Genetic Testing for Cardiac Ion Channelopathies

POLICY NUMBER

A.2.04.43

DESCRIPTION

Genetic testing is available for individuals 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.

Cardiac Ion Channelopathies

Cardiac ion channelopathies result from variants in genes that code for protein subunits of the cardiac ion channels. These channels are essential to cell membrane components that open or close to allow ions to flow into or out of the cell. Regulation of these ions is essential for the maintenance of a normal cardiac action potential. This group of disorders is associated with ventricular arrhythmias and an increased risk of sudden cardiac death (SCD). These congenital cardiac channelopathies can be difficult to diagnose, and the implications of an incorrect diagnosis could be catastrophic.

The prevalence of any cardiac channelopathy is still ill-defined but is thought to be between 1 in 2,000 and 1 in 3,000 persons in the general population. Data about the individual prevalences of LQTS, BrS, CPVT, and SQTS are presented in the table below.

Epidemiology of Cardiac Ion Channelopathies

LQTS: long QT syndrome; BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; SQTS: short QT syndrome.ª Type 1 electrocardiographic pattern.

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.

Congenital LQTS usually manifests itself before the age of 40 years. It is estimated that more than half of the 8,000 sudden unexpected deaths in children may be related to LQTS. The mortalityrate of untreated patients with LQTS is estimated at 1% to 2% per year, although this figure will vary with the genotype.

Brugada Syndrome

Brugada syndrome is characterized by cardiac conduction abnormalities that increase the risk of syncope, ventricular arrhythmia, and sudden cardiac death. The disorder primarily manifests during adulthood, although ages between 2 days and 85 years have been reported. Brugada syndrome is an autosomal dominant disorder with an unexplained male predominance. Males are more likely to be affected than females (approximate ratio, 8:1). Brugada syndrome is estimated to be responsible for 12% of sudden cardiac death cases. For both sexes, 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.

Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia is a rare, inherited channelopathy that may present with autosomal dominant or autosomal recessive inheritance. The disorder manifests as a bidirectional or polymorphic ventricular tachycardia precipitated by exercise or emotional stress. The prevalence of CPVT is estimated between 1 in 7,000 and 1 in 10,000 persons. Catecholaminergic polymorphic ventricular tachycardia has a mortality rate of 30% to 50% by age 35 years and is responsible for 13% of cardiac arrests in structurally normal hearts. Catecholaminergic polymorphic ventricular tachycardia was previously believed to manifest only during childhood, but studies have now identified presentation between infancy and 40 years of age.

Short QT Syndrome

Short QT syndrome is characterized by a shortened QT interval on the electrocardiogram (ECG) and, at the cellular level, a shortening of the action potential. The clinical manifestations are an increased risk of atrial and/or ventricular arrhythmias. Because of the disease’s rarity, the prevalence and risk of sudden death are currently unknown.

Sudden Cardiac Arrest or Sudden Cardiac Death

Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) refer to the sudden interruption of cardiac activity with circulatory collapse. The most common cause is coronary artery disease. Approximately 5% to 10% of SCA and SCD is due to arrhythmias without structural cardiac disease and are related to the primary electrical disease syndromes. The previously described cardiac ion channelopathies are among the primary electrical disease syndromes.

The evaluation and management of a survivor of SCA include an assessment of the circumstances of the event as well as a comprehensive physical examination emphasizing cardiovascular and neurologic systems, laboratory testing, electrocardiogram, and more advanced cardiac imaging or electrophysiologic testing as may be warranted. Genetic testing might be considered when, after completion of a comprehensive evaluation, there are findings consistent with a moderate-to-high likelihood of a primary electrical disease. Postmortem protocols for evaluation of a fatal SCA should be implemented when possible.

Genetics of Cardiac Ion Channelopathies

Long QT Syndrome

There are more than 1,200 unique variants on at least 13 genes encoding potassium-channel proteins, sodium-channel proteins, calcium channel-related factors, and membrane adaptor proteins that have been associated with LQTS. In addition to single variants, some cases of LQTS are associated with deletions or duplications of genes.

The absence of a variant does not imply the absence of LQTS; it is estimated that variants are only identified in 70% to 75% of patients with a clinical diagnosis of LQTS. A negative test is only definitive when there is a known variant identified in a family member and targeted testing for this variant is negative.

Another factor complicating interpretation of the genetic analysis is the penetrance of a given variant or the presence of multiple phenotypic expressions. For example, approximately 50% of variant carriers never have any symptoms. There is variable penetrance for the LQTS, and penetrance may differ for the various subtypes. While linkage studies in the past have indicated that penetrance was 90% or greater, a 1999 analysis using molecular genetics challenged this estimate and suggested that penetrance may be as low as 25% for some families.

Variants involving KCNQ1, KCNH2, and SCN5A are the most commonly detected in patients with genetically confirmed LQTS. Some variants are associated with extra-cardiac abnormalities in addition to the cardiac ion channel abnormalities. A summary of clinical syndromes associated with hereditary LQTS is shown in the table below. A 2021 analysis of 49 patients with channelopathies identified 3 rare variants that were pathogenic for LQTS and 8 rare variants that were likely pathogenic for LQTS, all involving KCNQ1 or KCNH2.

Genetics of Long QT Syndrome

AF: atrial fibrillation; ASD: autism spectrum disorder; LQT: long QT; JLNS: Jervell and Lange-Nielsen syndrome; RWS: Romano-Ward syndrome.

Brugada Syndrome

Brugada syndrome is typically inherited in an autosomal dominant manner with incomplete penetrance. The proportion of cases that are inherited, versus de novo variants, is uncertain. Although some have reported up to 50% of cases are sporadic, others have reported that the instance of de novo variants is very low and is estimated to be only 1% of cases.

Variants in 16 genes have been identified as causative of BrS, all of which lead to a decrease in the inward sodium or calcium current or to an increase in one of the outward potassium currents. Of these, SCN5A is the most important, accounting for more than an estimated 20% of cases, SCN10A has also been implicated. The other genes are of minor significance and account together for approximately 5% of cases. The absence of a positive test does not indicate the absence of BrS, with more than 65% of cases not having an identified genetic cause. Penetrance of BrS among persons with a SCN5A variant is 80% when undergoing electrocardiogram with sodium-channel blocker challenge and 25% when not using the electrocardiogram challenge. A 2021 analysis of 49 patients with channelopathies identified 1 rare variant that was pathogenic for BrS and 3 rare variants that were likely pathogenic for BrS, all involving the SCN5A gene.

Catecholaminergic Polymorphic Ventricular Tachycardia

Variants 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 variant. Variants of the gene encoding the cardiac ryanodine receptor (RYR2) or to KCNJ2 result in an autosomal dominant form of CPVT. CASQ2(cardiac calsequestrin) and TRDN-related CPVT exhibit autosomal recessive inheritance. A channelopathy expert panel review has also found moderate to definitive evidence for an autosomal dominant inheritance of CALM1, CALM2, and CALM3 and an autosomal recessive inheritance of TECRL. Some have reported heterozygotes for CASQ2 and TRDN variants for rare, benign arrhythmias. RYR2 variants represent most CPVT cases (50% to 55%), with CASQ2 accounting for 1% to 2% and TRDN accounting for an unknown proportion of cases. The penetrance of RYR2 variants is approximated at 83%.

An estimated 50% to 70% of patients will have the dominant form of CPVT with a disease-causing variant. Most variants (90%) to RYR2 are missense variants, but in a small proportion of unrelated CPVT patients, large gene rearrangements or exon deletions have been reported. Additionally, nearly a third of patients diagnosed as LQTS with normal QT intervals have CPVT due to identified RYR2 variants. Another misclassification, CPVT diagnosed as Anderson-Tawil syndrome, may result in more aggressive prophylaxis for CPVT whereas a correct diagnosis can spare this treatment because Anderson-Tawil syndrome is rarely fatal.

Short QT Syndrome

Short QT syndrome has been linked predominantly to variants in three genes (KCNH2, KCNJ2, and KCNQ1). Variants in genes encoding alpha- and beta-subunits of the L-type cardiac calcium channel (CACNA1C, CACNB2) have also been associated with SQTS. Some individuals with SQTS do not have a variant in these genes, suggesting changes in other genes may also cause this disorder. A channelopathy expert panel concluded that only KCNH2 had a definitive relationship with SQTS and KCNQ1, KCNJ2, and SLC4A3 had strong to moderate causative evidence. Short QT syndrome is believed to be inherited in an autosomal dominant pattern. Although sporadic cases have been reported, patients frequently have a family history of the syndrome or sudden cardiac death.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service;laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs 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.

POLICY

Long QT Syndrome

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

• Individuals who do not meet the clinical criteria for LQTS (ie, those with a Schwartz score <4), but who have a moderate-to-high pretest probability* based on the Schwartz score and/or other clinical criteria.

* 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.

Genetic testing of asymptomatic individuals to determine future risk of LQTS may be considered medically necessary when at least one of the following criteria is met:

Genetic testing for LQTS for all other situations not meeting the criteria outlined above, including but not limited to determining prognosis and/or directing therapy in patients with known LQTS, is considered investigational. 

Brugada Syndrome

Genetic testing to confirm a diagnosis of Brugada syndrome (BrS) may be considered medically necessary when signs and/or symptoms consistent with BrS (see Policy Guidelines section) are present but a definitive diagnosis cannot be made without genetic testing.

Genetic testing of asymptomatic individuals to determine future risk of BrS may be considered medically necessary when individuals have a close relative (ie, first-, second-, or third-degree relative) with a known BrS variant.

Genetic testing for BrS for all other situations not meeting the criteria outlined above is considered investigational. 

Catecholaminergic Polymorphic Ventricular Tachycardia

Genetic testing to confirm a diagnosis of CPVT may be considered medically necessary when signs and/or symptoms of CPVT are present, but a definitive diagnosis cannot be made without genetic testing.

Genetic testing of asymptomatic individuals to determine future risk of CPVT may be considered medically necessary when at least one of the following criteria is met:

Genetic testing for CPVT for all other situations not meeting the criteria outlined above is considered investigational. 

Short QT Syndrome

Genetic testing of asymptomatic individuals to determine future risk of short QT syndrome (SQTS) may be considered medically necessary when individuals have a close relative (ie, first-, second-, or third-degree relative) with a known SQTS variant.

Genetic testing for short QT syndrome for all other situations not meeting the criteria outlined above is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Genetic testing should be performed by an expert in genetic testing and/or cardiac ion channelopathies.

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.

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. An index 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.

Testing Strategy

In general, testing for patients with suspected congenital LQTS, CPVT, or BrS should begin with a known familial variant, if one has been identified.

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 nonindicated conditions); and panels that include variants for multiple conditions (clinical syndrome for which clinical diagnosis not possible).

For situations in which a relative of a proband with unexplained cardiac death or unexplained sudden cardiac arrest or an individual with unexplained sudden cardiac arrest is being evaluated, genetic testing may be part of a diagnostic strategy that includes a comprehensive history and physical exam and 12-lead electrocardiogram, along with exercise stress test, transthoracic echocardiography, and additional evaluation as guided by the initial studies. Studies have suggested that, in such cases, a probable diagnosis of an inherited cardiac condition can be made following a nongenetic evaluation in 50% to 80% of cases. If, after a comprehensive evaluation, a diagnosis of CPVT, LQTS, or BrS is suspected but not definitive (ie, if there is a moderate-to-high pretest probability of either condition), genetic testing could be considered.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

7/27/2006: Approved by Medical Policy Advisory Committee (MPAC)

1/14/2008: Policy description updated. Genetic testing in patients with known or suspected LQTS changed from investigational to may be considered medically necessary for clinical criteria as outlined in POLICY section. Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is investigational added to POLICY section.

3/27/2008: Reviewed and approved by MPAC.

8/26/2008: Quarterly HCPCS code updates applied.

1/05/2009: Policy reviewed. No changes.

08/11/2010: Policy reviewed; no changes.

08/11/2011: Policy reviewed; no changes.

09/25/2012: Policy reviewed. Policy statement unchanged. Added CPT codes 81280 - 81282 and ICD-9 codes 426.82 and 746.89 to the Code Reference section. 

08/01/2013: Added the following diagnosis codes to the Code Reference section: 427.5, V12.53, and V17.41. Removed deleted HCPCS codes S3860 and S3862 from the Code Reference section.

09/17/2014: Policy title changed from "Testing for Congenital Long QT Syndrome" to "Genetic Testing for Cardiac Ion Channelopathies." Policy description revised to include Brugada syndrome, CPVT, and short QT syndrome. Added medically necessary policy statement and criteria for genetic testing for CPVT. Added the following investigational statement: Genetic testing for short QT syndrome is considered investigational.

06/15/2015: Policy description revised and updated regarding genetics of cardiac ion channelopathies and genetic testing for cardiac ion channelopathies. First medically necessary policy statement revised to change "patients with known or suspected congenital long QT syndrome" to "patients with suspected congenital long QT syndrome." Added "(ie, those with a Schwartz score <4)" to the first policy statement regarding LQTS. Added the following investigational statement: Genetic testing for LQTS or CPVT is investigational for all other situations when the above criteria are not met. Policy guidelines updated to add testing strategy information.

08/26/2015: Medical policy revised to add ICD-10 codes.

04/21/2016: Policy description updated regarding clinical diagnosis and management of SQTS. Policy section updated to add section headings. Added medically necessary policy statements for diagnostic testing for Brugada syndrome and testing of an asymptomatic individual with a known familial mutation associated with Brugada syndrome. Added investigational statement that genetic testing for BrS for all other situations not meeting the criteria outlined is considered investigational. Policy guidelines updated to add the following information: 1) signs and symptoms suggestive of BrS  2) genetic counseling information and  3) medically necessary and investigative definitions.

06/06/2016: Policy number A.2.04.43 added.

12/30/2016: Code Reference section updated to add new 2017 CPT codes 81413 and 81414.

12/01/2017: Policy description updated. Policy statements for LQTS and CPVT revised to state that genetic testing to confirm a diagnosis of LQTS/CPVT may be medically necessary when signs and/or symptoms are present but a definitive diagnosis cannot be made without genetic testing. For LQTS and CPVT, added statements that genetic testing of asymptomatic individuals to determine future risk may be medically necessary when certain criteria are met. Policy statement updated to state that genetic testing for LQTS for all other situations not meeting the criteria outlined is considered investigational. Added statement that genetic testing of asymptomatic individuals to determine future risk of SQTS may be medically necessary when patients have a close relative with a known SQTS variant. Genetic testing for SQTS for all other situations not meeting criteria is considered investigational. Policy Guidelines updated regarding patients with suspected LQTS and SQTS.

02/14/2018: Policy description updated regarding sudden cardiac arrest or sudden cardiac death. Policy statements unchanged. Code Reference section updated to remove deleted CPT codes 81280, 81281, and 81282.

02/15/2019: Policy description updated to remove clinical diagnostic/management information and scoring criteria. Policy statements unchanged.

02/10/2020: Policy reviewed; no changes.

12/17/2020: Code Reference section updated to add new CPT code 0237U, effective 01/01/2021.

03/03/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

02/10/2022: Policy description updated regarding genetics of long QT syndrome, Brugada syndrome, CPVT, and short QT syndrome. Policy statements unchanged.

02/15/2023: Policy reviewed; no changes.

02/12/2024: Policy reviewed. Policy statements updated to change "patients" to "individuals."

10/01/2024: Code Reference section updated to add new ICD-10 diagnosis codes Q23.81, Q23.82, and Q23.88.

03/12/2025: Policy description updated with minor changes. Policy statements unchanged.

SOURCE(S)

Blue Cross Blue Shield Association Policy # 2.04.43

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.