

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

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 Thoracic Aortic Aneurysm and Dissection (Familial TAAD)

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.

 

Genetic Testing for Idiopathic Dilated Cardiomyopathy

Dilated cardiomyopathy (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.

 

Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy

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.

 

Arrhythmogenic Cardiomyopathy (ACM)/Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)/ Arrhythmogenic Right Ventricular Dysplasia (ARVD)

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:

  • This process disrupts the heart's electrical system, causing arrhythmias.
  • It usually affects teens and young adults.
  • Symptoms include heart palpitations and fainting after physical activity.
  • It can cause sudden cardiac arrest in young athletes.
  • It may require implantation of a device to prevent death from an arrhythmia 

 

Non-Compacted Left Ventricular Cardiomyopathy

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.

 

Panel Testing

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:

  • Arrhythmia Panels or Channelopathies Panels (multiple labs) 
  • Arrhythmia Panel (Blueprint Genetics) 
  • Blueprint Cardiomyopathy Panel (Blueprint Genetics)
  • Cardiac DNA Insight (Pathway Genomics)
  • CardioNext (Ambry Genetics) 
  • CardioGXOne (Admera)
  • Cardiomyopathy Panel (Knight Diagnostic Laboratories)
  • Cardiomyopathy (Panel GeneDx)
  • Cardiomyopathy and Arrhythmia Panel (ARUP Labratories) 
  • Cardiomyopathy Comprehensive Panel (Invitae)
  • Cardiomyopathy NGS Panel (Allele Diagnostics)
  • Cardio Familial Arrhythmia or Cardiomyopathy Panels (GenSeq)
  • Cardiomyopathies, Channelopathies, Arrhythmias, and Aortic Panels (HealthinCode)
  • Combined Cardiac Panel (GeneDx)
  • Comprehensive Arrythmia Panel (GeneDx)
  • Comprehensive Cardiology Panel (Blueprint Genetics) 
  • Comprehensive Cardiomyopathy Multi-Gene Panel (Mayo Clinic)
  • Comprehensive Cardiomyopathy Panel (Invitae)
  • Comprehensive Cardiovascular Deletion/Duplication Panel (EGL Genetic Diagnostics) 
  • Dilated Cardiomyopathy (DCM) Left Ventricular Non-Compaction (LVNC) (GeneDx)
  • GeneSeq: Cardio Familial Cardiomyopathy Profile (Labcorp)
  • Familion (Transgenomics)
  • HCMNext  (Ambry Genetics)
  • Invitae Arrhythmia & Cardiomyopathy Comprehensive Panel (Invitae)
  • Marfan/TAAD 23 gene panel (GeneDx)
  • Pan Cardiomyopathy Panel
  • RhythmNext/Rhythm First/RhythmNext Reflex (Ambry Genetics)

 

Examples of Cardiac Genetic Panel Testing (not all inclusive)

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.

 

Practice Guidelines and Position Statements

The Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)

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.

 

LQTS Class I
  • Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A) targeted LQTS genetic testing is recommended for any patient in whom a cardiologist has established a strong clinical index of suspicion for LQTS based on examination of the patient’s clinical history, family history, and expressed electrocardiographic (resting 12-lead ECGs and/or provocative stress testing with exercise or catecholamine infusion) phenotype.
  • Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A) targeted LQTS genetic testing is recommended for any asymptomatic patient with QT prolongation in the absence of other clinical conditions that might prolong the QT interval (such as electrolyte abnormalities, hypertrophy, bundle branch block, etc., ie, otherwise idiopathic) on serial 12-lead ECGs defined as QTc .480 ms (prepuberty) or .500 ms (adults).
  • Mutation-specific genetic testing is recommended for family members and other appropriate relatives subsequently following the identification of the LQTS-causative mutation in an index case.

 

LQTS Class II
  • Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A) targeted LQTS genetic testing may be considered for any asymptomatic patient with otherwise idiopathic QTc values .460 ms (prepuberty) or .480 ms (adults) on serial 12-lead ECGs. 

 

CPVT Class I
  • Comprehensive or CPVT1 and CVPT2 (RYR2 and CASQ2) targeted CPVT genetic testing is recommended for any patient in whom a cardiologist has established a clinical index of suspicion for CPVT based on examination of the patient’s clinical history, family history, and expressed electrocardiographic phenotype during provocative stress testing with cycle, treadmill, or catecholamine infusion. Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the CPVT-causative mutation in an index case. 

 

BrS Class I
  • Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the BrS-causative mutation in an index case. 

 

BrS Class IIa
  • Comprehensive or BrS1 (SCN5A) targeted BrS genetic testing can be useful for any patient in whom a cardiologist has established a clinical index of suspicion for BrS based on examination of the patient’s clinical history, family history, and expressed electrocardiographic (resting 12-lead ECGs and/or provocative drug challenge testing) phenotype. 

 

BrS Class III
  • Genetic testing is not indicated in the setting of an isolated type 2 or type 3 Brugada ECG pattern 

 

SQTS Class I
  • Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the SQTS-causative mutation in an index case. 

 

SQTS Class IIb
  • Comprehensive or SQT1-3 (KCNH2, KCNQ1, and KCNJ2) targeted SQTS genetic testing may be considered for any patient in whom a cardiologist has established a strong clinical index of suspicion for SQTS based on examination of the patient’s clinical history, family history, and electrocardiographic phenotype. 

 

*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.

 

The Evaluation of Genomic Applications in Practice and Prevention Working Group

(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.”

 

The Canadian Cardiovascular Society and Canadian Hearth Rhythm Society

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.

 

Heart Failure Society (HFS)/European Heart Rhythm Association (EHRA) (2008)

Regarding ARVC:

  • Comprehensive or targeted (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) ACM/ARVC genetic testing can be useful for patients satisfying task force diagnostic criteria for ACM/ARVC. (Class IIa)
  • Genetic testing may be considered for patients with possible ACM/ARVC (1 major or 2 minor criteria) according to the 2010 task force criteria. (Class IIb)
  • Genetic testing is not recommended for patients with only a single minor criterion according to the 2010 task force criteria. (Class III)
  • Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the ACM/ARVC-causative mutation in an index case. (Class I) 

 

European Society of Cardiology and European Association for Cardio-Thoracic Surgery

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.

 

American Heart Association, American College of Cardiology, and the Heart Rhythm Society

In 2017, the American Heart Association, American College of Cardiology, and the Heart Rhythm Society published guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. The recommendations relating to cardiac ion channelopathies are summarized as follows (2017):

  • In first-degree relatives of patients who have a causative mutation for long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, or Brugada syndrome, genetic counseling and mutation-specific genetic testing are recommended. Class of Recommendation: I (strong) Level of Evidence B-NR- moderate level of evidence
  • In patients with clinically diagnosed long QT syndrome, genetic counseling and genetic testing are recommended. Genetic testing offers diagnostic, prognostic, and therapeutic information. Class of Recommendation: I (strong) Level of Evidence B-NR- moderate level of evidence
  • In patients with catecholaminergic polymorphic ventricular tachycardia and with clinical VT or exertional syncope, genetic counseling and genetic testing are reasonable. Genetic testing may confirm a diagnosis; however, therapy for these patients is not guided by genotype status. Class of Recommendation: IIa (moderate) Level of Evidence B-NR- moderate level of evidence
  • In patients with suspected or established Brugada syndrome, genetic counseling and genetic testing may be useful to facilitate cascade screening of relatives, allowing for lifestyle modification and potential treatment. Class of Recommendation: IIb (weak) Level of Evidence C-EO- consensus of expert opinion based on clinical experience
  • In patients with short QT syndrome, genetic testing may be considered to facilitate screening of first-degree relatives. IIb (weak) Level of Evidence C-EO- consensus of expert opinion based on clinical experience

 

Heart Failure Society

The Heart Failure Society (2018) states:
"Guideline 4: Genetic testing is recommended for patients with cardiomyopathy (Level of evidence A)"
"4a: Genetic testing is recommended for the most clearly affected family member."
"4b: Cascade genetic testing of at-risk family members if recommended for pathogenic and likely pathogenic variants."
"Genetic testing is recommended to determine if a pathogenic variant can be identified to facilitate patient management and family screening."
"Testing should ideally be initiated on the person in a family with the most definitive diagnosis and most severe manifestations. This approach would maximize the likelihood of obtaining diagnostic results and detecting whether multiple pathogenic variants may be present and contributing to variable disease expression or severity."
"Molecular genetic testing for multiple genes with the use of a multigene panel is now the standard of practice for cardio-vascular genetic medicine."

 

American College of Medical Genetics and Genomics (ACMG)

In 2018, the American College of Medical Genetics and Genomics (ACMG) published clinical practice recommendations for the genetic evaluation of cardiomyopathy. The following recommendations were made for all types of cardiomyopathy:

  1. Genetic testing is recommended for the most clearly affected family member.
  2. Cascade genetic testing of at-risk family members is recommended for pathogenic and likely pathogenic variants.
  3. In addition to routine newborn screening tests, specialized evaluation of infants with cardiomyopathy is recommended, and genetic testing should be considered.

 

The ACMG also provided information on specific variants, noting that TTNtv represents the most common genetic variant found in DCM (10% to 20% of cases), with LMNA being the second most common variant identified (diagnostic yield of 5.5%).

 

When a cardiovascular phenotype has been identified, the ACMG recommends family-based genetic evaluations and surveillance screening.

 

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

 

Prior Approval:

Not applicable

 

Policy:

Comprehensive multigene panels* or multicondition* multi-gene panels with or without next generation sequencing (NGS) are considered investigational for all indications, including, but not limited to the following:

  • Arrhythmia Panel (Blueprint Genetics) 
  • Blueprint Cardiomyopathy Panel (Blueprint Genetics)
  • Cardiac DNA Insight (Pathway Genomics)
  • CardioNext (Ambry Genetics) 
  • CardioGXOne (Admera)
  • Cardiomyopathy Panel (Knight Diagnostic Laboratories)
  • Cardiomyopathy (Panel GeneDx)
  • Cardiomyopathy and Arrhythmia Panel (ARUP Labratories) 
  • Cardiomyopathy Comprehensive Panel (Invitae)
  • Cardiomyopathy NGS Panel (Allele Diagnostics)
  • Cardio Familial Arrhythmia or Cardiomyopathy Panels (GenSeq)
  • Cardiomyopathies, Channelopathies, Arrhythmias, and Aortic Panels (HealthinCode)
  • Combined Cardiac Panel (GeneDx)
  • Comprehensive Arrythmia Panel (GeneDx)
  • Comprehensive Cardiology Panel (Blueprint Genetics) 
  • Comprehensive Cardiomyopathy Multi-Gene Panel (Mayo Clinic)
  • Comprehensive Cardiomyopathy Panel (Invitae)
  • Comprehensive Cardiovascular Deletion/Duplication Panel (EGL Genetic Diagnostics) 
  • Dilated Cardiomyopathy (DCM) Left Ventricular Non-Compaction (LVNC) (GeneDx)
  • GeneSeq: Cardio Familial Cardiomyopathy Profile (Labcorp)
  • Familion (Transgenomics)
  • HCMNext  (Ambry Genetics)
  • Invitae Arrhythmia & Cardiomyopathy Comprehensive Panel (Invitae)
  • Pan Cardiomyopathy Panel
  • RhythmNext/Rhythm First/RhythmNext Reflex (Ambry Genetics)

 

*Multicondition Multigene Panels: Are available to analyze a broader range of genes   associated with a group of diseases, for example, inherited channelopathies. 

 

*Multigene Panel Tests: With or without next generation sequencing (NGS) technology, that simultaneously analyze many genes at one time.

 

Genetic Testing for Cardiac Ion Channelopathies

Short QT Syndrome 

Note: Short QT Syndrome genes include KCNH2 (81406/81479), KCNQ1 (81406/81479), KCNJ2(81403)

 

Genetic testing to determine future rist of Short QT Syndrome (SQTS) may be considered medically necessary when the patient has a close relative (first, second or third degree relative*) with known Short QT Syndrome (SQTS) variant.   

 

*A first-degree relative is defined as a close blood relative which includes the individual’s parents, full siblings, and children.

 

*A second-degree relative is defined as a blood relative which includes individual’s grandparents, grandchildren, aunts, uncles, nephews, nieces and half-siblings.

 

*A third-degree relative is defined as a blood relative which includes the individual’s first cousins, great-grandparents or great grandchildren

 

Note: A patient with suspected short QT syndrome (SQTS) would be expected to have a shortened (<2 standard deviation below from the mean) rate-corrected shortened QT interval (QTc). Cutoffs below 350 ms for men and 360 ms for women have been derived from population normal values. The presence of a short QTc interval alone does not make the diagnosis of SQTS. Clinical history, family history, other electrocardiographic findings, and genetic testing may be used to confirm the diagnosis.

 

Genetic Testing for Short QT Syndrome (SQTS) is considered investigational not meeting the above criteria and for all other indications.

 

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Note: CPVT genes include RYR2 (81408) and CASQ2 (81405)

 

Genetic testing ifor catecholaminergic polymorphic ventricular tachycardia (CPVT) may be considered medically necessary for on of the following indications:

  • When patient has a close relative (first, second or third degree relative*) with a known CPVT mutation; or
  • A close relative* has been diagnosed with CPVT; or
  • Signs and/or symptoms indicating a moderate-to-high pretest probability of CPVT, but a definitive diagnosis cannot be made without genetic testing; or
  • The patient being tested exhibits clinical features suggestive of CPTV including unexplained exercise or catecholamine-induced polymorphic ventricular arrhythmias (PVTs) and syncope during physical activity or emotional stress occurring in an individual with structurally normal heart.   

 

*A first-degree relative is defined as a close blood relative which includes the individual’s parents, full siblings, and children.

 

*A second-degree relative is defined as a blood relative which includes individual’s grandparents, grandchildren, aunts, uncles, nephews, nieces and half-siblings.

 

*A third-degree relative is defined as a blood relative which includes the individual’s first cousins, great-grandparents or great grandchildren

 

Note: CPVT patients generally present with syncope or cardiac arrest during the first or second decade of life. The symptoms are nearly always triggered by exercise or emotional stress. The resting ECG of patients with CPVT is typically normal, but exercise stress testing can induce a ventricular arrhythmia in most cases (75%-100%). Premature ventricular contractions (PVT), couplets, bigeminy, or polymorphic ventricular tachycardia (VT) are possible outcomes to the ECG stress test. For patients who are unable to exercise, an infusion of epinephrine may induce ventricular arrhythmia, but this is less effective than exercise testing.

 

Genetic testing for catecholaminergic polymorphic ventricular tachycardia (CPVT) is considered investigational not meeting the above criteria and for all other indications because the evidence is insufficient to determine the effects of this technology on net health outcomes.

 

Brugada Syndrome (BrS)

Note: BrS genes include SCN5A (81407)

Genetic testing for Brugada Syndrome (BrS) may be considered medically necessary for one of the following indications:

  • To confirm a diagnosis of Brugada syndrome (BrS) when signs and/or symptoms consistent with Brugada syndrome (BrS) are present (see below), but a definitive diagnosis cannot be made without genetic testing; or
  • To determine future risk of Brugada syndrome (BrS) when patient has a close relative (first, second or third degree relative*) with a known Brugada syndrome (BrS) variant. 

 

*A first-degree relative is defined as a close blood relative which includes the individual’s parents, full siblings, and children.

 

*A second-degree relative is defined as a blood relative which includes individual’s grandparents, grandchildren, aunts, uncles, nephews, nieces and half-siblings.

 

*A third-degree relative is defined as a blood relative which includes the individual’s first cousins, great-grandparents or great grandchildren

 

Note: Signs and symptoms suggestive of Brugada syndrome (BrS) include the presence of a characteristic electrocardiographic pattern, documented ventricular arrhythmia, sudden cardiac death in a family member younger than 45 years old, a characteristic electrocardiographic pattern in a family member, inducible ventricular arrhythmias on electrophysiologic studies, syncope, or nocturnal agonal respirations.

 

Genetic testing for Brugada Syndrome (BrS) is considered investigational not meeting the above criteria and for all other indications because the evidence is insufficient to determine the effects of this technology on net health outcomes.

 

Long QT Syndrome (LQTS)

Note: Long QT Syndrome genes include KCNQ1 (81406/81479), KCNH2 (81406/81479), and SCN5A (81407)

Genetic testing to confirm a diagnosis of congenital long QT syndrome (LQTS) may be considered medically necessary when signs and/or symptoms of long QT syndrome (LQTS) are present, but a definitive diagnosis cannot be made without genetic testing which includes the following:

  • Patient does not meet clinical criteria for long QT syndrome (LQTS) (i.e., those with Schwartz score < 4), but have a moderate-to-high pretest probability based on the Schwartz score and/or other clinical criteria.

 

Note: Determining the pretest probability of long QT syndrome (LQTS) is not standardized. An example of a patient with a moderate-to-high pretest probability of LQTS is a patient with a Schwartz score of 2 or 3.

 

Schwartz Score Diagnostic Criteria for LQTS

Electrocardiographic findings* (* In the absence of medications or disorders known to affect these electrocardiographic features) Points
  1. QTC
 
    • ≥480 ms
3
    • 460 to 479 ms
2
    • 450 to 459 ms (in males)
1
  1. QTc fourth minute of recovery from exercise stress test > 480 ms
1
  1. Torsades de points
2
  1. T-wave alternans
1
  1. Notched T wave in 3 leads
1
  1. Low heart rate for age (resting heart rate below the second percentile for age)
0.5
Clinical history Points
  1. Syncope
 
    • With stress
2
    • Without stress
1
  1. Congenital deafness
0.5
Family history Points
  1. Family members with definite LQTS (the same family member cannot be counted in A or B)
1
  1. Unexplained sudden cardiac death below age 30 among immediate family members (the same family member cannot be counted in A or B)
0.5

 

SCORE:

  • ≤1 point = low probability of long QT syndrome (LQTS)
  • 5 to 3 points = intermediate probability of LQTS
  • ≥3.5 points = high probability of LQTS

 

Genetic testing to determine future risk of long QT syndrome (LQTS) may be considered medically necessary when at least one of the following are met:

  • A close relative (first, second or third degree relative*) with a known long QT syndrome (LQTS) variant; or
  • A close relative (first, second or third degree relative*) diagnosed with long QT syndrome (LQTS) by clinical means whose genetic status is unavailable.

 

*A first-degree relative is defined as a close blood relative which includes the individual’s parents, full siblings, and children.

 

*A second-degree relative is defined as a blood relative which includes individual’s grandparents, grandchildren, aunts, uncles, nephews, nieces and half-siblings.

 

*A third-degree relative is defined as a blood relative which includes the individual’s first cousins, great-grandparents or great grandchildren

 

Genetic testing for long QT syndrome (LQTS) is considered investigational not meeting the above criteria and for all other indications because the evidence is insufficient to determine the effects of this technology on net health outcomes.

 

Genetic Testing for Cardiomyopathy and Other Cardiac Conditions

Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy 

Note: HCM genes include MYH7 (81407), MYBPC3 (81407), TNNT2 (81406), and TNNI3 (81405)

 

Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) may be considered medically necessary for patients who are at risk for development of hypertrophic cardiomyopathy (HCM) when the following is met:

  • The patient has a first-degree relative (a close blood relative which includes the patient’s parents, full siblings, and children) with established HCM, when there is a known pathogenic gene variation present in that affected relative 

 

Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) is considered investigational for patients with a family history of hypertrophic cardiomyopathy (HCM) in which a first-degree relative has tested negative for pathologic variant.

 

Genetic testing not meeting the above criteria and for determining the diagnosis and the management of all other hereditary cardiomyopathies, including,  but not limited to the following is considered investigational because the evidence is insufficient to determine the effects of this technology on net health outcomes:,

  • Restrictive cardiomyopathy
  • Left ventricular noncompaction cardiomyopathies

 

Genetic Testing for Idiopathic Dilated Cardiomyopathy (DCM)

Note: Idiopathic dilated cardiomyopathy genes include ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CRYAB,CSRP3, DES, DMD, DSG2, EYA4, GATAS1, LAMA4, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYPN, PLN, PSEN1, PSEN2, RBM20, SCN5A, SGDC, TAZ, TCAP, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, VCL

Genetic testing for dilated cardiomyopathy (DCM) may be considered medically necessary when the patient meets one of the following:

  • Patient has a clinical diagnosis of dilated cardiomyopathy (DCM); or
  • Patient has a significant cardiac conduction disorder (first, second or third-degree heart block) and/or a family history of premature cardiac death (< 50 years of age) in one or more first or second degree relative*; or
  • Individual is a candidate for an implantable or wearable cardioverter defibrillator

 

*A first-degree relative is defined as a close blood relative which includes the individual’s parents, full siblings, and children.

 

*A second-degree relative is defined as a blood relative which includes individual’s grandparents, grandchildren, aunts, uncles, nephews, nieces and half-siblings.

 

Genetic testing for dilated cardiomyopathy (DCM) is considered investigational when the above criteria is not met and for all other indications.

 

Genetic Testing for Thoracic Aortic Aneurysms and Dissections (TAAD)

Note: Thoracic Aortic Aneurysms and Dissections (TAAD) genes include ACTA2 (81405), TGFBR2 (81405), FBN1 (81408)

Genetic testing for thoracic aortic aneurysms and dissections (TAAD) may be considered medically necessary for:

  • first degree relative (a close blood relative which includes the individual’s parents, full siblings, and children) of persons with genetically confirmed TAAD

 

Genetic testing for thoracic aortic aneurysms and dissections (TAAD) is considered investigational when the above criteria is not met and for all other indication because the evidence is insufficient to determine the effects of this technology on net health outcomes.

 

Genetic Testing for Marfan Syndrome

Note: Marfan Syndrome genes include FBN1 (81408), MYH11 (81408), ACTA2 (81405), TGFBR1/2 (81405)

Genetic testing of gene FBN1 for Marfan Syndrome may be considered medically necessary for one of the following indications:

  • First degree relative (a close blood relative which includes the individual’s parents, full siblings, and children) of persons with genetically confirmed Marfan Syndrome; or
  • A patient with clinically suspected Marfan Syndrome, but a definitive diagnosis cannot be made without genetic testing.

 

Genetic testing of genes MYH11 (81408), ACTA2 (81405), TGFBR1/2 (81405) for Marfan Syndrome may be considered medically necessary when ALL of the following criteria are met:

  • First degree relatives of persons with genetically confirmed Marfan Syndrome; and
  • Patient with clinically suspected Marfan Syndrom, a definitive diagnosis cannot be made without genetic testing; and  
  • Testing of gene FBN1 has been completed and is negative 

 

Genetic testing for Marfan Syndrome is considered investigational when the above criteria is not met and for all other indications because the evidence is insufficient to determine the effects of this technology on net health outcomes.  

 

Expanded gentic panel testing for Marfan Syndrome is considered investigational including, but not limited to the following, because the evidence is insufficient to determine the effects of this technology on net health outcomes:

  • Marfan/TAAD 23 gene panel (GeneDx)

 

Genetic Testing for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)/ Arrhythmogenic Right Ventricular Dysplasia (ARVD)

Genetic testing for arrhythmogenic right ventricular cardiomyopathy (ARVC)/ arrhythmogenic right ventricular dysplasia (ARVD) including but not limited to the following genes DSC2 (81406), DSG2 (81406), DSP (81406), JUP (81406), PKP2 (81406), and TMEM43 (81406) may be considered medically necessary for one of the following indications:

  • When signs and/or symptoms consistent with ARVC/AVRD are present, but a definitive diagnosis cannot be made without genetic testing; or
  • Patient has a close relative (first, second or third degree relative*) with a known ARVC/ARVD variant.

 

Genetic testing for arrhythmogenic right ventricular cardiomyopathy (ARVC)/ arrhythmogenic right ventricular dysplasia (ARVD) is considered investigational when the above criteria is not met and for all other indications because the evidence is insufficient to determine the effects of this technology on net health outcomes.  

 

Genetic Testing for Miscellaneous Cardiac Conditions

Gene expression testing to predict coronary artery disease including but not limited to the following is considered investigational because the evidence is insufficient to determine the effects of this technology on net health outcomes: 

  • Corus CAD (CardioDX, Inc)

 

Genetic testing the following cardiac conditions including but not limited to the following is considered investigational because the evidence is insufficient to determine the effects of this technology on net health outcomes:

  • Atrial fibrillation,
  • Early Repolarization “J-wave” Syndrome,
  • Sinus Node Dysfunction (SND) 

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 81403 Molecular pathology procedure, Level 3 (eg, >10 SNPs, 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD]) (Specific gene(s) tested for cardiac conditions may be included in the following molecular pathology procedure codes, including but are not limited to the following KCNJ2)
  • 81404 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) (Specific gene(s) tested for cardiac conditions may be included in the following molecular pathology procedure codes, including but are not limited to the following SCN1B) 
  • 81405 Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) (Specific gene(s) tested for cardiac conditions may be included in the following molecular pathology procedure codes, including but are not limited to the following CASQ2, ACTA2, TGFBR1 or 2, TNNI3
  • 81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons) (Specific gene(s) tested for cardiac conditions may be included in the following molecular pathology procedure codes, including but are not limited to the following: KCNH2 (potassium voltage-gated channel, subfamily H [ead-related], member 2) (eg, short QT syndrome, long QT syndrome), full gene sequence;  KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (eg, short QT syndrome, long QT syndrome), full gene sequence;  DSC2; DSG2; DSP; JUP;  KCNH2, KCNQ1, LMNA, PKP2, TMEM43, TNNT2) 
  • 81407 Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform) (Specific gene(s) tested for cardiac conditions may be included in the following molecular pathology procedure codes, including but are not limited to the following: SCN5A (sodium channel, voltage-gated, type V, alpha subunit) (eg, familial dilated cardiomyopathy), full gene sequence; MYH6; MYH7; MYBPC3)
  • 81408 Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis) (Specific gene(s) tested for cardiac conditions may be included in the following molecular pathology procedure codes, including but are not limited to the following: RYR2 (ryanodine receptor 2 [cardiac]); FBN1 (fibrillin 1); MYH11)
  • 81410 Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis panel, must include sequencing of at least 9 genes, including FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, and MYLK
  • 81411 Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); duplication/deletion analysis panel, must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A1
  • 81413 Cardiac ion channelopathies (eg, Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); genomic sequence analysis panel, must include sequencing of at least 10 genes, including ANK2, CASQ2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, RYR2, and SCN5A
  • 81414 Cardiac ion channelopathies (eg, Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); duplication/deletion gene analysis panel, must include analysis of at least 2 genes, including KCNH2 and KCNQ1
  • 81439 Hereditary cardiomyopathy (eg, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy), genomic sequence analysis panel, must include sequencing of at least 5 cardiomyopathy-related genes (eg, DSG2, MYBPC3, MYH7, PKP2, TTN)
  • 81479 Unlisted molecular pathology procedure
  • 81493 Coronary artery disease, mRNA, gene expression profiling by real-time RT-PCR of 23 genes, utilizing whole peripheral blood, algorithm reported as a risk score
  • 81599 Unlisted multianalyte assay with algorithmic analysis
  • 84999 Unlisted chemistry procedure  
  • S3861 Genetic testing, sodium channel, voltage-gated, type V, alpha subunit (SCN5A) and variants for suspected Brugada Syndrome
  • S3865 Comprehensive gene sequence analysis for hypertrophic cardiomyopathy
  • S3866 Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family

 

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  • Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM 3rd, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019 May 9.pii: S1547-5271. PubMed PMID: 31078652.
  • Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline. J Card Fail. 2018 May;24(5):281-302. doi: 10.1016/j.cardfail.2018.03.004. Epub 2018 Mar 19. PubMed PMID: 29567486
  • Adler A, Novelli V, Amin AS, Abiusi E, Care M, Nannenberg EA, et al. an international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation. 2020 Feb 11;141(6):418-428. PubMed PMID: 31983240
  • UpToDate, Inc. Hypertrophic cardiomyopathy: gene mutations and clinical genetic testing.

 

Policy History:

  • June 2021 - Annual Review, Policy Revised
  • June 2020 - Annual Review, Policy Revised
  • June 2019 - Annual Review, Policy Revised
  • June 2018 - Annual Review, Policy Revised
  • June 2017 - Annual Review, Policy Revised
  • June 2016 - Annual Review, Policy Revised
  • June 2015 - Annual Review, Policy Revised
  • July 2014 - Annual Review, Policy Revised
  • September 2013 - Annual Review, Policy Renewed
  • October 2012 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.