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DESCRIPTIONGenetic 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 mutations 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 are the result of mutations 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. The 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. Data pertaining to the individual prevalences of LQTS, CPVT, BrS, and SQTS are presented in the table below. The channelopathies discussed in this policy are genetically heterogeneous with hundreds of identified mutations, but the group of disorders share 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.
Epidemiology of Cardiac Ion Channelopathies
BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; LQTS: long QT syndrome; SQTS: short QT syndrome.
a Type 1 ECG pattern.
b Type 1 ECG pattern.
Long QT Syndrome
Congenital long QT syndrome (LQTS) is an inherited disorder characterized by the lengthening of the repolarization phase of the ventricular action potential, increasing the risk of arrhythmic events, such as torsades de pointes, which may in turn result in syncope and sudden cardiac death. Management has focused on the use of beta blockers as first-line treatment, with pacemakers or implantation cardioverter defibrillators (ICD) as second-line therapy.
Congenital LQTS usually manifests itself before the age of 40 years, and may be suspected when there is a history of seizure, syncope, or sudden death in a child or young adult; this history may prompt additional testing in family members. It is estimated that more than one half of the 8,000 sudden unexpected deaths in children may be related to LQTS. The mortality of untreated patients with LQTS is estimated at 1%-2% per year, although this figure will vary with the genotype.
Frequently, syncope or sudden death occurs during physical exertion or emotional excitement, and thus LQTS has received some publicity regarding evaluation of adolescents for participation in sports. In addition, LQTS may be considered when a long QT interval is incidentally observed on an ECG. Diagnostic criteria for LQTS have been established, which focus on ECG findings and clinical and family history (i.e., Schwartz criteria, see following section, "Clinical Diagnosis"). However, measurement of the QT interval is not well standardized, and in some cases, patients may be considered borderline cases.
In recent years, LQTS has been characterized as an “ion channel disease”, with abnormalities in the sodium and potassium channels that control excitability of the cardiac myoctyes. A genetic basis for LQTS has also emerged, with 7 different subtypes recognized, each corresponding to mutations in different genes. In addition, typical ST-T wave patterns are also suggestive of specific subtypes. Some of the genetic subtypes are associated with abnormalities outside the cardiac conduction system.
The Schwartz criteria are commonly used as a diagnostic scoring system for LQTS. The most recent version of this scoring system is shown in the table below. A score of 4 or greater indicates a high probability that LQTS is present; a score of 2-3, a moderate-to-high probability; and a score of 1 or less indicates a low probability of the disorder. Prior to the availability of genetic testing, it was not possible to test the sensitivity and specificity of this scoring system; therefore, the accuracy of this scoring system is ill-defined.
Diagnostic Scoring System for LQTS
LQTS: long QT syndrome; QTc: QT corrected;
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 2 days and 85 years have been reported. 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. For both genders there is an equally high risk of ventricular arrhythmias or sudden death. Penetrance is highly variable, with phenotypes ranging from asymptomatic expression to death within the first year of life. Management has focused on the use of implantable cardiac defibrillators (ICD) in patients with syncope or cardiac arrest and isoproterenol for electrical storms. Patients who are asymptomatic can be closely followed to determine if ICD implantation is necessary.
The diagnosis of BrS is made by the presence of a type 1 Brugada pattern on the ECG in addition to other clinical features. 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 two or more of the right precordial ECG leads (V1 through V3). This pattern may be concealed and can be revealed by administering a sodium-channel-blocking agent (eg, ajmaline or flecainide). Two additional ECG patterns have been described (type 2 and type 3) but are less specific for the disorder. The diagnosis of BrS is considered definitive when the characteristic ECG pattern is present with at least one of the following clinical features: documented ventricular arrhythmia, sudden cardiac death 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.
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. 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. CPVT was previously believed to be only manifest during childhood, but studies have now identified presentation between infancy and 40 years of age.
Management of CPVT is primarily with the beta-blockers nadolol (1-2.5 mg/kg/d) or propranolol (2-4 mg/kg/d). If protection is incomplete (ie, recurrence of syncope or arrhythmia), then flecainide (100-300 mg/day) may be added. If recurrence continues an ICD may be necessary with optimized pharmacologic management continued postimplantation. Lifestyle modification with the avoidance of strenuous exercise is recommended for all CPVT patients.
Patients generally present with syncope or cardiac arrest during the first or second decade of life. The symptoms are nearly always triggered by exercise or emotional stress. The resting ECG of patients with CPVT is typically normal, but exercise stress testing can induce ventricular arrhythmia in the majority of cases (75%-100%). Premature ventricular contractions, couplets, bigeminy, or polymorphic 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.
Short QT Syndrome
SQTS is characterized by a shortened QT interval on the ECG and, at the cellular level, a shortening of the action potential. The clinical manifestations are an increased risk of atrial and/or ventricular arrhythmias. Because of the disease’s rarity, the prevalence and risk of sudden death are currently unknown.
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 mutations 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 who recur while on quinidine, an ICD is recommended.
Patients generally present with syncope, presyncope or cardiac arrest. An ECG with a corrected QT interval <330 ms, sharp T-wave at the end of the QRS complex, and a brief or absent ST-segment is characteristic of the syndrome. 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. Recently, a diagnostic scoring system has been proposed by Gollob et al to aid in decision-making after a review of 61 SQTS cases.
Diagnostic Scoring System for SQTS
QTc: QT corrected; SCD: sudden cardiac death; SQTS: short QT syndrome; VF: ventricular fibrillation; VT: ventricular tachycardia.
Genetics of Cardiac Ion Channelopathies
Long QT Syndrome
There are more than 1200 unique mutations 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 mutations, some cases of LQTS are associated with deletions or duplications of genes. This may be the case in up to 5% of total cases of LQTS. These types of mutations may not be identified by gene sequence analysis. They can be more reliably identified by chromosomal microarray analysis (CMA), also known as array comparative genomic hybridization (aCGH). Some laboratories that test for LQTS are now offering detection of LQTS-associated deletions and duplications by this testing method. This type of test may be offered as a separate test and may need to be ordered independently of gene sequence analysis when testing for LQTS.
The absence of a mutation does not imply the absence of LQTS; it is estimated that mutations are only identified in 70%-75% of patients with a clinical diagnosis of LQTS. 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. Other laboratories have investigated different testing strategies. For example, Napolitano and colleagues propose a 3-tiered approach, first testing for a core group of 64 codons that have a high incidence of mutations, followed by additional testing of less frequent mutations.
Another factor complicating interpretation of the genetic analysis is the penetrance of a given mutation or the presence of multiple phenotypic expressions. For example, approximately 50% of carriers of mutations 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, more recent analysis by molecular genetics has challenged this number, and suggested that penetrance may be as low as 25% for some families.
Mutations involving KCNQ1, KCNH2, and SCN5A are the most commonly detected in patients with genetically confirmed LQTS. Some mutations are associated with extracardiac abnormalities in addition to the cardiac ion channel abnormalities. A summary of clinical syndromes associated with hereditary LQTS is shown in the table below.
Genetics of Long QT Syndrome
Type of Other Names Chromosome Locus Mutated Gene Ion Current(s) Affected Associated Findings
Ion Current(s) Affected
AF: atrial fibrillation; ASD: autism spectrum disorder; LQT: long QT; JLNS: Jervell and Lange-Nielsen syndrome; RWS: Romano-Ward syndrome.
BrS is typically inherited in an autosomal dominant manner with incomplete penetrance. The proportion of cases that are inherited, versus de novo mutations, is uncertain. Although some authors report up to 50% of cases are sporadic in nature, others report that the instance of de novo mutations is very low and is estimated to be only 1% of cases.
Mutations in 16 genes have been identified as causative of BrS, all of which lead to either a decrease in the inward sodium or calcium current or an increase in one of the outward potassium currents, but of these SCN5A is the most important, accounting for more than an estimated 20% of cases. The other genes are of minor significance and account together for approximately 5% of cases. The absence of a positive test does not indicate the absence of BrS, with more than 65% of cases not having an identified genetic cause. Penetrance of BrS among persons with a SCN5A mutation is 80% when undergoing ECG with sodium channel blocker challenge and 25% when not using the ECG challenge.
Catecholaminergic Polymorphic Ventricular Tachycardia
Mutations in 4 genes are known to cause CPVT, and investigators believe other unidentified loci are involved as well. Currently, only 55% to 65% of patients with CPVT have an identified causative mutation. Mutations to the gene encoding the cardiac ryanodine receptor (RYR2) or to KCNJ2 result in an autosomal dominant form of CPVT. CASQ2 (cardiac calsequestrin) and TRDN-related CPVT exhibit autosomal recessive inheritance. Some authors have reported heterozygotes for CASQ2 and TRDN mutations for rare, benign arrhythmias. RYR2 mutations represent the majority of CPVT cases (50-55%) with CASQ2 accounting for 1-2% and TRDN accounting for an unknown proportion of cases. The penetrance of RYR2 mutations is approximated at 83%.
An estimated 50% to 70% of patients will have the dominant form of CPVT with a disease-causing mutation. Most mutations (90%) to RYR2 are missense mutations, but in a small proportion of unrelated CPVT patients large gene rearrangements or exon deletions have been reported. Additionally, nearly a third of patients diagnosed as LQTS with normal QT intervals have CPVT due to identified RYR2 mutations. 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 lethal.
Short QT syndrome
SQTS has been linked predominantly to mutations in three genes (KCNH2, KCNJ2, and KCNQ1). Mutations 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 mutation in these genes, suggesting changes in other genes may also cause this disorder. 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.
Genetic Testing for Cardiac Ion Channelopathies
Genetic testing can be comprehensive (testing for all possible mutations in multiple gene) or targeted (testing for a single mutation identified in a family member). For comprehensive testing, the probability that a specific mutation is pathophysiologically significant is greatly increased if the same mutation has been reported in other cases. A mutation may also be found that has not definitely been associated with a disorder and therefore may or may not be pathologic. Variants are classified by their pathologic potential; an example of such a classification system used in the Familion® assay is as follows:
Genetic testing for specific disorders, which may include one or more specific genes, is available from multiple academic and commercial laboratories, generally by next-generation sequencing or Sanger sequencing. In addition, panel testing for one or more cardiac ion channelopathies is available from a number of genetic diagnostics laboratories (see the table below). The John Welsh Cardiovascular Diagnostic Laboratory, GeneDX, and Transgenomic each offer panels that genotype LQTS, CPVT, BrS, and SQTS, but there is some variation among manufacturers on which genes to include in the assays.
Examples of Cardiac Ion Channelopathy Genetic Testing Laboratories in the United States
BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; LQTS: long QT syndrome; SQTS: short QT syndrome.
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 (eg, iGene Cardiac Panel [ApolloGen Inc., Irvine, CA]).
There are no assay kits approved by the U.S. Food and Drug Administration (FDA) for genetic testing for cardiac ion channelopathies. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.
POLICYGenetic testing in patients with suspected congenital long QT syndrome may be considered medically necessary for the following indications:
Individuals who do not meet the clinical criteria for LQTS (ie, those with a Schwartz score <4), but who have:
* 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 or 3.
Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is considered investigational.
Genetic testing for CPVT may be considered medically necessary for patients who do not meet the clinical criteria for CPVT but who have:
Genetic testing for LQTS or CPVT is investigational for all other situations when the above criteria are not met.
Genetic testing for short QT syndrome is considered investigational.
In cases where the family member’s genetic diagnosis is unavailable, testing is available through either single gene testing or panel testing. Panels for cardiac ion channelopathies are diagnostic test panels that may fall into one of several categories: panels that include mutations for a single condition; panels that include mutations for multiple conditions (indicated plus nonindicated conditions); panels that include mutations for multiple conditions (clinical syndrome for which clinical diagnosis not possible).
For situations in which a relative of a proband with unexplained cardiac death or unexplained sudden cardiac arrest or an individual with unexplained sudden cardiac arrest is being evaluated, genetic testing may be part of a diagnostic strategy that includes a comprehensive history and physical exam and 12-lead electrocardiogram (ECG), along with exercise stress test, transthoracic echocardiography, and additional evaluation as guided by the initial studies. Studies suggest that in such cases, a probable diagnosis of an inherited cardiac condition can be made following a nongenetic evaluation in 50% to 80% of cases. If, after a comprehensive evaluation, a diagnosis of CPVT or LQTS is suspected but not definitive (ie, if there is a moderate-to-high pretest probability of either condition), genetic testing could be considered.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY7/27/2006: Approved by Medical Policy Advisory Committee (MPAC)
1/14/2008: Policy description updated. Genetic testing in patients with known or suspected LQTS changed from investigational to may be considered medically necessary for clinical criteria as outlined in POLICY section. Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is investigational added to POLICY section.
3/27/2008: Reviewed and approved by MPAC
8/26/2008: Quarterly HCPCS code updates applied
1/05/2009: Policy reviewed. No changes.
08/11/2010: Policy reviewed; no changes.
08/11/2011: Policy reviewed; no changes.
09/25/2012: Policy reviewed. Policy statement unchanged. Added CPT codes 81280 - 81282 and ICD-9 codes 426.82 and 746.89 to the Code Reference section.
08/01/2013: Added the following diagnosis codes to the Code Reference section: 427.5, V12.53, and V17.41. Removed deleted HCPCS codes S3860 and S3862 from the Code Reference section.
09/17/2014: Policy title changed from "Testing for Congenital Long QT Syndrome” to “Genetic Testing for Cardiac Ion Channelopathies.” Policy description revised to include Brugada syndrome, CPVT, and short QT syndrome. Added medically necessary policy statement and criteria for genetic testing for CPVT. Added the following investigational statement: Genetic testing for short QT syndrome is considered investigational.
06/15/2015: Policy description revised and updated regarding genetics of cardiac ion channelopathies and genetic testing for cardiac ion channelopathies. First medically necessary policy statement revised to change "patients with known or suspected congenital long QT syndrome" to "patients with suspected congenital long QT syndrome." Added "(ie, those with a Schwartz score <4)" to the first policy statement regarding LQTS. Added the following investigational statement: Genetic testing for LQTS or CPVT is investigational for all other situations when the above criteria are not met. Policy guidelines updated to add testing strategy information.
SOURCE(S)Blue Cross Blue Shield Association Policy # 2.04.43
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.