CAM 20443

Genetic Testing for Cardiac Ion Channelopathies

Category:Laboratory   Last Reviewed:July 2018
Department(s):Medical Affairs   Next Review:July 2019
Original Date:April 2013    

Description   
Channelopathies, also known as primary electrical disease, are a group of cardiac diseases caused by genetic defects in ion channels of the heart leading to arrhythmias, syncope and the risk of sudden cardiac death (SCD) (Campuzano, Sarquella-Brugada, Brugada, & Brugada, 2015).    

Literature Review
The electromechanical pumping action of the heart maintains circulation and ensures the delivery of blood and nutrients to all organs to support their normal function. Synchronized contraction of the myocardium is necessary to generate sufficient pressure to drive blood flow (Voorhees & Han, 2015). Mechanical contraction of cardiac myocytes is coordinated by the generation and propagation of an action potential (Fernandez-Falgueras, Sarquella-Brugada, Brugada, Brugada, & Campuzano, 2017) through the synergistic activation and inactivation of several voltage-dependent ion channels. Membrane depolarization during the action potential leads to the opening of the voltage-gated calcium channels resulting in an inward current, followed by the efflux of potassium ions, generation of an outward current, and cell repolarization (Garcia-Elias & Benito, 2018). Action potential duration is determined by the magnitude and timing of inward and outward currents (Kirk & Kass, 2015). Differential expression, selectivity and gating properties of cardiac ion channels in distinct regions of the heart promote unidirectional propagation of electrical activity (Fernandez-Falgueras et al., 2017).

Mutations in genes encoding these specific channels or associated proteins may impair ionic conduction resulting in changes in action potential, synchronization, and/or propagation of electrical impulse and predispose to potentially malignant arrhythmias (Nerbonne & Kass, 2005; Roden, Balser, George, & Anderson, 2002). Dyssynchronous contraction of the ventricle, arising from electrical activation delays, also significantly worsens morbidity and mortality in heart failure (HF) patients (Kirk & Kass, 2015). Ion channelopathies have been identified as a significant cause of sudden cardiac death (SCD) in patients with structurally normal hearts (Campuzano et al., 2015; Magi, Lariccia, Maiolino, Amoroso, & Gratteri, 2017), and some cases of otherwise unexplained stillbirth (Munroe et al., 2018).

Patients can show early symptoms of palpitations or hemodynamic compromise, including dizziness, seizure, or syncope, particularly following exertion, however in many cases SCD is the only sign of cardiac trouble (Martin, Huang, & Matthews, 2013). Electrical disturbances in the heart rhythm that can be detected on electrocardiogram (ECG) of some patients with channelopathies result in diagnosis of:

  • Long QT Syndrome (LQTS), characterized by prolonged ventricular repolarization and electrocardiographic prolongation of the QTinterval (QTc ≥ 480 ms in repeated 12-lead ECG, although a QTc ≥ 460 ms is sufficient in the presence of unexplained syncope). The variable clinical manifestations of LQTS range from asymptomatic patients diagnosed through family screening, to SCD, syncope, convulsions, malignant ventricular arrhythmias, VF, and torsade de pointes (Fernandez-Falgueras et al., 2017). The prevalence of LQTS in infants is approximately to 1/2000 (Schwartz et al., 2009).
  • Brugada Syndrome (BrS) is clinically characterized by right ventricular conduction delay and ST-segment elevation in the anterior right precordial leads. Syncope is one of the main clinical manifestations; individuals with BrS develop a monomorphic ventricular tachycardia that may precipitate during sleep, rest or fever (Magi et al., 2017). Recent reports suggest that BrS could be responsible for 4%–12% of all SD and up to 20% of SD in patients with structurally normal hearts (Fernandez-Falgueras et al., 2017).
  • Short QT Syndrome (SQTS), is characterized by abnormally short QT intervals and an increased propensity to develop atrial and ventricular tachyarrhythmia in the absence of structural heart disease. Cardiac arrest seems to be the most frequent symptom (up to 40%). Palpitations are a common symptom (30%), followed by syncope (25%) and atrial fibrillation (AF), which are the first symptoms of the disease in up to 20% of patients. The episodes may occur in a wide range of situations such as in reaction to loud noise, at rest, during exercise, and during daily activity (Fernandez-Falgueras et al., 2017)
  • Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), is characterized by a normal ECG and ventricular arrhythmia in genetically predisposed individuals during intense physical exercise or acute emotional stress. Typical clinical manifestations of CPVT include dizziness and syncope. However, ventricular arrhythmia may degenerate into rapid polymorphic ventricular tachycardia and ventricular fibrillation, leading to SCD(Magi et al., 2017).

But not all are accompanied by changes in ECG, which makes them more difficult to diagnose. Genetic testing can contribute substantially both to the diagnosis of affected patients and with the identification of asymptomatic individuals at risk (Bastiaenen & Behr, 2011; Priori et al., 2013).

Currently, mutations associated with SCD have been identified in sodium, potassium and calcium channels and associated proteins (Fernandez-Falgueras et al., 2017). A general overview of the main genetic variants that have been linked to the major cardiac channelopathies is displayed in the table below (adapted from Magi et al, 2017; Monroe et al, 2018; Elias and Benito, 2018; Tester and Ackerman, 2011).

Gene

Protein

Prevalence

Other Associations

Brugada Syndrome (BrS)

 

Ion Channel Subunits 

SCN5A*

NaV1.5 (α-subunit of the voltage-dependent Na+channel)                                      

⋍25% (BrS1

DCM, ARVC, Heart block, LQTS, SSS, SIDS                      

SCN1B*

β1-subunit of the voltage-dependent Na+ channel                                          

<1%

CCD, Epilepsy                    

SCN2B*

β2-subunit of the voltage-dependent Na+ channel

<1%

AF

SCN3B*

β3-subunit of the voltage-dependent Na+ channel

<1%

AF, VF, SIDS

SCN10A*

NaV1.8 (α-subunit of the neuronal voltage-dependent Na+ channel)

⋍10%

LQTS, AF, painful small-fiber peripheral neuropathy

CACNA1C*

CaV1.2 (α1C-subunit of the volatge-dependent L-type Ca2+ channel)

<1%

Timothy syndrome, LQTS

CACNB2b*

β2-subunit of the voltage-dependent L-type Ca2+channel

<1%

SQTS

KCND3*

KV4.3 (α-subunit of the voltage-dependent K+channel)

<1%

SIDS, Spinocerebellar ataxia

KCNE3* 

minK-related peptide 2 (β-subunit of the voltage-dependent K+ channel) 

<1%

 

KCNAB2 

β2-subunit of the voltage-dependent K+ channel 

<1%

 

KCND2

KV4.2 (voltage-dependent K+ channel)

<1%

Epilepsy

KCNE5*

minK-related peptide 4 (β-subunit of the voltage-dependent K+ channel)

<1%

AF, VF

KCNJ8*

Kir6.1 (inward-rectifier K+channel, subunit of the ATP-sensitive K+ channel)

<1%

VF, SIDS, Cantu syndrome

ABCC9*       

SUR2 (sulfonylurea receptor, subunit of the ATP-sensitive K+ channel)

<1%          

DCM, ERS, Cantu syndrome and related disorders

KCNH2*

KV11.1/hERG (α-subunit of the voltage-dependent K+ channel)                        

<1%          

LQTS, SQTS

CACNA2D1*

α2/δ subunit of the volatge-dependent L-type Ca2+channel

<1%

Epilepsy

HCN4*

hyperpolarization-activated, cyclic nucleotide-gated ion channel 4

<1%

SSS, AF, AV block, Bradycardia, Tachycardia, NCC

TRPM4*

Transient receptor potential melastatin 4

<1%

Herat Block, LQTS

 

Auxillary Proteins 

FGF12

fibroblast growth factor 12

<1%

Epilepsy

GPD1L* 

glycerol-3-phosphate dehydrogenase 1-like 

<1% 

 

SLMAP 

sarcolemma associated protein (striatin-interacting phosphatase and kinase complex) 

<1% 

 

PKP2*

plakophillin-2

<1%

ARVC

SEMA3A

semaphorin-3A 

<1% 

 

RANGRF*

MOG1 (multicopy suppressor of Gsp1)

<1%

histiocytoid cardiomyopathy

HEY2

CHF1 (cardiovascular helix-loop-helix factor 1) 

<1% 

 

Long QT Syndrome (LQTS)

 

Ion Channel Subunits

 

 

KCNQ1*

KV7.1 (α-subunit of the voltage-dependent K+ channel)

⋍40% (LQT1)

JLNS, SQTS

KCNH2*

KV11.1/hERG (α-subunit of the voltage-dependent K+channel)

⋍30% (LQT2)

SQTS

SCN5A*

NaV1.5 (α-subunit of the voltage-dependent Na+ channel)

⋍10% (LQT3)

BrS, DCM, ARVC, Heart block, SSS, SIDS

KCNE1*

minK (β1-subunit of the voltage-dependent K+ channel)

<1%

JLNS

KCNE2*

MiRP1 (β2-subunit of the voltage-dependent K+ channel) 

<1% 

 

KCNJ2*

Kir2.1 (inward rectifying K+ channel)

<1% ( LQT7)

Andersen-Tawil syndrome, SQTS, AF

KCNJ5*

Kir3.4 (G protein-activated inward rectifying K+ channel 4)

<1%

LQTS, Hyperaldosteronism

SCN1B*

β1-subunit of the voltage-dependent Na+ channel

<1%

BrS, CCD, Epilepsy

SCN4B*

β4-subunit of the voltage-dependent Na+ channel

<1%

AF

CACNA1C*

CaV1.2 (α1C-subunit of the voltage-dependent L-type Ca2+ channel)

<1% ( LQT8)

BrS, Timothy syndrome

 

Auxillary Proteins

AKAP9*

A-kinase anchor protein-9 

<1% 

 

ANK2*

ankyrin B

<1%

Arrhythmia

CALM1*

calmodulin (CaM)

<1%

CVPT

CALM2*

calmodulin (CaM)

<1%

CVPT

CALM3*

calmodulin (CaM)

<1%

CVPT

SNTA1*

α1-syntrophin 

<1% 

 

TRDN*

triadin

<1%

CVPT

CAV3*

caveolin-3

<1%

HCM, LGMD, Rippling muscle disease, Tateyama-type distal myopathy, SIDS

TRPM4*

Transient receptor potential melastatin 4                                                              

<1%

Herat Block, BrS

RYR2*

ryanodine receptor 2 (RyR2)

<1%

ARVC, CPVT

Short QT Syndrome (SQTS)

 

Ion Channel Subunits 

KCNH2*

KV11.1/hERG (α-subunit of the voltage-dependent K+ channel)

⋍15% (SQT1)

LQTS

KCNQ1*

KV7.1 (α-subunit of the voltage-dependent K+channel)

<1%

JLNS, LQTS

KCNJ2*

Kir2.1 (inward rectifying K+ channel)

<1%

Andersen-Tawil syndrome, AF

CACNA1C*

CaV1.2 (α1C-subunit of the voltage-dependent L-type Ca2+ channel)

<1%

 

BrS, Timothy syndrome

 

CACNB2b*

β2-subunit of the voltage-dependent L-type Ca2+channel

<1%

 

BrS

 

CACNA2D1*

α2/δ-subunit of the voltage-dependent L-type Ca2+ channel

<1%

BrS, Epilepsy

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

RYR2*

ryanodine receptor 2 (RyR2)

⋍50–60% (CPVT1)

ARVC

CASQ2*

calsequestrin 2 

⋍5% 

 

TRDN*

triadin

<1%

LQTS

CALM1*

calmodulin (CaM)

<1%

LQTS

CALM2*

calmodulin (CaM)

<1%

LQTS

CALM3*

calmodulin (CaM)

<1%

LQTS

TECLR

trans-2,3-enoyl-CoA reductase- like 

<1% 

 

* - commercially available test

Abbreviations: AFAtrial fibrillation; ARVC- Arrhythmogenic right ventricular cardiomyopathy; AV Atrioventricular; BrS Brugada syndrome; CCD Cardiac conduction defect; CHD Congenital heart defects; CPVT Catecholaminergic polymorphic ventricular tachycardia; DCM Dilated cardiomyopathy; EMD Emery Dreifuss muscular dystrophy; ERS Early repolarization syndrome; HCM Hypertrophic cardiomyopathy; HCC - histiocytoid cardiomyopathy; JLNS Jervell and Lange-Nielsen syndrome; LGMD Limb girdle muscular dystrophy; LQTS Long QT syndrome; SIDS Sudden infant death syndrome; SQTS Short QT syndrome; SSS Sick sinus syndrome; SUDS Sudden unexpected death syndrome; VF Ventricular fibrillation

* - commercially available test

Abbreviations: AF – Atrial fibrillation; ARVC- Arrhythmogenic right ventricular cardiomyopathy; AV – Atrioventricular; BrS – Brugada syndrome; CCD – Cardiac conduction defect; CHD – Congenital heart defects; CPVT –Catecholaminergic polymorphic ventricular tachycardia; DCM – Dilated cardiomyopathy; EMD – Emery Dreifuss muscular dystrophy; ERS –Early repolarization syndrome; HCM – Hypertrophic cardiomyopathy; HCC - histiocytoid cardiomyopathy; JLNS – Jervell and Lange-Nielsen syndrome; LGMD – Limb girdle muscular dystrophy; LQTS – Long QT syndrome; SIDS – Sudden infant death syndrome; SQTS – Short QT syndrome; SSS – Sick sinus syndrome; SUDS – Sudden unexpected death syndrome; VF – Ventricular fibrillation 

Analytical Validity
Ware et al (2013) "compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and "hot spots" in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs.

Proost et al (2017) validated a targeted gene panel for next-generation sequencing of 51 genes associated with primary electrical disease with 20 Human Polymorphism Study Center samples and 19 positive control samples, with a total of 1479 variants. "An analytical sensitivity and specificity of 100% and 99.9% were obtained". After validation, the assay was applied to "114 PED patients which identified 107 variants in 36 different genes, 18 of which were classified as pathogenic or likely pathogenic, 54 variants were of unknown significance, and 35 were classified as likely benign". They concluded "that the PED Multiplex Amplification of Specific Targets for Resequencing Plus assay is a proficient and highly reliable test to routinely screen patients experiencing primary arrhythmias."

Clinical Validity and Utility
Hofman et al (2013) analyzed the yield of DNA testing over 15 years. They analyzed results from 7021 individuals who were counseled, 6944 from 2298 different families (aged 41±19 years; 49% male). In 702 families (31%), a possible disease-causing mutation was detected. The yield of DNA testing of probands with primary electric diseases was 47% in LQTS, 26% in BrS, and 37% in CPVT. Cascade screening revealed 1539 mutation-positive subjects, and in 372 families counseled after sudden unexplained death an inherited arrhythmia syndrome was diagnosed in 29% (n=108).

Le Scouarnec (2015) et al examined 167 index cases presenting with a Brugada pattern on the electrocardiogram as well as 167 individuals aged over 65-year old and showing no history of cardiac arrhythmia. They found that "a significant enrichment in rare coding variation (with a minor allele frequency below 0.1%) was observed only for SCN5A, with rare coding variants carried by 20.4% of cases with BrS versus 2.4% of control individuals (P = 1.4 × 10(-7)). No significant enrichment was observed for any other arrhythmia-susceptibility gene, including SCN10A and CACNA1C. These results indicate that, except for SCN5A, rarecoding variation in previously reported arrhythmia-susceptibility genes do not contribute significantly to the occurrence of BrS in a population with European ancestry. Extreme caution should thus be taken when interpreting genetic variation in molecular diagnostic setting, since rarecoding variants were observed in a similar extent among cases versus controls, for most previously reported BrS-susceptibility genes."  

Tester et al (2012) examined 173 cases of SUD that were referred for cardiac channel molecular autopsy. Overall, 45 putative pathogenic mutations absent in 400 to 700 controls were identified in 45 autopsy-negative SUD cases (26.0%).

As "Conventional cardiac evaluations may not accurately determine an individual’s true, underlying diagnosis." Garcia et al (2016) "developed simple, systematic approaches to three fundamental challenges: (1) evaluating the strength of the evidence suggesting that a particular condition is caused by pathogenic variants in a particular gene, (2) evaluating whether unusual genotype/phenotype observations represent a plausible expansion of clinical phenotype associated with a gene, and (3) establishing a molecular diagnostic strategy to capture overlapping clinical presentations. These approaches focus on the systematic evaluation of the pathogenicity of variants identified in clinically affected individuals, and the natural history of disease in those individuals. Here, we applied these approaches to the evaluation of more than 100 genes reported to be associated with inherited cardiomyopathies and arrhythmias" They "propose that a comprehensive panel test designed for the molecular diagnosis of a particular condition should include the following classes of genes:

  • Genes that have been conclusively proven to cause the condition in question.
  • Genes suspected but not yet proven to cause the condition in question.
  • Genes that have been conclusively proven to cause a condition within the clinical differential. This category should include genes that cause a condition that can progress into the condition in question, genes that cause a condition that can be confused with the condition in question, and genes that cause a syndrome that include the condition in question as a primary feature.

They suggest that the clinical validity of a panel is established when that panel includes a set of genes that account for a substantial proportion of the genetic causes of the disease in question. Conversely, a panel is NOT valid if it omits certain genes that account for a substantial proportion of the known genetic risk. A clinically valid panel may also include genes for which some preliminary evidence of clinical validity exists ("preliminary evidence genes").

Cirino et al (2017) reviewed the current literature on the role of genetic testing in cardiovascular disease and concluded that "By distinguishing phenotypic subgroups, identifying disease mechanisms, and focusing family care, gene-based diagnosis can improve management" and provided detailed of how in

Seidelmann et al (2017) evaluated the use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD. They found that "Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases."

Munroe et al (2018) examined tissue from 242 stillbirths (≥22 weeks), including those where no definite cause of death could be confirmed after a full autopsy. We obtained high-quality DNA from 70 cases, which were then sequenced for a custom panel of 35 genes. They found 1 putative pathogenic and several novel variants of uncertain significance variant resulting in cardiac channelopathies was identified in some cases of otherwise unexplained stillbirth, and these variants may have a role in fetal demise. 

Regulatory Status
This test is considered a laboratory developed test (LDT); developed, validated and performed by individual laboratories.

LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).

As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.  

Policy

  1. Genetic counseling is considered MEDICALLY NECESSARY for individuals undergoing genetic testing for congenital cardiac ion channelopathies.
  2. Sequencing of LQTS-associated genes, is considered MEDICALLY NECESSARY for:
    • Symptomatic individuals, (defined as a syncopal event) with a Schwartz score > 1 OR
    • Asymptomatic individuals with a first-, second-, or third-degree relative with confirmed LQTS and in whom the familial mutation is not known
  3. Testing for a known familial mutation is considered MEDICALLY NECESSARY for first-, second-, and third-degree relatives of an individual with a documented LQTS-causing mutation, even silent carriers.
  4. Genetic testing for LQTS with duplication/deletion analysis is considered MEDICALLY NECESSARY if sequence analysis is negative, and the clinical suspicion of congenital LQTS remains high, based on a Schwartz score > 1.
  5. Genetic testing for LQTS is considered NOT  MEDICALLY NECESSARY for symptomatic individuals with a Schwartz score ≤1.
  6. Genetic testing for LQTS to determine prognosis and/or direct therapy in patients with known LQTS is considered INVESTIGATIONAL.
  7. Genetic testing for CPVT is considered MEDICALLY NECESSARY in the following situations
    • A close relative (i.e., 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; or
    • Signs and/or symptoms indicating a moderate-to-high pretest probability of CPVT, but a definitive diagnosis cannot be made without genetic testing.
    • Persons who display exercise-, catecholamine-, or emotion-induced PVT or ventricular fibrillation, occurring in a structurally normal heart
  8. Genetic testing for LQTS or CPVT is INVESTIGATIONAL for all other situations when the above criteria are not met.
  9. Genetic testing for Brugada syndrome is considered MEDICALLY NECESSARY in the following situations:
    • When signs and/or symptoms consistent with Brugada Syndrome are present, but a definitive diagnosis cannot be made without genetic testing.
    • Patients have a close relative (ie, first-, second-, or third-degree relative) with a known Brugada Syndrome mutation.
  10. Genetic testing for Brugada Syndrome for all other situations not meeting the criteria outlined above is INVESTIGATIONAL.
  11. Genetic testing for Short QT Syndrome is considered MEDICALLY NECESSARY in patients with a close relative (i.e., first-, second-, or third-degree relative) with known SQTS mutation.
  12. Genetic testing for SQTS for all other situations not meeting the criteria outlined above is considered INVESTIGATIONAL.
  13. Genetic testing for Early Repolarization "J-wave" Syndrome is considered INVESTIGATIONAL.  

Rationale
American Heart Association, American College of Cardiology, and the Heart Rhythm Society
In 2017 the American Heart Association (AHA), the American College of Cardiology (ACC), and the Heart Rhythm Society (HRS) published the Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death which recommends:

  • Genetic Considerations in Arrhythmia Syndromes
    • In patients and family members in whom genetic testing for risk stratification for SCA or SCD is recommended, genetic counseling is beneficial. (I)
      • The diagnosis of most inherited arrhythmia syndromes is based on clinical features and family history. The availability of genetic testing for inherited arrhythmia syndromes can: 1) provide opportunity to confirm a suspected clinical diagnosis and sometimes provide prognostic information for the proband and 2) offer cascade screening of potentially affected family members when a disease-causing mutation is identified in the proband. The yield of genetic testing varies by disease.
      • Genotyping is frequently most useful when a pathogenic mutation is identified in the proband, such that screening can be applied to relatives who are in a preclinical phase, allowing institution of lifestyle changes, therapy, or ongoing monitoring for those who are gene mutation positive
      • In young patients (<40 years of age) without structural heart disease who have unexplained cardiac arrest, unexplained near drowning, or recurrent exertional syncope, genetic testing may be important to identify an inherited arrhythmia syndrome as a likely cause
  • Cardiac Channelopathies
    • 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)
      • Clinical screening of first-degree relatives of patients with inherited arrhythmia syndromes is crucial to identifying affected family members. Due to the increased risk of adverse cardiac events in genotype positive patients with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome, targeted screening for the identified family-specific mutation can identify individuals who are at risk for these adverse outcomes
  • Congenital Long QT Syndrome
    • In patients with clinically diagnosed long QT syndrome, genetic counseling and genetic testing are recommended (I)
      • Genetic testing for disease-causing mutations in long QT syndrome offers important diagnostic, prognostic, and therapeutic information in addition to the clinical evaluation, and a positive test can facilitate establishing risk for family members. The yield of genetic testing in long QT syndrome phenotype-positive patients is 50% to 86%, with the higher range present in patients with marked QT prolongation or positive family history of SCD. A negative genetic test does not exclude the diagnosis of long QT syndrome, which relies on the clinical evaluation.
  • Catecholaminergic Polymorphic Ventricular Tachycardia
    • In patients with catecholaminergic polymorphic ventricular tachycardia and with clinical VT or exertional syncope, genetic counseling and genetic testing are reasonable (IIa) 
      • Genetic testing may be useful to confirm the diagnosis of catecholaminergic polymorphic ventricular tachycardia, which is suggested by the development of bidirectional VT with exertion or stress. Recognition of catecholaminergic polymorphic ventricular tachycardia as the cause for exertional symptoms should prompt aggressive therapy to prevent the significant risk of SCD. Therapy for catecholaminergic polymorphic ventricular tachycardia is not guided by genotype status, but screening of first-degree relatives may be facilitated with genetic testing.
  • Brugada Syndrome
    • In patients with suspected or established Brugada syndrome, genetic counseling and genetic testing may be useful to facilitate cascade screening of relatives (IIb) 
      • The yield of genetic testing in phenotype positive patients is approximately 20% to 30% in Brugada syndrome. SCN5A variants account for most of this subset of genotype positive Brugada syndrome. However, 2% to 10% of otherwise healthy individuals host a rare variant of SCN5A. A negative genetic test does not exclude the diagnosis of Brugada syndrome, which is usually based on electrocardiographic and clinical characteristics. Risk stratification is based on symptoms and clinical findings; genotype status is not correlated with the risk of adverse events. Identification of a pathogenetic mutation may help facilitate recognition of carrier status in family members, allowing for lifestyle modification and potential treatment.
  • Short QT syndrome
    • In patients with short QT syndrome, genetic testing may be considered to facilitate screening of first-degree relatives (IIb)
      • Pathogenic mutations in potassium channels have been identified in approximately 10% to 20% of patients with short QT syndrome.
  • Early Repolarization "J-wave" Syndrome
    • In patients with early repolarization pattern on ECG, genetic testing is not recommended (III-no benefit)
  • Postmortem Evaluation of SCD
    • In first-degree relatives of SCD victims who were 40 years of age or younger, cardiac evaluation is recommended, with genetic counseling and genetic testing performed as indicated by clinical findings (I)
    • In victims of SCD with an autopsy that implicates a potentially heritable cardiomyopathy or absence of structural disease, suggesting a potential cardiac channelopathy, postmortem genetic testing is reasonable (IIa)  
      • For the purpose of family risk profiling, it is important to use the disease-specific genetic test panel that corresponds to the autopsy findings. Risk profiling of family members of an SCD victim suspected of having an inherited cardiomyopathy at autopsy is important. Although phenotyping of surviving family members is crucial, genotyping of the SCD proband provides a mechanism for efficient follow-up evaluation of those relatives with the disease-causing mutation found in the proband.

American College of Medical Genetics and Genomics (ACMG)
The American College of Medical Genetics and Genomics (ACMG) included the three main LQTS-associated genes in their "minimum" list of genes for which mutations should be reported when whole genome sequencing is performed for other primary purposes (incidental findings). ACMG recommends that only mutations known to be deleterious or expected to be deleterious should be reported(Green et al., 2013).

References 

  1. Bastiaenen, R., & Behr, E. R. (2011). Sudden death and ion channel disease: pathophysiology and implications for management. Heart, 97(17), 1365-1372. doi:10.1136/hrt.2011.223883
  2. Bezzina, C. R., Lahrouchi, N., & Priori, S. G. (2015). Genetics of Sudden Cardiac Death. doi:10.1161/CIRCRESAHA.116.304030
  3. Campuzano, O., Sarquella-Brugada, G., Brugada, R., & Brugada, J. (2015). Genetics of channelopathies associated with sudden cardiac death. Glob Cardiol Sci Pract, 2015(3), 39. doi:10.5339/gcsp.2015.39
  4. Cirino, A. L., Harris, S., Lakdawala, N. K., Michels, M., Olivotto, I., Day, S. M., . . . Ho, C. Y. (2017). Role of Genetic Testing in Inherited Cardiovascular Disease: A Review. JAMA Cardiol, 2(10), 1153-1160. doi:10.1001/jamacardio.2017.2352
  5. Fernandez-Falgueras, A., Sarquella-Brugada, G., Brugada, J., Brugada, R., & Campuzano, O. (2017). Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances. Biology (Basel), 6(1). doi:10.3390/biology6010007
  6. Garcia, J., Tahiliani, J., Johnson, N. M., Aguilar, S., Beltran, D., Daly, A., . . . Topper, S. (2016). Clinical Genetic Testing for the Cardiomyopathies and Arrhythmias: A Systematic Framework for Establishing Clinical Validity and Addressing Genotypic and Phenotypic Heterogeneity. Front Cardiovasc Med, 3, 20. doi:10.3389/fcvm.2016.00020
  7. Garcia-Elias, A., & Benito, B. (2018). Ion Channel Disorders and Sudden Cardiac Death. International Journal of Molecular Sciences, 19(3), 692. doi:10.3390/ijms19030692
  8. Giudicessi, J. R., & Ackerman, M. J. (2013). Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Transl Res, 161(1), 1-14. doi:10.1016/j.trsl.2012.08.005
  9. Green, R. C., Berg, J. S., Grody, W. W., Kalia, S. S., Korf, B. R., Martin, C. L., . . . Biesecker, L. G. (2013). ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med, 15(7), 565-574. doi:10.1038/gim.2013.73
  10. Hofman, N., Tan, H. L., Alders, M., Kolder, I., de Haij, S., Mannens, M. M., . . . Wilde, A. A. (2013). Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years' experience. Circulation, 128(14), 1513-1521. doi:10.1161/circulationaha.112.000091
  11. Kirk, J. A., & Kass, D. A. (2015). Cellular and Molecular Aspects of Dyssynchrony and Resynchronization. Card Electrophysiol Clin, 7(4), 585-597. doi:10.1016/j.ccep.2015.08.011
  12. Le Scouarnec, S., Karakachoff, M., Gourraud, J. B., Lindenbaum, P., Bonnaud, S., Portero, V., . . . Redon, R. (2015). Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome. Hum Mol Genet, 24(10), 2757-2763. doi:10.1093/hmg/ddv036
  13. Magi, S., Lariccia, V., Maiolino, M., Amoroso, S., & Gratteri, S. (2017). Sudden cardiac death: focus on the genetics of channelopathies and cardiomyopathies. J Biomed Sci, 24. doi:10.1186/s12929-017-0364-6   
  14. Martin, C. A., Huang, C. L., & Matthews, G. D. (2013). The role of ion channelopathies in sudden cardiac death: implications for clinical practice. Ann Med, 45(4), 364-374. doi:10.3109/07853890.2013.783994
  15. Munroe, P. B., Addison, S., Abrams, D. J., Sebire, N. J., Cartwright, J., Donaldson, I., . . . Thayyil, S. (2018). Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths. doi:10.1161/CIRCGEN.117.001817
  16. Nerbonne, J. M., & Kass, R. S. (2005). Molecular physiology of cardiac repolarization. Physiol Rev, 85(4), 1205-1253. doi:10.1152/physrev.00002.2005
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  18. Proost, D., Saenen, J., Vandeweyer, G., Rotthier, A., Alaerts, M., Van Craenenbroeck, E. M., . . . Van Laer, L. (2017). Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. J Mol Diagn, 19(3), 445-459. doi:10.1016/j.jmoldx.2017.01.010
  19. Roden, D. M., Balser, J. R., George, A. L., Jr., & Anderson, M. E. (2002). Cardiac ion channels. Annu Rev Physiol, 64, 431-475. doi:10.1146/annurev.physiol.64.083101.145105
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Coding Section

Code 

 Number

 Descpriton

CPT 

81401

Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant (typically using nonsequencing target variant analysis), or detection of a dynamic mutation disorder/triplet repeat) 

 

81403

Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons)

 

81404

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)

 

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis)

 

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication /deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia

 

81407

Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication /deletion variants of >50 exons, sequence analysis of multiple genes on one platform

 

81408

 

Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis)

         

81413    

Cardiac ion channelopathies (eg, Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); genomic sequence analysis panel, must include sequencing of at least 10 genes, including ANK2, CASQ2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, RYR2, and SCN5A

 

81414

Cardiac ion channelopathies (eg, Brugada syndrome, long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia); duplication/deletion gene analysis panel, must include analysis of at least 2 genes, including KCNH2 and KCNQ1

 

81439

Hereditary cardiomyopathy (e.g., hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy), genomic sequence analysis panel, must include sequencing of at least 5 cardiomyopathy-related genes (eg, DSG2, MYBPC3, MYH7, PKP2, TTN)

 

81479

Unlisted molecular pathology procedure

 

96040

Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family

 

S0265

Genetic counseling, under physician supervision, each 15 minute

 

S3861

 

Genetic testing, sodium channel, voltage-gated, type V, alpha subunit (SCN5A) and variants for suspected brugada syndrome

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/24/2018 

Annual review, reformatting policy. Adding language regarding genetic counseling and adding J wave testing as investigational. 

07/19/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references.

04/20/2017 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

1/9/2017 

Udating coding with new code 81539. 

11/08/2016 

Updating Coding section with 2017 new codes . 

04/27/2016 

Annual review, updating policy to contain medical necessity criteria for Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. Updating background, description, guidelines, rationale and references. 

04/22/2015 

Annual review, policy verbiage updated to include: Genetic testing for LQTS or CPVT is  INVESTIGATIONAL for all other situations when the above criteria are not met. Updated background, description, guidelines,rationale and references. Added regulatory status and coding. 

04/03/2014

 Annual review. Updated background, description, rationale and references. Added guidelines. Policy title being changed to Genetic Testing for Cardiac Ion Channelopathies. Added the following verbiage in the policy language: Genetic testing for CPVT may be considered medically necessary for patients who do not meet the clinical criteria for CPVT but who have:

  • 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; or
  • signs and/or symptoms indicating a moderate-to-high pretest probability of CPVT.

 Genetic testing for Brugada syndrome is considered INVESTIGATIONAL.

 Genetic testing for short QT syndrome is considered INVESTIGATIONAL.   


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