| Coverage Policy Manual | |
| Policy #: | 2006022 |
| Category: | Laboratory |
| Initiated: | June 2004 |
| Last Review: | February 2024 |
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| Genetic Test: Cardiac Ion Channelopathies (Long QT Syndrome, Brugada Syndrome, CPVT, Short QT Syndrome) | |
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| 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. Testing for variants associated with these channelopathies may assist in diagnosis, risk stratify prognosis, and/or identify susceptibility for the disorders in asymptomatic family members.
Cardiac ion channelopathies result from variants in genes that code for protein subunits of the cardiac ion channels. These channels are essential 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 1:2000 and 1:3000 persons in the general population (Abriel, 2013). 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 below:
LQTS
Prevalence – 1:2000-5000
Annual Mortality Rate – 0.3% (LQT1), 0.6% (LQT2), 0.56% (LQT3)
Mean age at first event – 14
BrS
Prevalence – 1:6000
Annual Mortality Rate – 4%
Mean age at first event – 42
CPVT
Prevalence – 1:7000-10,000
Annual Mortality Rate – 3.1%
Mean age at first event – 15
SQTS
Prevalence – Unidentified
Annual Mortality Rate – Unidentified
Mean age at first event – 40
Long QT Syndrome
Congenital long QT syndrome 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 sudden cardiac death.
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
BrS is characterized by cardiac conduction abnormalities which increase the risk of syncope, ventricular arrhythmia, and sudden cardiac death. The disorder primarily manifests during adulthood although ages between two days and 85 years have been reported (Huang, 2004). Brugada syndrome is an autosomal dominant disorder with an unexplained male predominance. Males are more likely to be affected than females (approximately an 8:1 ratio). BrS is estimated to be responsible for 12% of SCD cases (Abriel, 2013). For both genders there is an equally high risk of ventricular arrhythmias or sudden death (Brugada, 2012). Penetrance is highly variable, with phenotypes ranging from asymptomatic expression to death within the first year of life (Tester, 2011).
Catecholaminergic Polymorphic Ventricular Tachycardia
CPVT is a rare inherited channelopathy that may present with autosomal dominant or autosomal recessive inheritance. The disorder manifests as a bidirectional or polymorphic VT precipitated by exercise or emotional stress (Bennett, 2013). The prevalence of CPVT is estimated between 1 in 7000 and 1 in 10,000 persons. CPVT has a mortality rate of 30% to 50% by age 35 and is responsible for 13% of cardiac arrests in structurally normal hearts (Bennett, 2013). CPVT was previously believed to be only manifest during childhood but studies have now identified presentation between infancy and 40 years of age (Ackerman, 2013).
Short QT Syndrome
SQTS is characterized by a shortened QT interval on the EKG and, at the cellular level, a shortening of the action potential (Wilders, 2012). 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 (Bennett, 2013).
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 350ms for men and 360ms 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.
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.
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 (Eddy, 2008).
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 (Chiang, 2004). A negative test is only definitive when there is a known mutation identified in a family member and targeted testing for this mutation is negative.
Another factor complicating interpretation of the genetic analysis is the penetrance of a given variant or the presence of multiple phenotypic expressions. For example, approximately 50% of variant carriers never have any symptoms. There is variable penetrance for the LQTS, and penetrance may differ for the various subtypes. While linkage studies in the past 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 (Priori, 1999).
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 below. A 2021 analysis of 49 patients with channelopathies identified 3 rare variants that were pathogenic for LQTS and 8 rare variants that were likely pathogenic for LQTS, all involving KCNQ1 or KCNH2 (Sarquella-Brugada, 2021).
LQT1 (RWS)
Chromosome Locus - 11p15.5-p.15.4
Mutated Gene - KCNQ1
Ion Current(s) Affected - Potassium
LQT2 (RWS)
Chromosome Locus - 7qq36.1
Mutated Gene - KCNH2
Ion Current(s) Affected - Potassium
LQT3 (RWS)
Chromosome Locus - 3p22.2
Mutated Gene - SCN5A
Ion Current(s) Affected - Sodium
LQT4 (Ankyrin B syndrome)
Chromosome Locus - 4q25-26
Mutated Gene - ANK2
Ion Current(s) Affected - Sodium, potassium, calcium
Associated Findings: Catecholaminergic polymorphic ventricular arrhythmias, sinus node dysfunction, AF
LQT5 (RWS)
Chromosome Locus - 21q22.12
Mutated Gene - KCNE1
Ion Current(s) Affected - Potassium
LQT6 (RWS)
Chromosome Locus - 21q22.11
Mutated Gene - KNCE2
Ion Current(s) Affected - Potassium
LQT7 (Andersen-Tawil syndrome)
Chromosome Locus - 17.qq2432
Mutated Gene - KCNJ2
Ion Current(s) Affected - Potassium
Associated Findings: Episodic muscle weakness, congenital anomalies
LQT8 (Timothy syndrome)
Chromosome Locus - 12q13.33
Mutated Gene - CACNA1C
Ion Current(s) Affected - Calcium
Associated Findings: Congenital heart defects, hand/foot syndactyly, ASD
LQT9 (RWS)
Chromosome Locus - 3p25.3
Mutated Gene - CAV3
Ion Current(s) Affected - Sodium
LQT10 (RWS)
Chromosome Locus - 11q23.3
Mutated Gene - SCN4B
Ion Current(s) Affected - Sodium
LQT11 (RWS)
Chromosome Locus - 7q21.2
Mutated Gene - AKAP9
Ion Current(s) Affected - Potassium
LQT12 (RWS)
Chromosome Locus - 20q11.21
Mutated Gene - SNTAI
Ion Current(s) Affected - Sodium
LQT13 (RWS)
Chromosome Locus - 11q24.3
Mutated Gene - KCNJ5
Ion Current(s) Affected - Potassium
LQT14
Chromosome Locus - 14q32.11
Mutated Gene - CALM1
Ion Current(s) Affected - Calmodulin
LQT15
Chromosome Locus - 2p21
Mutated Gene - CALM2
Ion Current(s) Affected - Calmodulin
LQT16
Chromosome Locus - 19q13.32
Mutated Gene - CALM3
Ion Current(s) Affected - Calmodulin
JLNS1 (JLNS)
Chromosome Locus - 11p15.5-11p15.4
Mutated Gene - KCNQ1 (homozygotes or compound heterozygotes)
Ion Current(s) Affected - Potassium
Associated Findings: Congenital sensorineural hearing loss
JLNS2 (JLNS)
Chromosome Locus - 21q22.12
Mutated Gene - KCNE1 (homozygotes or compound heterozygotes)
Ion Current(s) Affected - Potassium
Associated Findings: Congenital sensorineural hearing loss
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 (Brugada, 2016).
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 (Ackerman, 2013). SCN10A has also been implicated. The other genes are of minor significance and account together for approximately 5% of cases (Bennett, 2013). 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 (Brugada, 2016). 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 (Sarquella-Brugada, 2021).
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 (Walsh, 2021). Some have reported heterozygotes for CASQ2 and TRDN variants for rare, benign arrhythmias (Napolitano, 2016). RYR2 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% (Napolitano, 2016).
An estimated 50% to 70% of patients have the dominant form of CPVT with a disease-causing variant. Most mutations (90%) of RYR2 are missense, variations, but in a small proportion of unrelated CPVT patients, large gene rearrangements or exon deletions have been reported (Ackerman, 2013). 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 as Anderson-Tawil syndrome is rarely fatal.
Short QT syndrome
SQTS has been linked predominantly to variants in 3 genes (KCNH2, KCNJ2, and KCNQ1) (Arking, 2014). 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 (Walsh, 2021). SQTS 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.
Coding
Effective in 2012, there are CPT codes for this testing:
81280: Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1, and ANK2); full sequence analysis
81281: known familial sequence variant
81282: duplication/deletion variants
Other analyses related to this testing are listed under the following CPT Tier 2 molecular pathology codes:
Under code 81403:
KCNJ2 (potassium inwardly-rectifying channel, subfamily J, member 2) (e.g., Andersen-Tawil syndrome), full gene sequence
Under code 81405:
CASQ2 (calsequestrin 2 [cardiac muscle]) (e.g., catecholaminergic polymorphic ventricular tachycardia), full gene sequence
Under code 81406:
KCNH2(potassium voltage-gated channel, subfamily H [ead-related], member 2) (e.g., short QT syndrome, long QT syndrome), full gene sequence
KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (e.g., short QT syndrome, long QT syndrome), full gene sequence
Under code 81407:
SCN5A (sodium channel, voltage-gated, type V, alpha subunit) (e.g., familial dilated cardiomyopathy), full gene sequence
Under code 81408:
RYR2 (ryanodine receptor 2 [cardiac]) (e.g., catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia), full gene sequence or targeted sequence analysis of > 50 exons
There is a HCPCS S code for testing for suspected Brugada syndrome:
S3861: Genetic testing, sodium channel, voltage-gated, type V, alpha subunit (SCN5A) and variants for suspected Brugada syndrome
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Policy/ Coverage: |
Effective February 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
Long QT Syndrome (LQTS)
Genetic testing to confirm a diagnosis of congenital LQTS meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes 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 (i.e., those with a Schwartz score of less than 4) but have a moderate-to-high pretest probability based on the Schwartz score and/or other clinical criteria.
Genetic testing of asymptomatic individuals to determine future risk of LQTS meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when at least one of the following criteria is met:
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Genetic testing to confirm a diagnosis of CPVT meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when a definitive diagnosis cannot be made without genetic testing.
Genetic testing of asymptomatic individuals to determine future risk of CVPT meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when at least one of the following criteria is met:
Brugada Syndrome (BrS)
Genetic testing to confirm a diagnosis of Brugada syndrome (BrS) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when signs and/or symptoms consistent with BrS are present but a definitive diagnosis cannot be made without genetic testing.
Genetic testing of asymptomatic individuals to determine future risk of BrS meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with a close relative (i.e., first-, second-, or third-degree relative) with a known BrS mutation.
*Signs and symptoms suggestive of BrS include:
Short QT Syndrome (SQTS)
Genetic testing of asymptomatic individuals to determine future risk of SQTS meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with a close relative (i.e., first-, second-, or third-degree relative) with a known SQTS mutation.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
Genetic testing for LQTS for all other situations, including but not limited to determining prognosis and/or directing therapy in individuals with known LQTS, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for LQTS for all other situations, including but not limited to determining prognosis and/or directing therapy in patients with known LQTS, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Genetic testing for CPVT for all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for CPVT for all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Genetic testing for Brugada syndrome for all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for Brugada syndrome for all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Genetic testing for short QT syndrome for all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for short QT syndrome for all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 2017 – January 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
Long QT Syndrome
Genetic testing in patients with suspected congenital long QT syndrome meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals who do not meet the clinical criteria for LQTS, but who have:
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Genetic testing for CPVT meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients who do not meet the clinical criteria for CPVT but who have:
Brugada Syndrome
Genetic testing in patients with suspected Brugada syndrome (BrS) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals when signs and/or symptoms consistent with BrS are present but a definitive diagnosis cannot be made without genetic testing but who have:
Short QT Syndrome
Genetic testing in patients with suspected SQTS meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals who do not meet the clinical criteria for LQTS, but who have:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Genetic testing for Brugada syndrome for all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for Brugada syndrome for all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Genetic testing for short QT syndrome for all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for short QT syndrome for all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to January 2017
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing in patients with suspected congenital long QT syndrome meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals who do not meet the clinical criteria for LQTS, but who have:
Genetic testing for CPVT meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients who do not meet the clinical criteria for CPVT but who have:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Genetic testing for Brugada syndrome does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for Brugada syndrome is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Genetic testing for short QT syndrome does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for short QT syndrome is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective August 2010 – July 2014
Genetic testing in patients with suspected congenital long QT syndrome meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
Individuals who do not meet the clinical criteria for LQTS, but who have:
* Determining the pretest probability of 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 2–3.
Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective, June 2004 to July 2010
Genetic testing for long QT syndrome must meet primary coverage criteria:
Genetic testing for long QT syndrome is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Genetic testing for asymptomatic patients is a specific contract exclusion in most member benefit contracts and is not covered. This includes cardiac ion channel genetic testing.
For contracts without primary coverage criteria, genetic testing for long QT syndrome is considered investigational and is not covered. Investigational services are an exclusion in the member benefit contract.
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| Rationale: |
This policy was originally developed in June 2004 to address genetic testing of Long QT syndrome. The most recent update covers the period through July 2014 and addresses genetic testing for cardiac ion channelopathies.
Validation of the clinical use of any genetic test focuses on 3 main principles: (1) the analytic validity of the test, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; (2) the clinical validity of the test, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and (3) the clinical utility of the test, ie, how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
Analytic Validity
Commercially available genetic testing for cardiac channelopathies involves a variety of methods such as chip-based oligonucleotide hybridization, direct sequencing of protein-coding portions and flanking regions of targeted exons, and next generation sequencing. The analytic sensitivity of these methods for each condition is between 95% to 99% (Tester, 2011).
Clinical Validity
The true clinical sensitivity and specificity of genetic testing for cardiac ion channelopathies cannot be determined with certainty, as there is no independent gold standard for the diagnosis. The clinical diagnosis can be compared to the genetic diagnosis, and vice versa, but neither the clinical diagnosis nor the results of genetic testing can be considered an adequate gold standard.
Long QT Syndrome
Hofman et al performed the largest study, comparing clinical methods with genetic diagnosis using registry data (Hofman, 2007). This study compared multiple methods for making the clinical diagnosis, including the Schwartz score, the Keating criteria, and the absolute length of the corrected QT (QTc) with genetic testing. These data indicate that only a minority of patients with a genetic mutation will meet the clinical criteria for LQTS. Using the most common clinical definition of LQTS, a Schwartz score of 4 or greater, only 19% of patients with a genetic mutation met the clinical criteria. Even at lower cutoffs of the Schwartz score, the percentage of patients with a genetic mutation who met clinical criteria was still relatively low, improving to only 48% when a cutoff of 2 or greater was used. When the Keating criteria were used for clinical diagnosis, similar results were obtained. Only 36% of patients with a genetic mutation met the Keating criteria for LQTS.
The best overall accuracy was obtained by using the length of the QTc as the sole criterion; however, even this criterion achieved only modest sensitivity at the expense of lower specificity. Using a cutoff of 430 ms or longer for the QT interval, a sensitivity of 72% and a specificity of 86% was obtained.
Tester et al completed the largest study to evaluate the percent of individuals with a clinical diagnosis of LQTS that are found to have a genetic mutation (Tester, 2006). The population in this study was 541 consecutive patients referred for evaluation of LQTS. A total of 123 patients had definite LQTS on clinical grounds, defined as a Schwartz score of 4 or greater and 274 patients were found to have a LQTS mutation. The genetic diagnosis was compared to the clinical diagnosis, defined as a Schwartz score of 4 or greater. Of all 123 patients with a clinical diagnosis of LQTS, 72% (89/123) were found to have a genetic mutation.
The evidence on clinical specificity focuses on the frequency and interpretation of variants that are identified that are not known to be pathologic. If a mutation is identified that is previously known to be pathologic, then the specificity of this finding is high. However, many variants are discovered on gene sequencing that are not known to be pathologic, and the specificity of these types of findings are lower. The rate of identification of variants is estimated to be in the range of 5% for patients who do not have LQTS (Kapa, 2009).
A publication from the National Heart, Lung, and Blood Institute (NHLBI) GO exome sequencing project (ESP) reported on the rate of sequence variations in a large number of patients without LQTS (Refsgaard, 2012). The ESP sequenced all genome regions of protein-coding in a sample of 5400 persons drawn from various populations, none of which included patients specifically with heart disease and/or channelopathies. Exome data were systematically searched to identify sequence variations that had previously been associated with LQTS, including both nonsense variations that are generally pathologic and missense variations that are less likely to be pathological. A total of 33 such sequence variations were identified in the total population, all of them being missense variations. The percent of the population that had at least one of these missense variations was 5.2%. There were no nonsense variations associated with LQTS found among the entire population.
Catecholaminergic Polymorphic Ventricular Tachycardia
Transgenomic’s 4 gene panel is expected to identify between 65% and 75% of patients who have a high clinical suspicion of CPVT. A lower yield is obtained by GeneDX for their 3 gene panel that estimates more than 51% of CPVT positive individuals having a mutation identified. Yield is affected by if the patient’s VT is bidirectional which has a high yield versus the more atypical presentation of IVF which has a lower (15%) yield. Penetrance of the disease has been estimated at 60% to 70% (Napolitano, 2013).
The specificity of known pathologic mutations for CPVT is not certain, but likely to be high. A publication from the NHLBI ESP reported on sequence variations in a large number of patients without CPVT (Jabbari, 2013). 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 variations that had previously been associated with CPVT. The authors identified 11% of the previously described variants in the ESP population in 41 putative CPVT cases. This data suggests that false positive results are low, but
Brugada Syndrome
The yield of genetic testing in BrS is low (Ackerman, 2011). Analyses of patients with a high clinical suspicion of BrS provided a yield of between 25% to 35% for a documented pathologic mutation (Tester, 2011). Mutational analysis of 27 SCN5A exons on cases from BrS databases at 9 international centers resulted in yields of 11% to 28%.(31) The most commonly identified of the eight identified genes for BrS is SCNA5 which is found more than 20% of genotype positive cases.
NHLBI ESP data identified a BrS prevalence of 4.7% when considering the maximal number of identified genes and mutations which is far higher than in the general population. 47% of the variants found in the published literature were determined to be pathogenic whereas 75% of the variants in ESP were determined to be pathogenic (Nielsen, 2013).
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, but has been reported by Transgenomic as between 15% to 20% of cases with a high clinical suspicion for SQTS (Familion, 2013).
Section Summary
This evidence indicates that genetic testing will identify more individuals with possible cardiac ion channelopathies compared with clinical diagnosis alone. It may often not be possible to determine with certainty whether patients with a genetic mutation have the true clinical syndrome of the disorder. None of the clinical sensitivities for the assays in this policy are above 80% suggesting that there are additional mutations associated with the channelopathies that have not been identified to date. Therefore, a negative genetic test is not definitive for excluding LQTS, CPVT, BrS, or SQTS at the present time.
Data on the clinical specificity was available for LQTS and very limited data for CPVT. The specificity varies according to the type of mutation identified. For LQTS nonsense mutations, 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 mutations, there is a rate of approximately 5% among patients without LQTS; therefore the specificity for these types of mutation is less and false positive results do occur.
Clinical Utility
Long QT Syndrome
LQTS is a disorder that may lead to catastrophic outcomes, ie, sudden cardiac death in otherwise healthy individuals. Diagnosis using clinical methods alone may lead to underdiagnosis of LQTS, thus exposing undiagnosed patients to the risk of sudden cardiac arrest. For patients in whom the clinical diagnosis of LQTS is uncertain, genetic testing may be the only way to further clarify whether LQTS is present. Patients who are identified as genetic carriers of LQTS mutations have a non-negligible risk of adverse cardiac events even in the absence of clinical signs and symptoms of the disorder. Therefore, treatment is likely indicated for patients found to have a LQTS mutation, with or without other signs or symptoms.
Treatment with beta blockers has been demonstrated to decrease the likelihood of cardiac events, including sudden cardiac arrest. Although there are no controlled trials of beta blockers, there are pre-post studies from registry data that provide evidence on this question. Two such studies reported large decreases in cardiovascular events and smaller decreases in cardiac arrest and/or sudden death after starting treatment with beta blockers (Moss, 2000; Priori, 2004). These studies reported a statistically significant reduction in cardiovascular events of greater than 50% following initiation of beta-blocker therapy. There was a reduction of similar magnitude in cardiac arrest/sudden death, which was also statistically significant.
Treatment with an implantable cardioverter-defibrillator (ICD) is available for patients who fail or cannot take beta-blocker therapy. One published study reported on outcomes of treatment with ICDs (Zareba, 2003). This study identified patients in the LQTS registry who had been treated with an ICD at the discretion of their treating physician. Patients in the registry who were not treated with an ICD, but had the same indications, were used as a control group. The authors reported that patients treated with an ICD had a greater than 60% reduction in cardiovascular outcomes.
One study reported on changes in management that resulted from diagnosing LQTS by testing relatives of affected patients with known LQTS (cascade testing) (Hofman, 2010). Cascade testing of 66 index patients with LQTS led to the identification of 308 mutation carriers. After a mean follow-up of 69 months, treatment was initiated in 199/308 (65%) of carriers. Beta-blockers were started in 163 patients, a pacemaker was inserted in 26 patients, and an ICD was inserted in 10 patients. All carriers received education on lifestyle issues and avoidance of drugs that can cause QT prolongation.
Two studies evaluated the psychological effects of genetic testing for LQTS. Hendriks et al studied 77 patients with a LQTS mutation and their 57 partners (Hendriks, 2008). 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 psychologic distress decreased over time but remained elevated at 18 months. Andersen et al conducted qualitative interviews with 7 individuals found to have LQTS mutations (Andersen, 2008). 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.
For determining LQTS subtype or specific mutation, the clinical utility is less certain. The evidence suggests that different subtypes of LQTS may have variable prognosis, thus indicating that genetic testing may assist in risk stratification. Several reports have compared rates of cardiovascular events in subtypes of LQTS (Priori, 2004; Priori, 2003; Schwartz, 2001; Zareba, 1998). These studies report that rates of cardiovascular events differ among subtypes, but there is not a common pattern across all studies. Three of the 4 studies(34,39,40) reported that patients with LQT2 have higher event rates than patients with LQT1, while Zareba et al(41) reported that patients with LQT1 have higher event rates than patients with LQT2.
More recent research has identified specific sequence variants that might be associated with higher risk of adverse outcomes. Albert et al examined genetic profiles from 516 cases of LQTS included in 6 prospective cohort studies (Albert, 2010). The authors identified 147 sequence variations found in 5 specific cardiac ion channel genes and tested the association of these variations with sudden cardiac death. Two common intronic variations, one in the KCNQ1 gene and one in the SCN5A gene were most strongly associated with sudden death. Migdalovich et al correlated gender-specific risks for adverse cardiac events with the specific location of mutations (pore-loop vs non-pore-loop) on the KCNH2 gene in 490 males and 676 females with LQTS (Migdalovich, 2011). They reported that males with pore-loop mutations had a greater risk of adverse events (hazard ratio [HR], 2.18; p=0.01) than males without pore-loop mutations but that this association was not present in females. Costa et al(44) combined information on mutation location and function with age and gender to risk-stratify patients with LQTS 1 by life-threatening events.
Other research has reported that the presence of genetic variants at different locations can act as disease “promoters” in patients with LQTS mutations (Amin, 2012; Park, 2012). Amin et al reported that 3 single-nucleotide polymorphisms (SNPs) in the untranslated region of the KCNQ1 were associated with alterations in the severity of disease (Amin, 2012). Patients with these SNPs had less severe symptoms and a shorter QT interval compared to patients without the SNPs. Park et al examined a large LQTS kindred that had variable clinical expression of the disorder. Patients were classified into phenotypes of mild and severe LQTS (Park, 2012). Two SNPs were identified that were associated with severity of disease, and all patients classified as having a severe phenotype also had one of these 2 SNPs present.
There is not sufficient evidence to conclude that the information obtained from genetic testing on risk assessment leads to important changes in clinical management. Most patients will be treated with beta-blocker therapy and lifestyle modifications, and it has not been possible to identify a group with low enough risk to forego this conservative treatment. Conversely, for high-risk patients, there is no evidence suggesting that genetic testing influences the decision to insert an ICD and/or otherwise intensify treatment.
Some studies that report outcomes of treatment with beta blockers also report outcomes by specific subtypes of LQTS (Priori, 2004; Schwartz, 2001). Priori et al reported pre-post rates of cardiovascular events by LQTS subtypes following initiation of beta-blocker therapy. (Priori, 2004). There was a decrease in event rates in all LQTS subtypes, with a similar magnitude of decrease in each subtype. Moss also reported pre-post event rates for patients treated with beta-blocker therapy. This study indicated a significant reduction in event rates for patients with LQT1 and LQT2 but not for LQT3 (Moss, 2000). This analysis was also limited by the small number of patients with LQT3 and cardiac events prior to beta-blocker treatment (4 of 28). Sauer et al evaluated differential response to beta-blocker therapy in a Cox proportional hazards analysis (Sauer, 2007). These authors reported an overall risk reduction in first cardiac event of approximately 60% (HR=0.41; 95% confidence interval [CI], 0.27 to 0.64) in adults treated with beta blockers and an interaction effect by genotype. Efficacy of beta-blocker treatment was worse in those with LQT3 genotype (p=0.04) compared with LQT1 or LQT2. There was no difference in efficacy between genotypes LQT1 and LQT2.
There is also some evidence on differential response to beta blockers according to different specific type and/or location of mutations. Barsheset et al examined 860 patients with documented mutations in the KCNQ1 gene and classified the mutations according to type and location (Barsheshet, 2012). Patients with missense mutations in the cytoplasmic loop (c-loop mutations) had a more marked risk reduction for cardiac arrest following treatment with beta blockers compared to patients with other mutations (HR=0.12; 95% CI, 0.02 to 0.73; p=0.02).
This evidence suggests that knowledge of the specific mutation present may provide some prognostic information but is not sufficient to conclude that knowledge of the specific mutation improves outcomes for a patient with known LQTS. These data suggest that there may be differences in response to beta-blocker therapy, according to LQTS subtype and the type/location of the specific mutation. However, the evidence is not consistent in this regard; for example, one of the 3 studies demonstrated a similar response to beta-blockers for LQT3 compared to other subtypes. Although response to beta-blocker therapy may be different according to specific features of LQTS, it is unlikely that this evidence could be used in clinical decision making, since it is not clear how this information would influence management.
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 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 pathologic mutation that is known to be associated with CPVT confirms the diagnosis. When the diagnosis is confirmed, treatment with B-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 sudden cardiac death. Therefore, there is clinical utility
There is currently no direct method of genotype-based risk stratification for management or prognosis of CPV. 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 beta-blockers and lifestyle changes. In addition, CPVT has been associated with SIDS and some investigators have considered testing at birth for prompt therapy in infants who are at risk due to CPVT in close family members.
Brugada Syndrome
The low clinical sensitivity of genetic testing for BrS limits its diagnostic capability. A finding of a genetic mutation is not diagnostic of the disorder but is an indicator of high risk for development of BrS. The diagnostic criteria for BrS does not presently include the presence of a genetic mutation. Furthermore, treatment is based on the presence of symptoms such as syncope or documented ventricular arrhythmias. Treatment is primarily with a implantable ICD, which is reserved for high-risk patients. The presence or absence of a genetic mutation is unlikely to change treatment decisions for patients with suspected or confirmed BrS.
Risk stratification criteria are currently inadequate and the contribution of genetic sequencing is limited to identification of SCN5A mutations which occur in less than 25% of cases. Meregalli et al investigated if type of SCN5A mutation was related to severity of disease and found that those mutations that caused more severe reductions in peak sodium current had the most severe phenotype (Meregalli, 2009). However, a meta-analysis of 30 BrS prospective studies found family history of SCD and presence of an SCN5A mutation as insufficient to predict risk for cardiac events in BrS (Modell, 2012).
Short QT Syndrome
No studies were identified that provide evidence for the clinical utility of genetic testing for SQTS. Clinical sensitivity for the test is low with laboratory testing providers estimating a yield as low as 15% (Familion, 2014).
Summary
A genetic mutation can be identified in approximately 72% to 80% of long QT syndrome (LQTS), 51% to 75% of catecholaminergic polymorphic ventricular tachycardia (CPVT), 25% to 35% of Brugada syndrome (BrS), and 15% to 20% of short QT syndrome (SQTS) patients. The majority of these are point mutations that are identified by gene sequencing analysis; however a small number are deletions/duplications that are best identified by chromosomal microarray analysis (CMA). The analytic validity of testing for point mutations by sequence analysis is high, while the analytic validity of testing for deletions/duplications by CMA is less certain. The clinical validity varies by condition. For LQTS, it is relatively high in the range of 70% to 80%, while for CPVT it is moderate in the range of 50% to 75%. For BrS and SQTS, the clinical validity is lower, in the range of 15% to 35%.
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 beta 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 sudden cardiac death. The clinical utility of testing is also high for close relatives of patients with known cardiac ion channel mutations, since these individuals should also be treated if they are found to have a pathologic mutation. For BrS and SQTS, the clinical utility is uncertain because there is not a clear link between the establishment of a definitive diagnosis and a change in management that will improve outcomes.
Therefore, genetic testing for the diagnosis of LQTS and CPVT may be considered medically necessary for the following individuals who do not have a definite clinical diagnosis but who have: (1) a close relative (ie, first-, second-, or third-degree relative) with a known pathologic mutation, (2) a close relative with a clinical diagnosis whose genetic status is unavailable, or (3) signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS or CPVT, but in whom a definitive diagnosis cannot be made clinically.
Practice Guidelines and Position Statements
The Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) jointly published an expert consensus statement on genetic testing for channelopathies and cardiomyopathies (Ackerman, 2011). This document made the following specific recommendations concerning testing for LQTS, CPVT, BrS, and SQTS :
*Class I: “is recommended” when an index case has a sound clinical suspicion for the presence of a channelopathy with a high PPV for the genetic test (>40%) with a signal to noise ratio of >10 AND/OR the test may provide diagnostic or prognostic information or may change therapeutic choices.; Class IIa: “can be useful”; Class IIb: “may be considered”; Class III (“is not recommended”): The test fails to provide any additional benefit or could be harmful in the diagnostic process.
The level of evidence of all recommendations is C (only consensus opinion of experts, case studies or standard of care).
The American College of Cardiology/American Heart Association/European Society of Cardiology issued guidelines in 2006 on the management of patients with ventricular arrhythmias and the prevention of sudden death (Zipes, 2006). These guidelines made a general statement that “In patients affected by LQTS, genetic analysis is useful for risk stratification and therapeutic decisions.” These guidelines did not address the use of genetic testing for the diagnosis of LQTS. The guidelines also state that for genetic testing for CPVT, BrS, or SQTS may identify silent carriers for clinical monitoring but does not assist with risk stratification.
The Canadian Cardiovascular Society and Canadian Hearth Rhythm Society published a joint position paper in 2011 (Gollob, 2011). Genetic testing was recommended for cardiac arrest survivors with LQTS for the purpose of familial screening as well as those with syncope with QTc prolongation as well as asymptomatic patients with QTc prolongation with a high clinical suspicion of LQTS. For clinically suspect CPVT testing is recommended for the purpose of familial screening. Genetic testing is also recommended for cardiac arrest survivors with a Type I Brugada EKG pattern for the purpose of familial screening as well as in patients with syncope and Type I Brugada EKG pattern or asymptomatic patients with Type I Brugada EKG pattern and a high clinical suspicion. No recommendations are given regarding SQTS.
2018 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
Brugada Syndrome
In 2017, Yamagata et al published a study investigating the correlation between SCN5A variants and cardiac events, using data from a multicenter registry that enrolled patients with BrS whose SCN5A gene was analyzed (Yamagata, 2017). Of the 415 patients in the registry, 60 had an SCN5A variant, and 355 did not have an SCN5A variant. Mean follow-up was 72 months. Patients with the SCN5A variant experienced a first cardiac event at a significantly younger age and experienced a significantly higher rate of cardiac events compared with patients without the SCN5A variant.
Van Malderen et al (2017) conducted a cross-sectional study to evaluate whether type of SCN5A variant was related to prolonged right ventricular ejection delay in patients with BrS (Van Malderaen, 2017). Right ventricular ejection delay was measured in 3 BrS patient populations: (1) those with a SCN5A T-variant (n=13), (2) those with a SCN5A M-variant (n=21), and (3) those without a SCN5A variant (n=66). Patients with T-variant had significantly longer right ventricular ejection delay compared with patients M-variant and patients without a SCN5A variant.
Genetic Testing for the Diagnosis of Cardiac Ion Channelopathy in Survivors of Unexpected Cardiac Arrest
In 2017, Mellor et al published results from genetic testing on patients in the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (Mellor, 2017). Among 375 unexplained cardiac arrest survivors in the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry from 2006 to 2015, 174 underwent genetic testing at physicians’ discretion, based on guidelines and availability. A pathogenic variant was detected in 29 (17%) of patients tested. By clinical phenotype, the number of patients for whom a variant was detected was: 5 of 25 patients with an LQTS clinical phenotype; 2 of 7 patients with a BrS clinical phenotype; and 2 of 8 patients with a CPVT clinical phenotype.
Practice Guidelines and Position Statements
American Heart Association, American College of Cardiology, and the Heart Rhythm Society
In 2017, the American Heart Association, American College of Cardiology, and the Heart Rhythm Society published guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. The recommendations relating to cardiac ion channelopathies are summarized as follows (Al-Khatib, 2017):
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Brugada Syndrome
Priori reported an early paper to describe the yield of genetic testing for BrS (Priori, 2000). In 58 probands with a clinical diagnosis of BrS, the yield of SCN5A testing was 15%.
Kapplinger et al 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 (Kapplinger, 2010).
Andorin et al described the yield of SCN5A genetic testing in 75 patients younger than 19 from 62 families who had a Brugada type I ECG pattern; only 20% were symptomatic (Andorin, 2016). 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.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Asatryan et al 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 (Asatryan, 2019). 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 was not reported.
Chen et al conducted a meta-analysis of 17 studies involving 1,780 unrelated and consecutive patients with BrS to assess the relationship between SCN5A mutation status and phenotypic features (Chen, 2020). 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=0.0003). 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=0.0002). SCN5A(+) patients had a higher proportion of sick sinus syndrome (43% vs. 5%; p<0.001) and atrial ventricular block (71% vs. 30%; p=0.01). However, there was a lower rate of ventricular tachycardia/ventricular fibrillation inducibility during electrophysiology study (41% vs. 51%; p=0.01), 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 ratio1.78; 95% CI, 1.19 to 2.26; p=0.005), Asian (odds ratio 1.82; 95% CI, 1.07 to 3.11; p=0.03), and Caucasian (odds ratio 2.24; 95% CI, 1.02 to 4.90; p=0.04) patient population.
Monasky et al 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 (Monasky, 2019). 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 reported data from the Genetics of Brazillian Arrhythmias (GenBra) registry (Sacilotto, 2020). 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=0.770). SCN5A carriers had a significantly higher frequency of aVR sign, S wave, and QRS-f.
Sodium-channel blockers (eg, mexiletine) are sometimes used, particularly in those with SCN5A variants. Preliminary modeling studies by Zhu et al designed to predict LQT3 mutations with enhanced mexiletine sensitivity have been successfully validated in a small initial cohort of patients (Zhu, 2019).
Shimizu et al conducted an observational study on 1,124 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 (Shimizu, 2019). 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=0.002). 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<0.001). 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<0.001). 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 studied LQTS patients (n=212) enrolled in the Rochester LQTS ICD registry who underwent ICD implantation for primary prevention of SCD (Biton, 2019). 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%. QTc ≥ 550 ms (HR 3.94; 95%CI 2.08 to 7.46; p<0.001) and prior syncope on β-blockers (HR 1.92, 95% CI 1.01 to 3.65; p=0.047) were associated with an increased risk of appropriate shock. Importantly, LQT2 genotype (HR 2.10, 95% CI 1.22 to 3.61; p=0.008) and the presence of multiple mutations (HR 2.87, 95% CI 1.49 to 5.53; p=0.002) 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 conducted a multicenter retrospective analysis of 148 pregnancies from 103 families with the 3 most common heterozygous pathogenic LQTS genotypes (KCNQ1, KCNH2, or SCN5A) (Cuneo, 2020). 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 vs paternal LQTS (24.4% vs 3.5%; P=0.36).
Rattanawong et al 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 sudden cardiac death) in patients with BrS (n=1049) (Rattanawong, 2019). SCN5A mutations were associated with major arrhythmic events in Asian patients (risk ratio 2.03; 95% CI 1.37 to 3.00; p=0..0004; I2=0.0%), symptomatic patients (risk ratio 2.66; 95% CI, 1.62 to 4.36; p=0.0001; I2=23.0%), and patients with spontaneous Brugada type 1 ECG pattern (risk ratio 1.84; 95% CI, 1.05 to 3.23; p=0.03; 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.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2021 analysis of 49 patients with channelopathies identified 3 rare variants that were pathogenic for LQTS and 8 rare variants that were likely pathogenic for LQTS, all involving KCNQ1 or KCNH2 (Sarquella-Brugada, 2021).
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 (Sarquella-Brugada, 2021).
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 (Walsh, 2021).
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 (Walsh, 2021).
Chiu et al performed genetic tests on 36 survivors of pediatric cardiac arrest (median age, 13.3 years) (Chiu, 2021). 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.
Milman et al published an observational study of 678 patients from 14 countries with a first arrhythmic event due to BrS (Milman, 2021). 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 (odds ratio, 5.41; 95% CI, 2.8 to 11.19; p<.001) and family history of SCD (odds ratio, 2.73; 95% CI, 1.28 to 5.82; p=.009) were associated with having a pathogenic/likely pathogenic genotype.
In 2021, the American Heart Association published a scientific statement on genetic testing for heritable cardiovascular diseases (including channelopathies) in children (Landstrom, 2021). 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, electrocardiogram (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 (Musunuru, 2020). 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.
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 (Stiles, 2021). 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.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Wang et al published an observational study of 79 patients in China who had BrS, 59 of whom underwent genetic testing (Wang, 2022). 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.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2023, the American Heart Association published a scientific statement on interpreting incidentally identified genes associated with heritable cardiovascular diseases (including cardiac ion channelopathies) (Landstrom, 2023). 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 an electrocardiogram (ECG) testing, a 24-hour or longer Holter monitor, and an exercise stress test (if possible) should be performed.
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