Medical Policy

Policy Num:      11.003.042
Policy Name:    Genetic Testing for Cardiac Ion Channelopathies
Policy ID:          [11.003.042]  [Ac / B / M+ / P+]  [2.04.43]

Last Review:    February 18, 2025
Next Review:    February 20, 2026
 

Related Policies:

11.003.023 General Approach to Evaluating the Utility of Genetic Sequencing

Genetic Testing for Cardiac Ion Channelopathies

Summary

Description

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 (SCD). 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.

Summary of Evidence

Long QT Syndrome

For individuals with suspected congenital long QT syndrome (LQTS) who receive genetic testing for variants associated with congenital LQTS, the evidence includes observational studies reporting on the testing yield. Relevant outcomes are overall survival (OS), test validity, changes in reproductive decision making, and morbid events. A genetic variant can be identified in approximately 70% of those with LQTS. The clinical utility of genetic testing for LQTS is high when there is a moderate-to-high pretest probability. There is a chain of evidence to suggest that testing for variants associated with LQTS in individuals who are suspected to have these disorders leads to improved outcomes. A definitive diagnosis of LQTS leads to treatment with β-blockers in most cases, and sometimes to treatment with an implantable cardioverter-defibrillator (ICD). As a result, confirming the diagnosis is likely to lead to a health outcome benefit by reducing the risk for ventricular arrhythmias and SCD. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close relative(s) with a known LQTS variant who receive genetic testing for variants associated with congenital LQTS, the evidence includes observational studies reporting on changes in management. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. A positive genetic test for an LQTS variant leads to treatment with β-blockers in most cases, and sometimes to treatment with an ICD; a negative test would allow family members to defer further testing. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Brugada Syndrome

For individuals with suspected Brugada syndrome (BrS) who receive genetic testing for variants associated with BrS, the evidence includes observational studies reporting on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. The clinical validity of testing for BrS is low: a genetic variant can only be identified in approximately 15% to 35% of BrS. Management changes, primarily use of ICDs, are directed by clinical symptoms. It is not clear that a genetic diagnosis in the absence of other clinical signs and symptoms leads to a change in management that improves outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close relative(s) with a known BrS variant who receive genetic testing for variants associated with BrS, the evidence includes observational studies reporting on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. Brugada syndrome management changes, primarily use of ICDs, are directed by clinical symptoms. There is limited evidence on the effect of changes in management based on genetic testing in an individual with family members who have a known variant. However, a negative test would allow family members to defer further testing. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Catecholaminergic Polymorphic Ventricular Tachycardia

For individuals with suspected catecholaminergic polymorphic ventricular tachycardia (CPVT) who receive genetic testing for variants associated with CPVT, the evidence includes observational studies reporting on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. A genetic variant can be identified in approximately 60% of CPVT patients. There is a chain of evidence to suggest that testing for variants associated with CPVT in individuals who are suspected to have these disorders. Confirming the diagnosis of CPVT is likely to lead to a health outcome benefit by initiating changes in management that reduce the risk of ventricular arrhythmias and sudden cardiac death (SCD). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close relative(s) with a known CPVT variant who receive genetic testing for variants associated with CPVT, the evidence includes observational studies reporting testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. For close relatives of patients with known CPVT variants who are found to have a pathogenic variant, preventive treatment can be initiated. Also, a negative test in the setting of a known familial variant should have a high negative predictive value. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Short QT Syndrome

For individuals with suspected short QT syndrome (SQTS) who receive genetic testing for variants associated with SQTS, the evidence includes limited data on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. The yield of genetic testing in SQTS is not well-characterized. Management changes, primarily use of ICDs, are directed by clinical symptoms. There is limited evidence on changes in management based on genetic testing in a symptomatic proband without a definitive diagnosis. It is not clear that a genetic diagnosis in the absence of other clinical signs and symptoms leads to a change in management that improves outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close relative(s) with a known SQTS variant who receive genetic testing for variants associated with SQTS, the evidence includes observational studies reporting on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. For patients with SQTS, management changes, primarily use of ICDs, are directed by clinical symptoms. There is limited evidence on changes in management based on genetic testing in an individual with family members who have a known variant. It is not clear that a genetic diagnosis in the absence of other clinical signs and symptoms leads to a change in management that improves outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close family member(s) who experienced SCD and a specific diagnosis has been made who receive genetic testing for variants associated with cardiac ion channelopathies, the evidence includes cohort studies that describe the genetic testing yield. In all studies identified, genetic testing was obtained only after a specific diagnosis was suspected based on history or ancillary testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Given the limited available evidence on genetic testing for BrS, clinical input was obtained in 2015. There was a consensus among the specialty societies and academic medical centers providing clinical input that genetic testing for BrS is medically necessary to establish a definitive diagnosis in patients with BrS symptoms and to evaluate family members of an individual with a known genetic variant of BrS. A review of guidelines from American and international cardiac specialty societies (American Heart Association, Heart Rhythm Society, European Heart Rhythm Association, Asia Pacific Heart Rhythm Society) was also conducted. The guidelines acknowledged that although the evidence is weak, genetic testing is recommended for both individuals with a suspected but not a definitive diagnosis of BrS and asymptomatic family members of individuals with known BrS variants.

Given the limited available evidence on genetic testing for SQTS, clinical input was obtained. Among the specialty societies and academic medical centers providing input, there was no consensus on the use of genetic testing for variants associated with SQTS; however, there was consensus that genetic testing to predict future risk of disease in individuals with close relatives who have a known variant associated with SQTS is useful in management that may lead to improved outcomes. A review of guidelines was also conducted. The use of genetic testing for patients with suspected SQTS was not addressed in many guidelines; however, one stated that testing may be considered if a cardiologist has established a strong clinical index of suspicion. Additionally, the guidelines acknowledged that although the evidence is weak, genetic testing may be considered for asymptomatic family members of individuals with known SQTS variants.

OBJECTIVE

The objective of this evidence review is to examine whether genetic testing for cardiac ion channelopathies (eg, long QT syndrome, short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia) improves health outcomes in individuals with suspected channelopathies or individuals with a close relative with known or suspected channelopathies.

POLICY STATEMENT

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 have a moderate-to-high pretest probability (see Policy Guidelines section) based on the Schwartz score and/or other clinical criteria.

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:

• A close relative (ie, first-, second-, or third-degree relative) with a known LQTS variant; or

• A close relative diagnosed with LQTS by clinical means whose genetic status is unavailable.

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 individuals 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 catecholaminergic polymorphic ventricular tachycardia (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:

• A close relative (ie, first-, second-, or third-degree relative) with a known CPVT variant; or

• A close relative diagnosed with CPVT by clinical means whose genetic status is unavailable.

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 SQTS for all other situations not meeting the criteria outlined above is considered investigational.

POLICY GUIDELINES

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 (SCD) 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 (Tristani-Firouzi, 2014). 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, catecholaminergic polymorphic ventricular tachycardia (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. The evaluation of the clinical utility of panel testing is outlined in evidence review 2.04.92 (on a general approach to evaluating the utility of genetic panels). 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 (SCA) or an individual with unexplained SCA is being evaluated, genetic testing may be part of a diagnostic strategy that includes a comprehensive history and physical exam and 12-lead electrocardiogram (ECG), 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 (Behr et al, 2008; Krahn et al, 2009; Kumar et al, 2013; Wong et al, 2014). 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.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing. In some cases, coverage for testing the index case may be available through the contract that covers the unaffected, at-risk individual who will benefit from knowing the results of the genetic test.

Recommendations indicate that, when possible, genetic testing for long QT syndrome be performed in an affected family member so that testing in unaffected, at-risk family members can focus on the variant found in the affected family member. However, coverage for testing of the affected index case (proband) is dependent on contract benefit language.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage. 

BACKGROUND

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 2000 and 1 in 3000 persons in the general population.^1, Data about the individual prevalences of long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome (SQTS) are presented in Table 1.

Table 1. Epidemiology of Cardiac Ion Channelopathies

Adapted from Modell et al (2012).2,
BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; LQTS: long QT syndrome; SQTS: short QT syndrome.
a Type 1 electrocardiographic pattern.

Long QT Syndrome

Congenital LQTS is an inherited disorder characterized by the lengthening of the repolarization phase of the ventricular action potential, increasing the risk for arrhythmic events, such as torsades de pointes, which may, in turn, result in syncope and SCD.

Congenital LQTS usually manifests before the age of 40 years. It is estimated that more than half of the 8000 sudden unexpected deaths in children may be related to LQTS. The mortality rate of untreated patients with LQTS is estimated at 1% to 2% per year, although this figure varies with the genotype.

Brugada Syndrome

Brugada syndrome is characterized by cardiac conduction abnormalities that increase the risk of syncope, ventricular arrhythmia, and SCD. The disorder primarily manifests during adulthood, although ages between 2 days and 85 years have been reported.^3, 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 SCD cases.^1, For both sexes, there is an equally high risk of ventricular arrhythmias or sudden death.^4, Penetrance is highly variable, with phenotypes ranging from asymptomatic expression to death within the first year of life.^5,

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.^6, The prevalence of CPVT is estimated between 1 in 7000 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.^6, 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.^7,

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.^8, 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.^6,

Sudden Cardiac Arrest or Sudden Cardiac Death

Sudden cardiac arrest (SCA) and 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, ECG, 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 1200 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.^9,

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.^10, 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 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.^11,

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 Table 2. 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.^12,

Table 2. Genetics of Long QT Syndrome

Adapted from Beckmann et al ( 2021),^13, Arking et al (2014),^14, and Alders (2015).^15,
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 that 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.^4,

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 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^7,; SCN10A has also been implicated. The other genes are of minor significance and account together for approximately 5% of cases.^6, 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 an SCN5A variant is 80% when undergoing ECG with sodium-channel blocker challenge and 25% when not using the ECG challenge.^4, 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.^12,

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.^16, Some have reported heterozygotes for CASQ2 and TRDN variants for rare, benign arrhythmias.^17,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%.^17,

An estimated 50% to 70% of patients have the dominant form of CPVT with a disease-causing variant. Most variants (90%) of RYR2 are missense variants, but in a small proportion of unrelated CPVT patients, large gene rearrangements or exon deletions have been reported.^7, 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 3 genes (KCNH2, KCNJ2, KCNQ1).^14, 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.^16, 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 SCD.

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 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.

Rationale

This evidence review was created in June 2005 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through December 5, 2024. (see Appendix Table 1 for genetic testing categories).

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Genetic Testing for Variants Associated with Cardiac Ion Channelopathies

Clinical Context and Test Purpose

The purpose of genetic testing in individuals with unexplained cardiac arrhythmias and/or other conduction abnormalities is to confirm the presence or absence of a cardiac ion channelopathy and inform clinical management.

The following PICO was used to select literature to inform this review.

Populations

The population of interest are individuals with suspected cardiac ion channelopathies (eg, long QT syndrome [LQTS], Brugada syndrome [BrS], catecholaminergic polymorphic ventricular tachycardia [CPVT], short QT syndrome [SQTS]) or asymptomatic individuals with a close relative(s) with a known cardiac ion channelopathy variants.

The channelopathies discussed herein are genetically heterogeneous with hundreds of identified variants, but the group of disorders shares basic clinical expression. The most common presentation is spontaneous or exercise-triggered syncope due to ventricular dysrhythmia. These can be self-limiting or potentially lethal cardiac events. The electrocardiographic features of each channelopathy are characteristic, but the electrocardiogram (ECG) is not diagnostic in all cases, and some secondary events (eg, electrolyte disturbance, cardiomyopathies, or subarachnoid hemorrhage) may result in an ECG similar to those observed in a cardiac channelopathy.

Interventions

The intervention being considered is genetic testing for variants associated with cardiac ion channelopathies. Genetic tests are conducted in clinical laboratories. Genetic testing should be accompanied by genetic counseling including discussions with the individuals or guardians about the importance and interpretation of genetic information and sharing of information with potentially affected family members as appropriate.

Genetic testing can be comprehensive (testing for all possible variants in multiple genes) or targeted (testing for a single variant identified in a family member). For comprehensive testing, the probability that a specific variant is pathophysiologically significant is greatly increased if the same variant has been reported in other cases. A variant may also be found that has not been associated with a disorder and therefore may or may not be pathogenic. Variants are classified by their pathogenic potential; an example of such a classification system used in the Familion assay is as follows in Table 3.

Table 3. Familion Assay Classification System

LQTS: long QT syndrome.

Genetic testing for specific disorders, which may include 1 or more specific genes, is available from multiple academic and commercial laboratories, generally by next-generation sequencing or Sanger sequencing. Also, panel testing for 1 or more cardiac ion channelopathies is available from a number of genetic diagnostics laboratories, but there is some variation among manufacturers in the included genes.

There are also commercially available panels that include genetic testing for cardiac ion channelopathies along with other hereditary cardiac disorders, such as hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy.

Comparators

The following practice is currently being used: standard management without genetic testing. Diagnosis and management are described in the following sections by the condition.

Long QT Syndrome Diagnosis

The Schwartz criteria are commonly used as a diagnostic scoring system for long QT syndrome (LQTS).^18, The most recent version is shown in Table 4. A score of 3.5 or higher indicates a high probability that LQTS is present; a score of 1.5 to 3, an intermediate probability; and a score of 1 or less indicates a low probability of the disorder. Before the availability of genetic testing, it was not possible to test the sensitivity and specificity of this scoring system, and because there is still no perfect criterion standard for diagnosing LQTS, the accuracy of this scoring system remains ill-defined.

Table 4. Diagnostic Scoring System for Long QT Syndrome

Adapted from Perrin and Gollob (2012).^19,
LQTS: long QT syndrome.

Long QT Standard Management

Primary management of asymptomatic or symptomatic long QT is β-blocker treatment with an intensification of therapy, if necessary due to recurrent arrhythmic events or intolerable side effects, including additional medication, left cardiac sympathetic denervation or placement of an implantable cardioverter-defibrillator (ICD). Avoidance of medications known to prolong the QT interval and the aggressive treatment of electrolyte imbalances are also advised.

Brugada Diagnosis

The diagnosis of Brugada syndrome (BrS) is made by the presence of a type 1 Brugada pattern on the ECG in addition to other clinical features.^20, This ECG pattern includes a coved ST-segment and a J-point elevation of 0.2 mV or higher followed by a negative T wave. This pattern should be observed in 2 or more of the right precordial ECG leads (V₁-V₃). This pattern may be concealed and can be revealed by administering a sodium-channel-blocking agent (eg, flecainide).^21, Two additional ECG patterns have been described (type 2, type 3) but are less specific for the disorder.^22, The diagnosis of BrS is considered definitive when the characteristic ECG pattern is present with at least 1 of the following clinical features: documented ventricular arrhythmia, sudden cardiac death (SCD) in a family member younger than 45 years old, characteristic ECG pattern in a family member, inducible ventricular arrhythmias on electrophysiology studies, syncope, or nocturnal agonal respirations.

Brugada Standard Management

Management has focused on the use of ICDs 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.

Catecholaminergic Polymorphic Ventricular Tachycardia Diagnosis

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 catecholaminergic polymorphic ventricular tachycardia (CPVT) is typically normal, but exercise stress testing can induce a ventricular arrhythmia in most cases (75% to 100%).^19, Premature ventricular contractions, 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.^23,

Catecholaminergic Polymorphic Ventricular Tachycardia Standard Management

Management of CPVT is primarily with the β-blockers nadolol (1 to 2.5 mg/kg/d) or propranolol (2 to 4 mg/kg/d). If protection is incomplete (ie, recurrence of syncope or arrhythmia), then flecainide (100 to 300 mg/d) may be added. If recurrence continues, an ICD may be necessary with optimized pharmacologic management continued post-implantation.^17, Lifestyle modification with the avoidance of strenuous exercise is recommended for all CPVT patients.

Short QT Diagnosis

Patients generally present with syncope, pre-syncope, or cardiac arrest. An ECG with a corrected QT interval less than 330 ms, sharp T wave at the end of the QRS complex, and a brief or absent ST-segment are characteristic of the syndrome.^24, However, higher QT intervals on ECG might also indicate SQTS, and the clinician has to determine if this is within the normative range of QT values. An index patient with suspected short QT syndrome (SQTS) would be expected to have a shortened (<2 standard deviations 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.^25, The length of the QT interval was not associated with severity of symptoms in a 2006 series of 29 patients with SQTS.^26, Electrophysiologic studies may be used to diagnose SQTS if the diagnosis is uncertain to evaluate for short refractory periods and inducible VT. However, in the series of 29 patients with SQTS described above, VT was inducible in only 3 of 6 subjects who underwent an electrophysiologic study.^26, A diagnostic scoring system was proposed by Gollob et al (2011) to help decision making after a review of 61 SQTS cases (see Table 5).^27,

Table 5. Diagnostic Scoring System for Short QT Syndrome

Adapted from Perrin and Gollob (2012).^19,
AF: atrial fibrillation; SCD: sudden cardiac death; SQTS: short QT syndrome; VT: ventricular tachycardia.

Short QT Standard Management

The primary management of SQTS is with ICD therapy. Decisions about ICD therapy are based on the degree to which SQTS is considered likely, which depends on ECG features, family history, personal history of cardiac arrest or ventricular arrhythmias, and the ability to induce VT on electrophysiologic studies.

Anti-arrhythmic drug management of the disease is complicated because the binding target for QT-prolonging drugs (eg, sotalol) is Kv11.1, which is coded for by KCNH2, the most common site for variants in SQTS (subtype 1). Treatment with quinidine (which is able to bind to both open and inactivated states of Kv11.1) is an appropriate QT-prolonging treatment. This treatment has been reported to reduce the rate of arrhythmias from 4.9% to 0% per year. For those with recurrence while on quinidine, an ICD is recommended.^19,

Outcomes

The general outcomes of interest are overall survival (OS), test validity, changes in reproductive decision making, and morbid events (eg, cardiac events).

A positive diagnosis of LQTS or CPVT in symptomatic patients may lead to treatment with β-blockers or with ICDs, which can reduce the risk for ventricular arrhythmias and SCD.

A positive test for BrS in symptomatic patients may influence the decision for treatment with an ICD.

It is unknown how a positive SQTS test in symptomatic patients would influence treatment decisions.

Positive tests in asymptomatic family members can inform lifestyle changes and prevention treatment decisions.

The genetic assays may be recommended as part of a diagnostic strategy for patients who exhibit clinical symptoms that are not considered definitive.

The tests may also be recommended for asymptomatic family members of patients with known cardiac ion channel variants.

The evidence related to the clinical validity and utility of genetic testing for the cardiac channelopathies consists primarily of studies that evaluate the yield of genetic testing and the impact of genetic testing on the diagnosis and subsequent management of a specific cardiac channelopathy. Many cardiac channelopathies lead to a common clinical outcome - increased risk of ventricular arrhythmias leading to an increased risk of SCD. Studies that evaluate the role of genetic testing for cardiac channelopathies as part of a diagnostic strategy in the evaluation of ventricular fibrillation or SCD from an unknown cause are discussed separately.

The evidence is presented as follows. First, for patients who are candidates for testing of specific channelopathies (LQTS, BrS, CPVT, SQTS) and asymptomatic family members of variant-positive probands. Finally, the evidence is presented for the genetic testing of family members in cases of SCD when a specific clinical diagnosis has not been made.

Study Selection Criteria

For the evaluation of clinical validity of genetic testing for specific cardiac ion channelopathies, studies that meet the following eligibility criteria were considered:

• Reported on the yield of genetic testing in patients with suspected or confirmed channelopathy;

• Included clinical diagnosis;

• Patient/sample clinical characteristics were described;

• Patient/sample selection criteria were described.

In addition, studies reporting on the clinical specificity will be discussed briefly when available.

Genetic Testing for the Diagnosis of Specific Cardiac Ion Channelopathies

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

The true clinical sensitivity and specificity of genetic testing for specific cardiac ion channelopathies cannot be determined with certainty because there is no independent criterion standard for the diagnosis. The clinical diagnosis can be compared with the genetic diagnosis, and vice versa, but neither the clinical diagnosis nor the results of genetic testing can be considered an adequate criterion standard.

Survivors of Sudden Cardiac Arrest

Asatryan et al (2019) evaluated the diagnostic validity and clinical utility of genetic testing in sudden cardiac arrest (SCA) survivors (n=60) with or without previous clinical evidence of heart disease.^28, Patients without coronary artery disease were included; 24 (40%) with clear detectable cardiac phenotype [Ph(+)SCA] and 36 (60%) with no clear cardiac phenotype [Ph(-)SCA]. Targeted exome sequencing was performed using the TruSight-One Sequencing Panel (Illumina). A total of 32 pathogenic or likely pathogenic gene variants were found in 27 (45%) patients: 17 (71%) in the Ph(+)SCA group and 10 (28%) in the Ph(-)SCA group. Mutations in 16 (67%) Ph(+)SCA patients were congruent with the suspected phenotype, consisting of 12 (50%) cardiomyopathies and 4 (17%) channelopathies. Mutations in 6 (17%) Ph(-)SCA patients revealed a cardiac ion channelopathy explaining their SCA event. An additional 4 (11%) mutations in this group could not explain the phenotype and require additional studies. Overall, cardiac genetic testing was positive in 2/3 of the Ph(+)SCA group and 1/6 of the Ph(-)SCA group. The study was limited in its description of clinical criteria for establishing a diagnostic clinical phenotype. While the authors suggest the testing was useful to identify or confirm an inherited heart disease, with important impact on patient care and first-degree relatives at risk, health outcomes pertaining to clinical management of patients or asymptomatic familial probands were not reported.

Chiu et al (2022) performed genetic tests on 36 survivors of pediatric cardiac arrest (median age, 13.3 years).^29, The yield rate of genetic testing in the study cohort was 84.6%, including 14 pathogenic and 8 likely pathogenic variants. Long QT syndrome, CPVT, and BrS were diagnosed in 25%, 16.7%, and 6% of patients, respectively; genetic testing led to a change in diagnosis from CPVT to LQTS in 1 patient. Assessment of long-term outcomes showed that 10-year transplant-free survival was higher among patients who received genetic testing soon after the cardiac arrest event. Subsequent testing of family members of 15 probands identified 8 family members with positive genetic tests, but information on subsequent management of these patients was lacking.

Long QT Syndrome

Tester et al (2006) completed the largest study to evaluate the percentage of individuals with a clinical diagnosis of LQTS found to have a genetic variant.^30, The sample was 541 consecutive patients referred for evaluation of LQTS. Clinical assessments of the patients were made while blinded to the genetic testing results. Among the 123 patients with a high probability of LQTS based on clinical assessments, defined as a Schwartz score of 4 or more, 72% (89/123) had a genetic variant. Among patients with a QTc greater than 480 ms, 62% had a genetic variant. Characteristics and results of selected studies are shown in Tables 6 and 7 below.

Table 6. Characteristics of Clinical Validity Studies of Genetic Testing for Long QT Syndrome

BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; LQTS: long QT syndrome; NR: not reported; SCD: sudden cardiac death.

Table 7. Yield of Genetic Testing for Long QT Syndrome

Dx: diagnosis; NR: not reported.

The purpose of limitations tables (see Tables 8 and 9) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 8. Study Relevance Limitations of Clinical Validity Studies of Genetic Testing for Long QT Syndrome

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity, and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 9. Study Design and Conduct Limitations of Clinical Validity Studies of Genetic Testing for Long QT Syndrome

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).
^b Blinding key: 1. Not blinded to results of reference or other comparator tests.
^c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

The evidence on clinical specificity focuses on the frequency and interpretation of variants identified but not known to be pathogenic. If a variant identified is known to be pathogenic, then the specificity of this finding is high. However, many variants are not known to be pathogenic, and the specificity for these variants is lower. The rate of identification of variants is estimated at 5% for patients who do not have LQTS.^32,

A 2012 publication from the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) reported on the rate of sequence variants in a large number of patients without LQTS.^33, The ESP sequenced all genome regions of protein-coding in a sample of 5400 persons drawn from various populations, none of whom specifically had heart disease and/or channelopathies. Exome data were systematically searched to identify sequence variants previously associated with LQTS, including both nonsense variants, which are generally pathogenic, and missense variants, which are less likely to be pathogenic. Thirty-three such sequence variants were identified in the total population (all missense variations). The percentage of the population that had at least 1 of these missense variants was 5.2%. No nonsense variants were associated with LQTS found among the entire population.

Brugada Syndrome

Priori et al (2000) reported an early paper to describe the yield of genetic testing for BrS.^34, In 58 probands with a clinical diagnosis of BrS, the yield of SCN5A testing was 15%.

Kapplinger et al (2010) reported results from an international compendium of SCN5A variants of more than 2000 patients referred for BrS genetic testing which yielded almost 300 distinct mutations in 438 of 2111 (21%) patients, ranging from 11% to 28% across the 9 testing centers.^35,

Hu et al (2014) evaluated the prevalence of SCN10A variants in 120 probands with BrS.^36, Seventeen SCN10A variants were identified in 25 probands, with a variant detection rate of 16.7% in BrS probands.

Behr et al (2015) evaluated 7 candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, TBX5) among 156 patients negative for SCN5A variants with symptoms indicative of BrS (64%) and/or a family history of sudden death (47%) or BrS (18%).^37, Eighteen (11.5%) patients were found to have variants, most often in SCN10A (12/18 [67%]).

Andorin et al (2016) described the yield of SCN5A genetic testing in 75 patients younger than 19 years of age from 62 families who had a Brugada type I ECG pattern; only 20% were symptomatic.^38, The ECG pattern was spontaneous in 34% and drug-induced in 66%. The yield was very high compared to previous studies at 77%. The authors hypothesized that the high yield might have been due to the inclusion of only a pediatric population.

Chen et al (2019) conducted a meta-analysis of 17 studies involving 1780 unrelated and consecutive patients with BrS to assess the relationship between SCN5A mutation status and phenotypic features.^39, A history of syncope and spontaneous type 1 ECG pattern were observed in 31% and 59% of BrS patients, respectively. A total of 52% of patients had ICD implantation. The average frequency of SCN5A mutations was 20%, which ranged from 11% to 43% across studies. The onset of symptoms was found to occur at a younger age in the SCN5A(+) group (34 ± 17 vs. 42 ± 16 years; p=.0003). The presence of a spontaneous type 1 ECG pattern was associated with an increased risk of cardiac events in BrS patients based on a pooled analysis of 12 studies (71% vs. 57%; p=.0002). SCN5A(+) patients had a higher proportion of sick sinus syndrome (43% vs. 5%; p<.001) and atrial ventricular block (71% vs. 30%; p=.01). However, there was a lower rate of VT/ventricular fibrillation inducibility during electrophysiology study (41% vs. 51%; p=.01), which may partially be explained by heterogeneity in electrophysiology study protocols. The SCN5A mutation was associated with an increased risk of major adverse events in the overall BrS (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.19 to 2.26; p=.005), Asian (OR, 1.82; 95% CI, 1.07 to 3.11; p=.03), and Caucasian (OR, 2.24; 95% CI, 1.02 to 4.90; p=.04) patient populations.

Monasky et al (2019) evaluated 15 BrS-associated genes (CACNA1C, CACNA2D1, CACNB2, GPD1L, HCN4, KCND2, KCND3, PKP2, RANGRF, SCN10A, SCN1B, SCN2B, SCN3B, SCN5A, and TRPM4) with the TruSight One sequencing kit and NextSeq platform in 297 BrS patients screened for study enrollment.^40, The 2 most common mutations were SCN5A (84 [28.3%]) followed by SCN10A (8 [2.7%]). Clinical characteristics of BrS patients harboring SCN5A or SCN10A mutations were not found to be significantly different between probands, although patients with a variety of type I-III ECG patterns were represented in both cohorts.

Sacilotto et al (2020) reported data from the Genetics of Brazillian Arrhythmias (GenBra) registry.^41, From 1999 to 2020, 138 (22 symptomatic) consecutive patients with type-1 BrS were assessed for invasive and noninvasive parameters and SCN5A mutation status. No difference in the rate of SCN5A-positive patients was found between asymptomatic and symptomatic groups (20/76 [26.3%] vs. 5/17 [29.4%]; p=.770). SCN5A carriers had significantly higher frequencies of aVR sign, S wave, and QRS-f.

Milman et al (2021) published an observational study of 678 patients from 14 countries with a first arrhythmic event due to BrS.^42, Of the 392 probands, 23.5% were SCN5A(+) with 44 pathogenic/likely pathogenic variants and 48 variants of unknown significance. The remaining probands were SCN5A(-). Patients with pathogenic/likely pathogenic variants were more likely to be aged <16 years (p=.023), female (p=.013), and have a family history of SCD (p<.001) compared to patients who were SCN5A(-). Logistic regression found that White ethnicity (OR, 5.41; 95% CI, 2.8 to 11.19; p<.001) and family history of SCD (OR, 2.73; 95% CI, 1.28 to 5.82; p=.009) were associated with having a pathogenic/likely pathogenic genotype.

Wang et al (2022) published an observational study of 79 patients in China who had BrS, 59 of whom underwent genetic testing.^44, Abnormal genetic results occurred in 25 (42.37%) patients, with pathogenic or likely pathogenic mutations in 8 (13.56%) patients. The genes most commonly associated with genetic mutations were SCN5A (44%), SCN10A (20%), and DSP (16%). Genetic carriers were more likely to have prolonged P-wave duration, QRS duration, QTc interval, decreased QRS amplitude, and T-wave or R-wave axis deviation than individuals without abnormal genetic findings.

The description of the studies are below in Table 10 and results are shown in Table 11.

Table 10. Characteristics of Clinical Validity Studies of Genetic Testing for Brugada Syndrome

   BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; ECG: electrocardiogram; EPS: electrophysiological study; LQTS: long QT syndrome; NR: not reported; SCD: sudden cardiac death.

Table 11. Yield of Genetic Testing for Brugada Syndrome

   Dx: diagnosis; NR: not reported.

The purpose of limitations tables (see Tables 12 and 13) is to display notable limitations identified in selected primary studies. This information is synthesized as a summary of the body of evidence and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 12. Study Relevance Limitations of Clinical Validity Studies of Genetic Testing for Brugada Syndrome

    ECG: electrocardiogram. The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity, and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests). e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 13. Study Design and Conduct Limitations of Clinical Validity Studies of Genetic Testing for Brugada Syndrome

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). b Blinding key: 1. Not blinded to results of reference or other comparator tests. c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

Catecholaminergic Polymorphic Ventricular Tachycardia

Studies reporting the yield of RyR2 testing in CPVT have been conducted in patients with clinically diagnosed CPVT.^31,45,46,47,

Characteristics are shown in Table 14 and results are shown in Table 15. The yield in cases with a ‘strong’ diagnosis of CPVT is around 60%.

Table 14. Characteristics of Clinical Validity Studies of Genetic Testing for Catecholaminergic Polymorphic Ventricular Tachycardia

   BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; LQTS: long QT syndrome; NR: not reported; SCD: sudden cardiac death; VT: ventricular tachycardia.

Table 15. Yield of Genetic Testing for Catecholaminergic Polymorphic Ventricular Tachycardia

    Dx: diagnosis; NR: not reported.

The purpose of the limitations tables (see Tables 16 and 17) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 16. Study Relevance Limitations of Clinical Validity Studies of Genetic Testing for Catecholaminergic Polymorphic Ventricular Tachycardia

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest. c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose. d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity, and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests). e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 17. Study Design and Conduct Limitations of Clinical Validity Studies of Genetic Testing for Catecholaminergic Polymorphic Ventricular Tachycardia

   The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience). b Blinding key: 1. Not blinded to results of reference or other comparator tests. c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described. d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication. e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data. f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

The specificity of known pathogenic variants for CPVT is uncertain but is likely high. A 2013 publication from the National Heart, Lung, and Blood Institute ESP reported on sequence variants in a large number of patients without CPVT.^48, The ESP sequenced all genome regions of protein-coding in a sample of 6503 persons drawn from various populations who did not specifically have CPVT or other cardiac ion channelopathies. Exome data were systematically searched to identify missense variants previously associated with CPVT. Authors identified 11% previously described variants in the ESP population in 41 putative CPVT cases. These data suggested that false-positive results are low, but authors cautioned against attributing clinical CPVT to a single missense variant.

Short QT Syndrome

Limited data on the clinical validity of SQTS were identified in the peer-reviewed literature due to the rarity of the condition. A precise genetic testing yield is unknown.

Section Summary: Clinical Validity of Genetic Testing for the Diagnosis of a Specific Channelopathy

In probands with LQTS and CPVT, genetic testing has a yield for identifying a disease-causing variant of approximately 70% and 60%, respectively. In probands with BrS, genetic testing has a much lower yield probably ranging from about 15% to 30% depending on the genes included. The yield of genetic testing is not well established in SQTS.

Data on the clinical specificity are available for LQTS but there are limited data for CPVT. The specificity varies according to the type of variant identified. For LQTS nonsense variants, which have the highest rate of pathogenicity, there are very few false-positives among patients without LQTS, and therefore a high specificity. However, for missense variants, the rate is approximately 5% among patients without LQTS; therefore, the specificity for these types of variants is lower, and false-positive results do occur.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Long QT Syndrome

Long QT syndrome may lead to catastrophic outcomes (ie, SCD) in otherwise healthy individuals. Diagnosis using clinical methods alone may lead to underdiagnosis of LQTS, thus exposing undiagnosed patients to the risk of SCA. For patients in whom the clinical diagnosis of LQTS is uncertain, genetic testing may be necessary to clarify whether LQTS is present. Patients who are identified as genetic carriers of LQTS variants 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 an LQTS variant, with or without other signs or symptoms.

Treatment with β-blockers has been demonstrated to decrease the likelihood of cardiac events, including SCA.

Sodium-channel blockers (eg, mexiletine) are sometimes used, particularly in those with SCN5A variants. Preliminary modeling studies by Zhu et al (2018) designed to predict LQT3 mutations with enhanced mexiletine sensitivity have been successfully validated in a small initial cohort of patients.^49,

Treatment with an ICD is available for patients who fail or cannot take β-blockers.

Two studies evaluated the psychological effects of genetic testing for LQTS. Hendriks et al (2008) studied 77 patients with an LQTS variant and their 57 partners.^50, Psychologic testing was performed after the diagnosis of LQTS had been made and repeated twice over an 18-month period. Disease-related anxiety scores were increased in the index patients and their partners. This psychological distress decreased over time but remained elevated at 18 months. Andersen et al (2008) conducted qualitative interviews with 7 individuals with LQTS variants.^51, They reported that affected patients had excess worry and limitations in daily life associated with the increased risk of sudden death, which was partially alleviated by acquiring knowledge about LQTS. The greatest concern was expressed for their family members, particularly children and grandchildren.

The evidence suggests that different LQTS subtypes may have variable prognoses, thus indicating that genetic testing may assist in risk stratification. Several reports have compared rates of cardiovascular events in subtypes of LQTS.^52,53,54,55, These studies have reported that rates of cardiovascular events differ among subtypes, but there is no common pattern across all studies. Three of the 4 studies^52,53,54, reported that patients with LQT2 have higher event rates than patients with LQT1, while Zareba et al (1998)^55, reported that patients with LQT1 have higher event rates than patients with LQT2.

Some studies that have reported outcomes of treatment with β-blockers have also reported outcomes by specific subtypes of LQTS.^52,54, Priori et al (2004) reported pre-post rates of cardiovascular events by LQTS subtypes following initiation of β-blocker therapy.^52, There was a decrease in event rates in all LQTS subtypes, with a similar magnitude of decrease in each subtype. Moss et al (2000) also reported pre-post event rates for patients treated with β-blocker therapy.^56, This study indicated a significant reduction in event rates for patients with LQT1 and LQT2 but not for LQT3. This analysis was limited by the small number of patients with LQT3 and cardiac events before β-blocker treatment (4/28). Sauer et al (2007) evaluated differential response to β-blocker therapy in a Cox proportional hazards analysis.^57, They reported an overall risk reduction in the first cardiac event of approximately 60% (hazard ratio [HR], 0.41; 95% CI, 0.27 to 0.64) in adults treated with β-blockers and an interaction effect by genotype. Efficacy of β-blocker treatment was worse in those with LQT3 genotype (p=.04) than in those with LQT1 or LQT2. There was no difference in efficacy between LQT1 and LQT2 genotypes.

Shimizu et al (2019) conducted an observational study on 1124 Japanese patients with LQTS and various pathogenic variants (eg, nonpore membrane-spanning variants, pore site and segment 5 to segment 6 [S5-pore-S6] variants, and N/C-terminus variants) for LQT1, LQT2, and LQT3.^58, For patients with LQT1, the membrane-spanning pathogenic variant was associated with a higher risk of arrhythmic events compared to the N/C-terminus variant in female patients (HR, 1.60; 95% CI, 1.19 to 2.17; p=.002). Patients with LQT2 S5-pore-S6 variants were found to have a higher risk of arrhythmic events compared to others (HR, 1.88; 95% CI, 1.44 to 2.44; p<.001). In patients with LQT3, S5-pore-S6 variants were associated with lethal arrhythmic events compared with other (HR, 4.2; 95% CI, 2.09 to 8.36; p<.001). While these findings suggest that risk stratification of arrhythmic events may potentially be informed by specific pathogenic gene variants in LQTS, the study is limited by its retrospective analysis.

Biton et al (2019) studied LQTS patients (n=212) enrolled in the Rochester LQTS ICD registry who underwent ICD implantation for primary prevention of SCD.^59, During median follow-up duration of 9.2 ± 4.9 years, 42 patients experienced at least 1 appropriate shock. The cumulative probability of appropriate shock at 8 years was 22%. QT_c ≥550 ms (HR, 3.94; 95% CI, 2.08 to 7.46; p<.001) and prior syncope on β-blockers (HR, 1.92 ; 95% CI, 1.01 to 3.65; p=.047) were associated with an increased risk of appropriate shock. Importantly, LQT2 genotype (HR, 2.10; 95% CI, 1.22 to 3.61; p=.008) and the presence of multiple mutations (HR, 2.87; 95% CI, 1.49 to 5.53; p=.002) were associated with an increased risk of recurrent shocks compared to LQT1 genotype, suggesting that both clinical and genetic variables may have utility in the risk stratification of high-risk patients undergoing evaluation for an ICD.

Cuneo et al (2020) conducted a multicenter retrospective analysis of 148 pregnancies from 103 families with the 3 most common heterozygous pathogenic LQTS genotypes (KCNQ1, KCNH2, or SCN5A).^60, Fetal death at >20 weeks gestation was 8 times more frequent compared to the general population. The likelihood of fetal death was found to be significantly greater with maternal versus paternal LQTS (24.4% vs. 3.5%; p=.36).

Brugada Syndrome

The diagnostic testing yield for BrS limits its clinical usefulness. A finding of a genetic variant is not diagnostic of the disorder but is an indicator of high risk for development of BrS. The diagnostic criteria for BrS do not presently include the presence of a genetic variant. Furthermore, treatment decisions are based on the presence of symptoms such as syncope or documented ventricular arrhythmias. Treatment is primarily with an implantable ICD, which is reserved for high-risk patients. However, for family members of patients with a known BrS variant, a negative test can rule out the disorder.

Rattanawong et al (2019) conducted a systematic review and meta-analysis of 7 cohort and case-control studies investigating the association of SCN5A mutations with major arrhythmic events (eg, VT, ventricular fibrillation, appropriate implantable ICD shocks, aborted cardiac arrest, and SCD) in patients with BrS (n=1049).^61,SCN5A mutations were associated with major arrhythmic events in Asian patients (risk ratio, 2.03; 95% CI, 1.37 to 3.00; p=.0004; I²=0.0%), symptomatic patients (risk ratio, 2.66; 95% CI, 1.62 to 4.36; p=.0001; I²=23.0%), and patients with spontaneous Brugada type 1 ECG pattern (risk ratio, 1.84; 95% CI, 1.05 to 3.23; p=.03; I²=0.0%). The inclusion criteria did not specify criteria for establishing a clinical diagnosis of BrS, and therefore, the analysis was limited by heterogeneity in clinical, genetic, and outcome reporting among included studies. Reporting on specific major arrhythmic events relevant to health outcomes such as delivery of appropriate ICD shocks and aborted cardiac arrests was not individually reported. Therefore, the clinical utility of SCN5A genetic variant risk stratification in this population remains unclear. In the Doundoulakis et al (2024) meta-analysis described above, the authors evaluated the risk of major arrhythmic events in patients with BrS who were SCN5A(+) or SCN5A(-).^40, Major arrhythmic events were significantly greater in SCN5A(+) patients (OR, 2.15; 95% CI, 1.53 to 2.99).

Catecholaminergic Polymorphic Ventricular Tachycardia

The clinical utility for genetic testing in CPVT follows a similar chain of logic as that for LQTS. In patients for whom the clinical diagnosis can be made with certainty, there is a limited utility for genetic testing. However, there are some patients in whom signs and symptoms of CPVT are present, but for whom the diagnosis cannot be made with certainty. In this case, documentation of a pathogenic variant that is known to be associated with CPVT confirms the diagnosis. When the diagnosis is confirmed, treatment with β-blockers is indicated, and lifestyle changes are recommended. Although high-quality outcome studies are lacking to demonstrate a benefit of medication treatment, it is very likely that treatment reduces the risk of SCD. Therefore, there is a clinical utility.

There is currently no direct method of genotype-based risk stratification for management or prognosis of CPVT. However, testing can have important implications for all family members for presymptomatic diagnosis, counseling, or therapy. Asymptomatic patients with confirmed CPVT should also be treated with β-blockers and lifestyle changes. Also, CPVT has been associated with sudden infant death syndrome, and some investigators have considered testing at birth for prompt therapy in infants who are at-risk due to CPVT in close family members.

Short QT Syndrome

No studies were identified that provide evidence for the clinical utility of genetic testing for SQTS, consistent with the clinical rarity of the condition. Clinical sensitivity for the test is low, with laboratory test providers estimating a yield as low as 15%.

Section Summary: Clinical Utility of Genetic Testing for the Diagnosis of a Specific Channelopathy

The clinical utility of genetic testing for LQTS or CPVT is high when there is a moderate-to-high pretest probability and when the diagnosis cannot be made with certainty by other methods. A definitive diagnosis of either channelopathy leads to treatment with β-blockers in most cases, and sometimes to treatment with an ICD. As a result, confirming the diagnosis is likely to lead to a health outcome benefit by reducing the risk for ventricular arrhythmias and SCD. The clinical utility of testing is also high for close relatives of patients with known cardiac ion channel variants because these individuals should also be treated if they have a pathogenic variant.

For BrS, the clinical utility is less certain, but there is potential for genetic testing to change treatment decisions by stratifying patients for the need for ICD. A meta-analysis reported that the presence of SCN5A variants could not predict cardiac events; however, a registry study published after the meta-analysis reported that patients with the SCN5A variant experienced more cardiac events and experienced the first event at a younger age than patients who did not have the SCN5A variant. An updated meta-analysis associated SCN5A gene variants with arrhythmic risk. Studies have been conducted to further determine risk level by type of variant, but the studies have small sample sizes, so interpretation is limited.

For SQTS, the clinical utility is uncertain because there is no clear link between the establishment of a definitive diagnosis and a change in management that will improve outcomes.

Summary Evidence

Population Reference No. 1 & 2

Long QT Syndrome

For individuals with suspected congenital long QT syndrome (LQTS) who receive genetic testing for variants associated with congenital LQTS, the evidence includes observational studies reporting on the testing yield. Relevant outcomes are overall survival (OS), test validity, changes in reproductive decision making, and morbid events. A genetic variant can be identified in approximately 70% of those with LQTS. The clinical utility of genetic testing for LQTS is high when there is a moderate-to-high pretest probability. There is a chain of evidence to suggest that testing for variants associated with LQTS in individuals who are suspected to have these disorders leads to improved outcomes. A definitive diagnosis of LQTS leads to treatment with β-blockers in most cases, and sometimes to treatment with an implantable cardioverter-defibrillator (ICD). As a result, confirming the diagnosis is likely to lead to a health outcome benefit by reducing the risk for ventricular arrhythmias and SCD. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close relative(s) with a known LQTS variant who receive genetic testing for variants associated with congenital LQTS, the evidence includes observational studies reporting on changes in management. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. A positive genetic test for an LQTS variant leads to treatment with β-blockers in most cases, and sometimes to treatment with an ICD; a negative test would allow family members to defer further testing. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No 3 & 4

Brugada Syndrome

For individuals with suspected Brugada syndrome (BrS) who receive genetic testing for variants associated with BrS, the evidence includes observational studies reporting on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. The clinical validity of testing for BrS is low: a genetic variant can only be identified in approximately 15% to 35% of BrS. Management changes, primarily use of ICDs, are directed by clinical symptoms. It is not clear that a genetic diagnosis in the absence of other clinical signs and symptoms leads to a change in management that improves outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Cinical Input: Given the limited available evidence on genetic testing for BrS, clinical input was obtained. There was a consensus among the specialty societies and academic medical centers providing clinical input that genetic testing for BrS is medically necessary to establish a definitive diagnosis in patients with BrS symptoms and to evaluate family members of an individual with a known genetic variant of BrS. A review of guidelines from American and international cardiac specialty societies (American Heart Association, Heart Rhythm Society, European Heart Rhythm Association, Asia Pacific Heart Rhythm Society) was also conducted. The guidelines acknowledged that although the evidence is weak, genetic testing is recommended for both individuals with a suspected but not a definitive diagnosis of BrS and asymptomatic family members of individuals with known BrS variants.

For individuals who are asymptomatic with a close relative(s) with a known BrS variant who receive genetic testing for variants associated with BrS, the evidence includes observational studies reporting on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. Brugada syndrome management changes, primarily use of ICDs, are directed by clinical symptoms. There is limited evidence on the effect of changes in management based on genetic testing in an individual with family members who have a known variant. However, a negative test would allow family members to defer further testing. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5 & 6

Catecholaminergic Polymorphic Ventricular Tachycardia

For individuals with suspected catecholaminergic polymorphic ventricular tachycardia (CPVT) who receive genetic testing for variants associated with CPVT, the evidence includes observational studies reporting on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. A genetic variant can be identified in approximately 60% of CPVT patients. There is a chain of evidence to suggest that testing for variants associated with CPVT in individuals who are suspected to have these disorders. Confirming the diagnosis of CPVT is likely to lead to a health outcome benefit by initiating changes in management that reduce the risk of ventricular arrhythmias and sudden cardiac death (SCD). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close relative(s) with a known CPVT variant who receive genetic testing for variants associated with CPVT, the evidence includes observational studies reporting testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. For close relatives of patients with known CPVT variants who are found to have a pathogenic variant, preventive treatment can be initiated. Also, a negative test in the setting of a known familial variant should have a high negative predictive value. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 7 & 8

Short QT Syndrome

For individuals with suspected short QT syndrome (SQTS) who receive genetic testing for variants associated with SQTS, the evidence includes limited data on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. The yield of genetic testing in SQTS is not well-characterized. Management changes, primarily use of ICDs, are directed by clinical symptoms. There is limited evidence on changes in management based on genetic testing in a symptomatic proband without a definitive diagnosis. It is not clear that a genetic diagnosis in the absence of other clinical signs and symptoms leads to a change in management that improves outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close relative(s) with a known SQTS variant who receive genetic testing for variants associated with SQTS, the evidence includes observational studies reporting on testing yields. Relevant outcomes are OS, test validity, changes in reproductive decision making, and morbid events. For patients with SQTS, management changes, primarily use of ICDs, are directed by clinical symptoms. There is limited evidence on changes in management based on genetic testing in an individual with family members who have a known variant. It is not clear that a genetic diagnosis in the absence of other clinical signs and symptoms leads to a change in management that improves outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close family member(s) who experienced SCD and a specific diagnosis has been made who receive genetic testing for variants associated with cardiac ion channelopathies, the evidence includes cohort studies that describe the genetic testing yield. In all studies identified, genetic testing was obtained only after a specific diagnosis was suspected based on history or ancillary testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Cinical Input: Given the limited available evidence on genetic testing for SQTS, clinical input was obtained. Among the specialty societies and academic medical centers providing input, there was no consensus on the use of genetic testing for variants associated with SQTS; however, there was consensus that genetic testing to predict future risk of disease in individuals with close relatives who have a known variant associated with SQTS is useful in management that may lead to improved outcomes. A review of guidelines was also conducted. The use of genetic testing for patients with suspected SQTS was not addressed in many guidelines; however, one did state that testing may be considered if a cardiologist has established a strong clinical index of suspicion. Additionally, the guidelines acknowledged that although the evidence is weak, genetic testing may be considered for asymptomatic family members of individuals with known SQTS variants.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2015 Input

In response to requests, input was received from 3 specialty societies (4 reviewers) and 4 academic medical centers (9 reviewers) while this policy was under review in 2015. Input was limited to the use of genetic testing for Brugada syndrome (BrS) and short QT syndrome (SQTS). There was a consensus that genetic testing for BrS is medically necessary to establish the diagnosis of BrS in an individual with a suspected but not definitive diagnosis of BrS and to evaluate family members of an individual with a known pathogenic genetic variant for BrS. There was less consensus on whether genetic testing for variants associated with SQTS is medically necessary to establish the diagnosis of SQTS in an individual with a suspected but not definitive diagnosis of SQTS, but there was consensus that testing for SQTS to evaluate family members of an individual with a known pathogenic genetic variant for SQTS is medically necessary. However, reviewers acknowledged that the rarity of SQTS somewhat limited conclusions that could be made.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Heart Association

In 2023, the American Heart Association published a scientific statement on interpreting incidentally identified genes associated with heritable cardiovascular diseases (including cardiac ion channelopathies).^62, The statement notes that: "In partnership with a specialized inherited cardiovascular disease (CVD) center, individuals found to have an incidentally identified variant should undergo a comprehensive clinical evaluation for the CVD in question. This pretest probability of having the CVD in question should be modified by the strength of the gene variant with CVD to arrive at a posttest probability that the variant in question places the patient at risk of developing disease. This determines the need for additional clinical evaluation, management, and follow-up." In their proposed framework for the evaluation of a patient with incidental findings of genetic variants associated with channelopathies, the American Heart Association suggests that a electrocardiogram (ECG) testing, a 24-hour or longer Holter monitor, and an exercise stress test (if possible) should be performed.

In 2021, the American Heart Association published a scientific statement on genetic testing for heritable cardiovascular diseases (including channelopathies) in children.^63, The statement recommends that genetic testing be performed when a cardiac channelopathy is likely to be present, including after a variant has been found in a family member. Testing to identify at-risk relatives can be considered. Brugada syndrome is difficult to identify since not all adults express genetic variants; therefore, identifying at-risk children may require clinical evaluation, ECG testing, and/or pharmacologic challenge of all of the child’s first-degree relatives. Genetic testing should also be performed in children who are resuscitated from cardiac arrest with no clear cause. Several factors can be considered when deciding the appropriate age for genetic testing of an individual child, including whether the disease is expected to present during childhood, whether the channelopathy can be fatal, whether therapies exist to mitigate mortality risk, and family preferences. Ongoing follow-up genetic testing can confirm pathogenicity of the variant over time.

In 2020, the American Heart Association authored a scientific statement on genetic testing for inherited cardiovascular disease.^64, Prior guidelines from several international cardiovascular clinical organizations and published studies were reviewed. For BrS, the authors concluded that genetic testing supports the clinical diagnosis. For patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS), genetic testing is needed for diagnosis and subtype classification. Management of LQTS may also differ depending on the causative gene. Genetic testing for all of these conditions facilitates identifying at-risk family members. Specific genes with the strongest causative evidence for cardiac channelopathies are listed in Table 18.

Table 18. Specific Genes for Testing in Cardiac Channelopathies

    BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; LQTS: long QT syndrome; SQTS: short QT syndrome.

American Heart Association, American College of Cardiology, and 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 (SCD).^65, Table 19 summarizes the recommendations relating to cardiac ion channelopathies.

Table 19. Recommendations for Genetic Testing in Cardiac Channelopathies

    B-NR: moderate level of evidence, nonrandomized studies; BrS: Brugada syndrome; C-EO: consensus of expert opinion based on clinical experience; COR: class of recommendation; CPVT: catecholaminergic polymorphic ventricular tachycardia; LOE: level of evidence; LQTS: long QT syndrome; SQTS: short QT syndrome; VT: ventricular tachycardia.

Heart Rhythm Society and Asia Pacific Heart Rhythm Society

In 2020, the Heart Rhythm Society and Asia Pacific Heart Rhythm Society authored an expert consensus statement on investigation of individuals who have died from sudden unexplained death, patients with sudden cardiac arrest (SCA), and their families.^66, Suspicion for a genetic cause of SCD or a resuscitated SCA warrants genetic testing and counseling. Genetic testing should include the most likely genes for the suspected phenotype and should include clinical and genetic evaluation of family members to identify other at-risk individuals. Testing of many genes can lead to uncertainty and misinterpretation of results and is generally discouraged. Genetic investigation should only be undertaken by multidisciplinary teams with expertise in cardiology, genetics, and pathology. The document provides detailed guidance on specific scenarios for which genetic testing is warranted but does not describe specific genes that should be tested.

Heart Rhythm Society, European Heart Rhythm Association, and Asia Pacific Heart Rhythm Society

In 2013, the Heart Rhythm Society, the European Heart Rhythm Association, and the Asia Pacific Heart Rhythm Society issued an expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.^67, The consensus statement refers to the 2011 guidelines on genetic testing for channelopathies and cardiomyopathies discussed next for the indications for genetic testing in patients affected by inherited arrhythmias and their family members and for diagnostic, prognostic, and therapeutic implications of the results of genetic testing. The 2013 consensus statement provided guidance for the evaluation of patients with idiopathic ventricular fibrillation, sudden unexplained death syndrome, and sudden unexplained death in infancy. Guidance on genetic testing for these patients was included (see Table 20). Idiopathic ventricular fibrillation is defined as a resuscitated cardiac arrest victim, preferably with documentation of ventricular fibrillation, in whom known cardiac, respiratory, metabolic, and toxicologic etiologies have been excluded through clinical evaluation.

The guidelines defined several terms related to specific types of SCD, including sudden unexplained death syndrome, which refers to an unexplained sudden death in an individual older than 1 year of age, sudden arrhythmic death syndrome, which refers to a sudden unexplained death syndrome case with negative pathologic and toxicologic assessment, and sudden unexplained death in infancy, which refers to an unexplained sudden death in an individual younger than 1 year of age with negative pathologic and toxicologic assessment.

Table 20. Recommendations for Genetic Testing in Idiopathic Ventricular Fibrillation, Sudden Unexplained Death Syndrome, and Sudden Unexplained Death in Infancy

In 2011, the Heart Rhythm Society and European Heart Rhythm Association jointly published an expert consensus statement on genetic testing for channelopathies and cardiomyopathies.^24, This document made the following specific recommendations on testing for LQTS, BrS, CPVT, and SQTS (see Table 21).

Table 21. Cardiac Ion Channelopathy Testing Recommendations

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 22.

Table 22. Summary of Key Trials

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