Cardiac Ion Channelopathies

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

The prevalence of any cardiac channelopathy is still ill-defined but is thought to be between 1 in 2000 and 1 in 3000 persons in the general population.^1, Data about the individual prevalences of long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome (SQTS) are presented in Table 1.

Table 1. Epidemiology of Cardiac Ion Channelopathies

Variables	LQTS	Brugada Syndrome	CPVT	SQTS
Prevalence	1:2000-5000	1:6000	1:7000-10,000	Unidentified
Annual mortality rate	0.3% (LQT1) 0.6% (LQT2) 0.56% (LQT3)	4%a	3.1%	Unidentified
Mean age at first event, y	14	42a	15	40

Adapted from Modell et al (2012).^2,

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

^a Type 1 electrocardiographic pattern.

Long QT Syndrome

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

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

Brugada Syndrome

BrS is characterized by cardiac conduction abnormalities that increase the risk of syncope, ventricular arrhythmia, and SCD. The disorder primarily manifests during adulthood, although ages between 2 days and 85 years have been reported.^3, BrS is an autosomal dominant disorder with an unexplained male predominance. Males are more likely to be affected than females (approximate ratio, 8:1). BrS is estimated to be responsible for 12% of SCD cases.^1, For both sexes, there is an equally high-risk of ventricular arrhythmias or sudden death.^4, Penetrance is highly variable, with phenotypes ranging from asymptomatic expression to death within the first year of life.^5,

Catecholaminergic Polymorphic Ventricular Tachycardia

CPVT is a rare, inherited channelopathy that may present with autosomal dominant or autosomal recessive inheritance. The disorder manifests as a bidirectional or polymorphic ventricular tachycardia precipitated by exercise or emotional stress.^6, The prevalence of CPVT is estimated between 1 in 7000 and 1 in 10000 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.^6, CPVT was previously believed to manifest only during childhood, but studies have now identified presentation between infancy and 40 years of age.^7,

Short QT Syndrome

SQTS is characterized by a shortened QT interval on the electrocardiogram and, at the cellular level, a shortening of the action potential.^8, The clinical manifestations are an increased risk of atrial and/or ventricular arrhythmias. Because of the disease’s rarity, the prevalence and risk of sudden death are currently unknown.^6,

Sudden Cardiac Arrest or Sudden Cardiac Death

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 are due to arrhythmias without structural cardiac disease and are related to the primary electrical disease syndromes. The previously described cardiac ion channelopathies are among the primary electrical disease syndromes.

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

Genetics of Cardiac Ion Channelopathies

Long QT Syndrome

There are more than 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 associatedwith LQTS. In addition to single variants, some cases of LQTS are associated with deletions or duplications of genes.^9,

The absence of a variant does not imply the absence of LQTS; it is estimated that variants are only identified in 70% to 75% of patients with a clinical diagnosis of LQTS.^10, A negative test is only definitive when there is a known variant identified in a family member and targeted testing for this variant is negative.

Another factor complicating interpretation of the genetic analysis is the penetrance of a given variant or the presence of multiple phenotypic expressions. For example, approximately 50% of variant carriers never have any symptoms. There is variable penetrance for the LQTS, and penetrance may differ for the various subtypes. While linkage studies in the past have indicated that penetrance was 90% or greater, a 1999 analysis using molecular genetics challenged this estimate and suggested that penetrance may be as low as 25% for some families.^11,

Variants involving KCNQ1, KCNH2,and SCN5A are the most commonly detected in patients with genetically confirmed LQTS. Some variants are associated with extra-cardiac abnormalities in addition to the cardiac ion channel abnormalities. A summary of clinical syndromes associated with hereditary LQTS is shown in Table 2.

Table 2. Genetics of Long QT Syndrome

Type	Other Names	Chromosome Locus	Mutated Gene	Ion Current(s) Affected	Associated Findings
LQT1	RWS	11p15.5	KVLQT1 or KCNQ1 (heterozygotes)	Potassium
LQT2	RWS	7q35-36	HERG, KCNH2	Potassium
LQT3	RWS	3p21-24	SCN5A	Sodium
LQT4	Ankyrin B syndrome	4q25-27	ANK2, ANKB	Sodium, potassium, calcium	Catecholaminergic polymorphic ventricular arrhythmias, sinus node dysfunction, AF
LQT5	RWS	21q22.1-22.2	KCNE1 (heterozygotes)	Potassium
LQT6	RWS	21q22.1-22.2	MiRP1, KNCE2	Potassium
LQT7	Andersen-Tawil syndrome	17.q23.1-q24.2	KCNJ2	Potassium	Episodic muscle weakness, congenital anomalies
LQT8	Timothy syndrome	12q13.3	CACNA1C	Calcium	Congenital heart defects, hand/foot syndactyly, ASD
LQT9	RWS	3p25.3	CAV3	Sodium
LQT10	RWS	11q23.3	SCN4B	Sodium
LQT11	RWS	7q21-q22	AKAP9	Potassium
LQT12	RWS	20q11​.21	SNTAI	Sodium
LQT13	RWS	11q24​.3	KCNJ5	Potassium
JLN1	JLNS	11p15.5	KVLQT1 or KCNQ1 (homozygotes or compound heterozygotes)	Potassium	Congenital sensorineural hearing loss
JLN2	JLNS	21q22.1-22.2	KCNE1 (homozygotes or compound heterozygotes)	Potassium	Congenital sensorineural hearing loss

Adapted from Beckmann et al (2013),^12, Arking et al (2014),^13, and Alders (2015).^14,

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

Brugada Syndrome

BrS is typically inherited in an autosomal dominant manner with incomplete penetrance. The proportion of cases that are inherited, vs de novo variants, is uncertain. Although some have reported up to 50% of cases are sporadic, others have reported that the instance of de novovariants is very low and is estimated to be only 1% of cases.^4,

Variants in 16 genes have been identified as causative of BrS, all of which lead to a decrease in the inward sodium or calcium current or an increase in one of the outward potassium currents. Of these, SCN5A is the most important, accounting for more than an estimated 20% of cases^7,; SCN10A has also been implicated. The other genes are of minor significance and account together for approximately 5% of cases.^6, The absence of a positive test does not indicate the absence of BrS, with more than 65% of cases not having an identified genetic cause. Penetrance of BrS among persons with an SCN5A variant is 80% when undergoing electrocardiogram with sodium-channel blocker challenge and 25% when not using the electrocardiogram challenge.^4,

Catecholaminergic Polymorphic Ventricular Tachycardia

Variants in four 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 ofthe 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 have reported heterozygotes for CASQ2 and TRDN variants for rare, benign arrhythmias.^15,RYR2 variants represent most CPVT cases (50%-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%.^15,

An estimated 50% to 70% of patients will have the dominant form of CPVT with a disease-causing variant. Most variants (90%) to RYR2 are missense variants, but in a small proportion of unrelated CPVT patients, large gene rearrangements or exon deletions have been reported.^7, Additionally, nearly a third of patients diagnosed as LQTS with normal QT intervals have CPVT due to identified RYR2 variants. Another misclassification, CPVT diagnosed as Anderson-Tawil syndrome may result in more aggressive prophylaxis for CPVT whereas a correct diagnosis can spare this treatment because Anderson-Tawil syndrome is rarely fatal.

Short QT Syndrome

SQTS has been linked predominantly to variants in three genes (KCNH2, KCNJ2, KCNQ1).^13,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. 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 Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Related Policies

• General Approach to Evaluating the Utility of Genetic Panels (Policy #083 in the Pathology Section)

1. Genetic testing to confirm a diagnosis of congenital long QT syndrome (LQTS) is considered medically necessary when signs and/or symptoms of LQTS are present but a definitive diagnosis cannot be made without genetic testing. This includes:
• Individuals who do not meet the clinical criteria for LQTS (ie, those with a Schwartz score <4): but have a moderate-to-high pretest probability (see Policy Guidelines section) based on the Schwartz score and/or other clinical criteria.

2. Genetic testing of asymptomatic individuals to determine future risk of LQTS is considered medically necessary when at least one of the following criteria is met:
• A close relative (ie, first-, second-, or third-degree relative) with a known LQTS mutation; or
• A close relative diagnosed with LQTS by clinical means whose genetic status is unavailable.

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

1. Genetic testing to confirm a diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) is considered medically necessary when signs and/or symptoms of CPVT are present, but a definitive diagnosis cannot be made without genetic testing.

2. Genetic testing of asymptomatic individuals to determine future risk of CPVT is considered medically necessary when at least one of the following criteria is met:
• A close relative (ie, first-, second-, or third-degree relative) with a known CPVT mutation; or
• A close relative diagnosed with CPVT by clinical means whose genetic status is unavailable.

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

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

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

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

1. Genetic testing of asymptomatic individuals to determine future risk of SQTS is considered medically necessary when members have a close relative (ie, first-, second-, or third-degree relative) with a known SQTS mutation.

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

Testing Strategy
In general, testing for patients with suspected congenital LQTS, catecholaminergic polymorphic ventricular tachycardia (CPVT), or BrS should begin with a known familial variant, if one has been identified.

In cases where the family member’s genetic diagnosis is unavailable, testing is available through either single-gene testing or panel testing. The evaluation of the clinical utility of panel testing is outlined in 'General Approach to Evaluating the Utility of Genetic Panels' (Policy #083 in the Pathology Section). Panels for cardiac ion channelopathies are diagnostic test panels that may fall into one of several categories: panels that include variants for a single condition; panels that include variants for multiple conditions (indicated plus nonindicated conditions); and panels that include variants for multiple conditions (clinical syndrome for which clinical diagnosis not possible).

For situations in which a relative of a proband with unexplained cardiac death or unexplained sudden cardiac arrest or an individual with unexplained sudden cardiac arrest is being evaluated, genetic testing may be part of a diagnostic strategy that includes a comprehensive history and physical exam and 12-lead electrocardiogram, along with exercise stress test, transthoracic echocardiography, and additional evaluation as guided by the initial studies. Studies have suggested that, in such cases, a probable diagnosis of an inherited cardiac condition can be made following a nongenetic evaluation in 50% to 80% of cases (Behr et al, 2008; Krahn et al, 2009; Kumar et al, 2013; Wong et al, 2014). If, after a comprehensive evaluation, a diagnosis of CPVT, LQTS, or BrS is suspected but not definitive (ie, if there is a moderate-to-high pretest probability of either condition), genetic testing could be considered.

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


[RATIONALE: This policy was created in 2008 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through October 30, 2018.

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

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

Genetic testing for variants associated with cardiac ion channelopathies

Clinical Context and Test Purpose

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

The question addressed in this policy is: Does genetic testing for cardiac ion channelopathies (eg, long QT syndrome [LQTS], Brugada syndrome [BrS], catecholaminergic polymorphic ventricular tachycardia [CPVT], short QT syndrome [SQTS]) improve health outcomes in individuals with suspected channelopathies or in individuals with a close relative with known or suspected channelopathies?

The following PICOTS were used to select literature to inform this review.

Patients

The populations of interest are patients with suspected cardiac ion channelopathies or individuals with a close relative with known or suspected cardiac ion channelopathies.

The channelopathies discussed herein are genetically heterogeneous with hundreds of identified variants, 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.

Interventions

The intervention of interest is genetic testing for cardiac ion channelopathies.

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

Table 3. Familion Assay Classification System

Class	Description
I	Deleterious and probable deleterious mutations. They are mutations that have either previously been identified as pathologic (deleterious mutations), represent a major change in the protein, or cause an amino acid substitution in a critical region of the protein(s) (probable deleterious mutations).
II	Possible deleterious mutations. These variants encode changes to protein(s) but occur in regions that are not considered critical. Approximately 5% of unselected patients without LQTS will exhibit mutations in this category.
III	Variants not generally expected to be deleterious. These variants encode modified protein(s); however, they are considered more likely to represent benign polymorphisms. Approximately 90% of unselected patients without LQTS will have one or more of these variants; therefore patients with only class III variants are considered “negative.”
IV	Non-protein-altering variants. These variants are not considered to have clinical significance and are not reported in the results of the Familion test.

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. Also, panel testing for one or more cardiac ion channelopathies is available from a number of genetic diagnostics laboratories, but there is some variation among manufacturers on the included genes.

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

Comparators

The comparator of interest is diagnosis and management without genetic testing. Diagnosis and management are described in the following sections by the condition.

Long QT Syndrome Diagnosis

The Schwartz criteria are commonly used as a diagnostic scoring system for LQTS.^16, The most recent version is shown in Table 4. A score of 3.5 or higher indicates a high probability that LQTS is present; a score of 1.5 to 3, an intermediate probability; and a score of 1 or less indicates a low probability of the disorder. Before the availability of genetic testing, it was not possible to test the sensitivity and specificity of this scoring system; and because there is still no perfect criterion standard for diagnosing LQTS, the accuracy of this scoring system remains ill-defined.

Table 4. Diagnostic Scoring System for Long QT Syndrome

Schwartz Criteria	Points
Electrocardiographic findings QT corrected >480 ms QT corrected 460-470 ms QT corrected <450 ms	3 2 1
History of torsades de pointes	2
T-wave alternans	1
Notched T waves in 3 leads	1
Low heart rate for age	0.5
Clinical history Syncope brought on by stress Syncope without stress Congenital deafness	2 1 0.5
Family history Family members with definite long QT syndrome Unexplained sudden death in immediate family members <30 y of age	1 0.5

Adapted from Perrin and Gollob (2012).^17,

Long QT standard management

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

Brugada Diagnosis

The diagnosis of BrS is made by the presence of a type 1 Brugada pattern on the ECG in addition to other clinical features.^18, 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-V₃). This pattern may be concealed and can be revealed by administering a sodium-channel-blocking agent (eg, ajmaline or flecainide).^19, Two additional ECG patterns have been described (type 2, type 3) but are less specific for the disorder.^20, 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 (SCD) in a family member younger than 45 years old, characteristic ECG pattern in a family member, inducible ventricular arrhythmias on electrophysiology studies, syncope, or nocturnal agonal respirations.

Brugada standard management

Management has focused on the use of ICDs in patients with syncope or cardiac arrest and isoproterenol for electrical storms. Patients who are asymptomatic can be closely followed to determine if ICD implantation is necessary.

Catecholaminergic Polymorphic Ventricular Tachycardia Diagnosis

Patients generally present with syncope or cardiac arrest during the first or second decade of life. The symptoms are nearly always triggered by exercise or emotional stress. The resting ECG of patients with CPVT is typically normal, but exercise stress testing can induce a ventricular arrhythmia in most cases (75%-100%).^17, Premature ventricular contractions, couplets, bigeminy, or polymorphic ventricular tachycardia (VT) are possible outcomes to the ECG stress test. For patients who are unable to exercise, an infusion of epinephrine may induce ventricular arrhythmia, but this is less effective than exercise testing.^21,

Catecholaminergic Polymorphic Ventricular Tachycardia Standard Management

Management of CPVT is primarily with the β-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/d) may be added. If recurrence continues, an ICD may be necessary with optimized pharmacologic management continued post-implantation.^15, Lifestyle modification with the avoidance of strenuous exercise is recommended for all CPVT patients.

Short QT Diagnosis

Patients generally present with syncope, pre-syncope, or cardiac arrest. An ECG with a corrected QT interval less than 330 ms, sharp T wave at the end of the QRS complex, and a brief or absent ST-segment are characteristic of the syndrome.^22, However, higher QT intervals on ECG might also indicate SQTS, and the clinician has to determine if this is within the normative range of QT values. An index patient with suspected SQTS would be expected to have a shortened (<2 standard deviations below from the mean) rate-corrected shortened QT interval (QTc). Cutoffs below 350 ms for men and 360 ms for women have been derived from population normal values.^23, The length of the QT interval was not associated with severity of symptoms in a 2006 series of 29 patients with SQTS.^24, Electrophysiologic studies may be used to diagnose SQTS if the diagnosis is uncertain to evaluate for short refractory periods and inducible VT. However, in the series of 29 patients with SQTS described above, VT was inducible in only 3 of 6 subjects who underwent an electrophysiologic study.^24, A diagnostic scoring system was proposed by Gollob et al (2011) to help decision making after a review of 61 SQTS cases (see Table 5).^25,

Table 5. Diagnostic Scoring System for Short QT Syndrome

Gollob Criteria	Points
Electrocardiographic findings QT corrected <370 ms QT corrected <350 ms QT corrected <330 ms J point-T peak interval <120 ms	1 2 3 1
Clinical history History of sudden cardiac death Documented polymorphic ventricular fibrillation or ventricular tachycardia Unexplained syncope Atrial fibrillation	2 2 1 1
Family history First- or second-degree relative with high probability short QT syndrome First- or second-degree relative with autopsy-negative sudden cardiac death Sudden infant death syndrome	2 1 1
Genotype Genotype positive Mutation of undetermined significance in a culprit gene	2 1

Adapted from Perrin and Gollob (2012).^17,

Short QT Standard Management

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

Antiarrhythmic drug management of the disease is complicated because the binding target for QT-prolonging drugs (eg, sotalol) is Kv11.1, which is coded for by KCNH2, the most common site for variants in SQTS (subtype 1). Treatment with quinidine (which is able to bind to both open and inactivated states of Kv11.1) is an appropriate QT-prolonging treatment. This treatment has been reported to reduce the rate of arrhythmias from 4.9% to 0% per year. For those with recurrence while on quinidine, an ICD is recommended.^17,

Outcomes

Outcomes of interest include overall survival (OS) and cardiac events. Positive results may also influence reproductive decisions.

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

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

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

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

Timing

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

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

Setting

Genetic tests are conducted in clinical laboratories. Genetic testing should be accompanied by genetic counseling including discussions with the patient or guardians about the importance and interpretation of genetic information and sharing of information with potentially affected family members as appropriate.

The evidence related to the clinical validity and utility of genetic testing for the cardiac channelopathies consists primarily of studies that evaluate the yield of genetic testing and the impact of genetic testing on the diagnosis and subsequent management of a specific cardiac channelopathy. Many cardiac channelopathies lead to a common clinical outcome¾increased risk of ventricular arrhythmias leading to an increased risk of SCD. Studies that evaluate the role of genetic testing for cardiac channelopathies as part of a diagnostic strategy in the evaluation of ventricular fibrillation or SCD from an unknown cause are discussed separately.

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

Genetic Testing for the Diagnosis of Specific cardiac ion Channelopathies

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist.

Clinically Valid

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

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

Study Selection Criteria

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

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

·         Included clinical diagnosis;

·         Patient/sample clinical characteristics were described;

·         Patient/sample selection criteria were described.

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

Long QT Syndrome

Tester et al (2006) completed the largest study to evaluate the percentage of individuals with a clinical diagnosis of LQTS found to have a genetic variant.^26, The sample was 541 consecutive patients referred for evaluation of LQTS. Clinical assessments of the patients were made while blinded to the genetic testing results. Among the 123 patients with a high probability of LQTS based on clinical assessments, defined as a Schwartz score of 4 or more, 72% (89/123) had a genetic variant. Among patients with a QTc greater than 480 ms, 62% had a genetic variant. The study is described in Table 6 below and results are shown in Table 7.

Table 6. Characteristics of Clinical Validity Studies of Genetic Testing for LQTS

Study	Study Population	Design	Clinical Diagnosis	Genes included	Blinding of Assessors
Tester (2006)26,	Unrelated patients referred to Mayo Clinic’s Sudden Death Genomics Laboratory for LQTS genetic testing from 1997 to 2004	Consecutive; prospective	Schwartz and Moss score (≥4 suggests strong probability for LQTS)	Unclear but described as ‘comprehensive mutational analysis’	Yes
Bai (2009)27,	Patients from a sample of 1394 consecutive probands with either a clinically confirmed or suspected diagnosis of LQTS, BrS, or CPVT or a personal or family history of idiopathic ventricular fibrillation /cardiac arrest /SCD referred for molecular diagnosis	Consecutive; prospective	Diagnosed clinically as conclusive or possible; criteria not specified	KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2	NR

Table 7. Yield of Genetic Testing for LQTS

Study	N	Excluded Samples	Yield of Genetic Testing
Tester (2006)26,
Overall	541	None	NR
Schwartz and Moss ≥4	123	Unknown Schwartz/Moss (n=124)	72%
Schwartz and Moss <4	294	Unknown Schwartz/Moss (n=124)	44%
Bai (2009)27,
Overall	546	NR	40%
Conclusive dx	304	NR	64%
Possible dx	160	NR	14%

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

Table 8. Relevance Gaps of Clinical Validity Studies of Genetic Testing for LQTS

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-Upe
Tester (2006)		1: Not clear which genes were tested
Bai (2009)	3: Criteria for clinical diagnosis unclear

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^bIntervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.

^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.

^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).

^e Follow-Up key: 1. Follow-up duration not sufficient with respect tonatural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Table 9. Study Design and Conduct Gaps of Clinical Validity Studies of Genetic Testing for LQTS

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Tester (2006)					2: Insufficient data for clinical score in 23% of samples that had genetic testing
Bai (2009)		1: Blinded not described			1: No description of exclusions or indeterminate results

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).

^bBlinding key: 1. Not blinded to results of reference or other comparator tests.

^cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.

^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.

^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

The evidence on clinical specificity focuses on the frequency and interpretation of variants identified but not known to be pathologic. If a variant identified is known to be pathologic, then the specificity of this finding is high. However, many variants are not known to be pathologic, and the specificity for these variants is lower. The rate of identification of variants is estimated at 5% for patients who do not have LQTS.^28,

A 2012 publication from the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) reported on the rate of sequence variants in a large number of patients without LQTS.^29, The ESP sequenced all genome regions of protein-coding in a sample of 5400 persons drawn from various populations, none of whom specifically had heart disease and/or channelopathies. Exome data were systematically searched to identify sequence variants previously associated with LQTS, including both nonsense variants, which are generally pathologic, and missense variants, which are less likely to be pathologic. Thirty-three such sequence variants were identified in the total population¾all missense variations. The percentage of the population that had at least one of these missense variants was 5.2%. No nonsense variants were associated with LQTS found among the entire population.

Brugada Syndrome

Priori (2000) reported an early paper to describe the yield of genetic testing for BrS.^30, In 58 probands with a clinical diagnosis of BrS, the yield of SCN5A testing was 15%.

Kapplinger et al (2010) reported results from an international compendium of SCN5A variants of more than 2000 patients referred for BrS genetic testing which yielded almost 300 distinct mutations in 438 of 2111 (21%) patients, ranging from 11% to 28% across the 9 testing centers.^31,

Hu et al (2014) evaluated the prevalence of SCN10A variants in 120 probands with BrS.³²Seventeen SCN10A variants were identified in 25 probands, with a variant detection rate of 16.7% in BrS probands.

Behr et al (2015) evaluated 7 candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, TBX5) among 156 patients negative for SCN5A variants with symptoms indicative of BrS (64%) and/or a family history of sudden death (47%) or BrS (18%).^33, Eighteen (11.5%) patients were found to have variants, most often in SCN10A (12/18 [67%]).

Andorin et al (2016) described the yield of SCN5A genetic testing in 75 patients younger than 19 from 62 families who had a Brugada type I ECG pattern; only 20% were symptomatic.^34, 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.

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

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

Study

Study Population

Design

Clinical Diagnosis

Genes included

Blinding of Assessors

Priori (2000)

Patients with the typical Brugada ECG pattern, without structural heart disease

Retrospective

Clinical and ECG diagnosis, criteria not specified

SCN5A

Unclear

Bai (2009)

Patients from a sample of 1394 consecutive probands with either a clinically confirmed or suspected diagnosis of LQTS, BrS, or CPVT or a personal or family history of idiopathic ventricular fibrillation /cardiac arrest /SCD referred for molecular diagnosis

Consecutive; prospective

Diagnosed clinically as conclusive or possible; criteria not specified

SCN5A

NR

Kapplinger (2010)

Unrelated cases of clinically suspected BrS from international BrS databases (5 Europe, 3 United States, 1 Japan)

Retrospective; unclear whether the samples were consecutive

Referring physician made a clinical diagnosis of either possible or definite BrS, criteria not specified

27 translated exons in SCN5A

Unclear

Hu (2014)

Unrelated patients with BrS referred to a single center for genetic testing

Retrospective; not clear if selection was consecutive

2005 Consensus Conference diagnostic criteria (Heart Rhythm Society and the European Heart Rhythm Association)

SCN10A

Unclear

Behr (2015)

Unrelated BrS Caucasian patients negative for SCN5A variants with symptoms and/or a family history of sudden death or BrS from 8 centers in Europe and US

Retrospective; not clear if selection was consecutive

Locally diagnosed, criteria not specified

SCN10A, HAND1, CASQ2, TKT, PLN, TBX5, TBX3

Unclear

Andorin (2016)

Patients (some from same family) <19 years of age at “diagnosis” of BrS (based on ECG pattern alone) in 16 European hospitals; 20% were symptomatic

Retrospective; not clear if selection was consecutive

Brugada type 1 ECG pattern either spontaneously or after challenge with a sodium channel blocker

SCN5A

Unclear

Table 11. Yield of Genetic Testing for Brugada

Study	N			Excluded Samples		Yield of Genetic Testing
Priori (2000)	52			NR		15%
Bai (2009)27,
Overall		798			8%
Conclusive dx		405			13%
Possible dx		248			4%
Kapplinger (2010)	2111			NR		21% (range 11% to 28%)
Hu (2014)	150			NR		17%
Behr (2015)	156			SCN5A re-sequencing (n=2) revision of the diagnosis (n=4), non-European ancestry (n=3).		11.5%
Andorin (2016)	75 (from 62 families)			Only 75/106 have genetic analysis; reasons for lack of genetic analysis unclear		77%

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

Table 12. Relevance Gaps of Clinical Validity Studies of Genetic Testing for Brugada

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-Upe
Priori (2000)	3: Criteria for clinical diagnosis unclear
Bai (2009)	3: Criteria for clinical diagnosis unclear
Kapplinger (2010)	3: Criteria for clinical diagnosis unclear
Hu (2014)
Behr (2015)	3: Criteria for clinical diagnosis unclear
Andorin (2016)	4: Majority of probands had only Brugada pattern ECG without symptoms

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^bIntervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.

^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.

^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).

^e Follow-Up key: 1. Follow-up duration not sufficient with respect tonatural history of disease (true positives, true negatives, flase positives, false negatives cannot be determined).

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

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Priori (2000)	1: Not clear if all eligible patients were included	1: Blinded not described			1: No description of exclusions or indeterminate results
Bai (2009)		1: Blinded not described			1: No description of exclusions or indeterminate results
Kapplinger (2010)	1: Not clear if all eligible patients were included	1: Blinded not described			1: No description of exclusions or indeterminate results
Hu (2014)	1, 2: Not clear if all eligible patients were included; not clear how samples were selected	1: Blinded not described			1: No description of exclusions or indeterminate results
Behr (2015)	1, 2: Not clear if all eligible patients were included; not clear how samples were selected	1: Blinded not described
Andorin (2016)	1, 2: Not clear if all eligible patients were included; not clear how samples were selected	1: Blinded not described			1: Unclear why ~30% of patients did not have genetic analysis

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).

^bBlinding key: 1. Not blinded to results of reference or other comparator tests.

^cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.

^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.

^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

Catecholaminergic Polymorphic Ventricular Tachycardia

Studies reporting the yield of RyR2 testing in CPVT have been conducted in patients with clinically diagnosed CPVT.^27,35,36,37, Characteristics are shown in Table 14 and results are shown in table 15. The yield in cases with a ‘strong’ diagnosis of CPVT is around 60%.

Table 14. Characteristics of Clinical Validity Studies of Genetic Testing for CPVT

Study	Study Population		Design		Clinical Diagnosis		Genes included		Blinding of Assessors
Priori (2002)	Patients with documented polymorphic ventricular arrhythmias occurring during physical or emotional stress with a normal heart		Retrospective; unclear whether samples were consecutive		Ventricular fibrillation elicited by physical or emotional stress in the absence of identifiable precipitating factors and in the absence of ventricular tachycardia documented at Holter and/or exercise stress testing		RyR2		NR
Medeiros-Domingo (2009)	Patients referred for genetic testing with “strong” diagnosis of CPVT		Retrospective; unclear whether samples were consecutive		Exertional syncope plus documentation of bidirectional or polymorphic ventricular tachycardia		RyR2		NR
Bai (2009)	Patients from a sample of 1394 consecutive probands with either a clinically confirmed or suspected diagnosis of LQTS, BrS, or CPVT or a personal or family history of idiopathic ventricular fibrillation /cardiac arrest /SCD referred for molecular diagnosis	Consecutive; prospective		Diagnosed clinically as conclusive or possible; criteria not specified		RyR2		NR
Kapplinger (2018)	Patients referred for commercial genetic testing with well-phenotyped cases and “strong” diagnosis of CPVT		Retrospective; unclear whether samples were consecutive		History of exertional syncope with documentation of exercise-related bidirectional or polymorphic ventricular tachycardia		RyR2		NR

Table 15. Yield of Genetic Testing for CPVT

Study	N	Excluded Samples	Yield of Genetic Testing
Priori (2002)	30	Not reported	47%
Medeiros-Domingo (2009)	78	Not reported	60%
Bai (2009)27,
Overall	175	NR	35%
Conclusive dx	81	NR	62%
Possible dx	21	NR	5%
Kapplinger (2018)	78	Not reported	59%

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

Table 16. Relevance Gaps of Clinical Validity Studies of Genetic Testing for CPVT

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of Follow-Upe
Priori (2002)
Medeiros-Domingo (2009)
Bai (2009)	3: Criteria for clinical diagnosis unclear
Kapplinger (2018)

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^bIntervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.

^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.

^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).

^e Follow-Up key: 1. Follow-up duration not sufficient with respect tonatural history of disease (true positives, true negatives, false positives, false negatives cannot be determined).

Table 17. Study Design and Conduct Gaps of Clinical Validity Studies of Genetic Testing for CPVT

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Priori (2002)	1,2: Not clear if all eligible patients were included	1: Blinded not described			1: No description of exclusions or indeterminate results
Medeiros-Domingo (2009)	1,2: Not clear if all eligible patients were included	1: Blinded not described			1: No description of exclusions or indeterminate results
Bai (2009)		1: Blinded not described			1: No description of exclusions or indeterminate results
Kapplinger (2018)	1,2: Not clear if all eligible patients were included	1: Blinded not described			1: No description of exclusions or indeterminate results

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).

^bBlinding key: 1. Not blinded to results of reference or other comparator tests.

^cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.

^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.

^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

The specificity of known pathologic variants for CPVT is uncertain but is likely high. A 2013 publication from the National Heart, Lung, and Blood Institute ESP reported on sequence variants in a large number of patients without CPVT.^38, ESP sequenced all genome regions of protein-coding in a sample of 6503 persons drawn from various populations who did not specifically have CPVT or other cardiac ion channelopathies. Exome data were systematically searched to identify missense variants previously associated with CPVT. Authors identified 11% previously described variants in the ESP population in 41 putative CPVT cases. These data suggested that false-positive results are low, but authors cautioned against attributing clinical CPVT to a single missense variant.

Short QT Syndrome

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

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

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

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

Clinically Useful

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

Long QT Syndrome

LQTS may lead to catastrophic outcomes (ie, SCD) in otherwise healthy individuals. Diagnosis using clinical methods alone may lead to underdiagnosis of LQTS, thus exposing undiagnosed patients to the risk of sudden cardiac arrest. For patients in whom the clinical diagnosis of LQTS is uncertain, genetic testing may be necessary to clarify whether LQTS is present. Patients who are identified as genetic carriers of LQTS variants have a non-negligible risk of adverse cardiac events even in the absence of clinical signs and symptoms of the disorder. Therefore, treatment is likely indicated for patients found to have an LQTS variant, with or without other signs or symptoms.

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

Sodium-channel blockers (eg, mexiletine) are sometimes used, particularly in those with SCN5A variants.

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

Two studies evaluated the psychologic effects of genetic testing for LQTS. Hendriks et al (2008) studied 77 patients with an LQTS variant and their 57 partners.^43, 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 (2008) conducted qualitative interviews with 7 individuals with LQTS variants.^44, They reported that affected patients had excess worry and limitations in daily life associated with the increased risk of sudden death, which was partially alleviated by acquiring knowledge about LQTS. The greatest concern was expressed for their family members, particularly children and grandchildren.

The evidence suggests that different LQTS subtypes may have variable prognoses, thus indicating that genetic testing may assist in risk stratification. Several reports have compared rates of cardiovascular events in subtypes of LQTS.^40,45,46,47, These studies have reported that rates of cardiovascular events differ among subtypes, but there is no common pattern across all studies. Three of the 4 studies^40,45,46, reported that patients with LQT2 have higher event rates than patients with LQT1, while Zareba et al (1998)^47, reported that patients with LQT1 have higher event rates than patients with LQT2.

Some studies that have reported outcomes of treatment with β-blockers have also reported outcomes by specific subtypes of LQTS.^40,46, Priori et al (2004) reported pre-post rates of cardiovascular events by LQTS subtypes following initiation of β-blocker therapy.^40, There was a decrease in event rates in all LQTS subtypes, with a similar magnitude of decrease in each subtype. Moss et al (2000) also reported pre-post event rates for patients treated with β-blocker therapy.^39, This study indicated a significant reduction in event rates for patients with LQT1 and LQT2 but not for LQT3. This analysis was limited by the small number of patients with LQT3 and cardiac events before β-blocker treatment (4/28). Sauer et al (2007) evaluated differential response to β-blocker therapy in a Cox proportional hazards analysis.^48, They reported an overall risk reduction in the first cardiac event of approximately 60% (hazard ratio, 0.41; 95% confidence interval, 0.27 to 0.64) in adults treated with β-blockers and an interaction effect by genotype. Efficacy of β-blocker treatment was worse in those with LQT3 genotype (p=0.04) than in those with LQT1 or LQT2. There was no difference in efficacy between LQT1 and LQT2 genotypes.

Brugada Syndrome

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

Catecholaminergic Polymorphic Ventricular Tachycardia

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

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

Short QT Syndrome

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

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

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

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

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

Summary of Evidence

Long QT Syndrome

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

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

Brugada Syndrome

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

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

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

Catecholaminergic Polymorphic Ventricular Tachycardia

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

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

Short QT Syndrome

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

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

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

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

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

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

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

Practice Guidelines and Position Statements

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

The American Heart Association, American College of Cardiology, and the Heart Rhythm Society (2017) published guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.^49,Table 18 summarizes the recommendations relating to cardiac ion channelopathies.

Table 18. Recommendations for Genetic Testing in Cardiac Channelopathies

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

B-NR: moderate level of evidence, nonrandomized studies; C-EO: consensus of expert opinion based on clinical experience; COR: class of recommendation; LOE: level of evidence; VT: ventricular tachycardia.

Heart Rhythm Society, European Heart Rhythm Association, et al

The Heart Rhythm Society, the European Heart Rhythm Association, and the Asia Pacific Heart Rhythm Society (2013) issued an expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.^50, The consensus statement refers to the 2011 guidelines on genetic testing for channelopathies and cardiomyopathies discussed next for the indications for genetic testing in patients affected by inherited arrhythmias and their family members and for diagnostic, prognostic, and therapeutic implications of the results of genetic testing. The 2013 consensus statement provided guidance for the evaluation of patients with idiopathic ventricular fibrillation, sudden unexplained death syndrome, and sudden unexplained death in infancy. Guidance on genetic testing for these patients was included (see Table 19). Idiopathic ventricular fibrillation is defined as a resuscitated cardiac arrest victim, preferably with documentation of ventricular fibrillation, in whom known cardiac, respiratory, metabolic, and toxicologic etiologies have been excludedthrough clinical evaluation.

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

Table 19. Recommendations for Genetic Testing in IVF, SUDS, and SUDI

	Consensus Recommendation	Class
IVF	Genetic testing in IVF can be useful when there is suspicion of a specific genetic disease following clinical evaluation of the IVF patient and/or family members.	IIa
	Genetic screening of a large panel of genes in IVF patients in whom there is no suspicion of an inherited arrhythmogenic disease after clinical evaluation should not be performed.	III
SUDS	Collection of blood and/or suitable tissue for molecular autopsy/postmortem genetic testing is recommendedin all SUDS victims.	I
	Genetic screening of the first-degree relatives of a SUDS victim is recommended whenever a pathogenic mutation in a gene associated with increased risk of sudden death is identified by molecular autopsy in the SUDS victim.	I
SUDI	Collection of blood and/or suitable tissue for molecular autopsy is recommended in all SUDI victims.	I
	An arrhythmia syndrome-focused molecular autopsy/postmortem genetic testing can be useful for all SUDI victims.	IIa
	Genetic screening of the first-degree relatives of a SUDI victim is recommended whenever a pathogenic mutation in a gene associated with increased risk of sudden death is identified by molecular autopsy in the SUDI victim. Obligate mutations carriers should be prioritized.	I

IVF: idiopathic ventricular fibrillation; SUDI: sudden unexplained death in infancy; SUDS: sudden unexplained death syndrome.

The Heart Rhythm Society and European Heart Rhythm Association (2011) jointly published an expert consensus statement on genetic testing for channelopathies and cardiomyopathies.²² This document made the following specific recommendations on testing for long QT syndrome (LQTS), BrS, catecholaminergic polymorphic ventricular tachycardia (CPVT), and SQTS (see Table 20).

Table 20. Cardiac Ion Channelopathy Testing Recommendations

	Consensus Recommendation	Classa	LOEb
LQTS	• Comprehensive or LQT1-3 (KCNQ1, KCNH2, SCN5A) targeted LQTS genetic testing is recommended for any patient in whom a cardiologist has established a strong clinical index of suspicion for LQTS based on examination of the patient’s clinical history, family history, and expressed electrocardiographic (resting 12-lead ECGs and/or provocative stress testing with exercise or catecholamine infusion) phenotype. • Comprehensive or LQT1-3 (KCNQ1, KCNH2, SCN5A) targeted LQTS genetic testing is recommended for any asymptomatic patient with QT prolongation in the absence of other clinical conditions that might prolong the QT interval (such as electrolyte abnormalities, hypertrophy, bundle branch block, etc., ie, otherwise idiopathic) on serial 12-lead ECGs defined as QTc.480 ms (prepuberty) or.500 ms (adults). • Mutation-specific genetic testing is recommended for family members and other appropriate relatives subsequently following the identification of the LQTS-causative mutation in an index case.	I	C
	• Comprehensive or LQT1-3 (KCNQ1, KCNH2, SCN5A) targeted LQTS genetic testing may be considered for any asymptomatic patient with otherwise idiopathic QTc values.460 ms (prepuberty) or.480 ms (adults) on serial 12-lead ECGs.	IIb	C
BrS	• Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the BrS-causative mutation in an index case.	I	C
	• Comprehensive or BrS1 (SCN5A) targeted BrS genetic testing can be useful for any patient in whom a cardiologist has established a clinical index of suspicion for BrS based on examination of the patient’s clinical history, family history, and expressed electrocardiographic (resting 12-lead ECGs and/or provocative drug challenge testing) phenotype.	IIa	C
	• Genetic testing is not indicated in the setting of an isolated type 2 or type 3 Brugada ECG pattern.	III	C
CPVT	• Comprehensive or CPVT1 and CVPT2 (RYR2, CASQ2) targeted CPVT genetic testing is recommended for any patient in whom a cardiologist has established a clinical index of suspicion for CPVT based on examination of the patient’s clinical history, family history, and expressed electrocardiographic phenotype during provocative stress testing with cycle, treadmill, or catecholamine infusion. Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the CPVT-causative mutation in an index case.	I	C
SQTS	• Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the SQTS-causative mutation in an index case.	I	C
	• Comprehensive or SQT1-3 (KCNH2, KCNQ1, KCNJ2) targeted SQTS genetic testing may be considered for any patient in whom a cardiologist has established a strong clinical index of suspicion for SQTS based on examination of the patient’s clinical history, family history, and electrocardiographic phenotype.	IIb	C

BrS: Brugada syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; ECG: electrocardiogram; LOE: level of evidence; LQTS: long QT syndrome; QTc: corrected QT; SQTS: short QT syndrome.

^a Class I: “is recommended” when an index case has a sound clinical suspicion for the presence of a channelopathy with a high positive predictive value 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.

^b Only consensus opinion of experts, case studies or standard of care.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 21.

Table 21. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01705925a	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome	500	Dec 2019
NCT02425189	The Canadian National Long QT Syndrome Registry (LQTSREG)	600	Dec 2026

NCT: national clinical trial.

^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Genetic Testing for Cardiac Ion Channelopathies
Genetic Testing for Congenital Long QT Syndrome (LQTS)
Genetic Testing for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Genetic Testing for Brugada Syndrome (BrS)
Genetic Testing for Short QT Syndrome (SQTS)
Familion Test
Long QT Syndrome, Genetic Testing
LQTS, Genetic Testing
Catecholaminergic Polymorphic Ventricular Tachycardia, Genetic Testing
CPVT, Genetic Testing
Brugada Syndrome, Genetic Testing
BrS, Genetic Testing
Short QT Syndrome, Genetic Testing
SQTS, Genetic Testing

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81403
81405
81406
81407
81408
81413
81414
81479

S3861