Proprietary Testing (Channelopathies)

Proprietary gene panels exist for the assessment of cardiac ion channelopathies. For example, GeneDX offers several customizable panels for various channelopathies and cardiomyopathies. Conditions such as ARVC, Brugada Syndrome, and CPVT are available as separate panels, and GeneDX offers combined panels such as a “Custom Arrhythmia Panel”, a “Custom Cardiomyopathy Panel”, and a “Combined Cardiac Panel” (GeneDX, 2024). Other commercially available panels include offerings from Invitae (Invitae, 2024), Fulgent, (Fulgent, 2024) and BluePrint Genetics (BluePrint, 2024).

Analytical Validity (Channelopathies)

Ware et al. (2013) compared two NGS approaches for diagnostic sequencing inherited arrhythmia syndromes. PCR-based target enrichment and long-read sequencing (PCR-LR) was compared to in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long QT genes (KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2) 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 was identical. In both assays, the major limitation was upstream target capture, particularly in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89% sensitivity at a fraction of current costs (Ware et al., 2013).

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” (Proost et al., 2017).

Clinical Utility and Validity (Channelopathies)

Garcia et al. (2016) proposed a framework for establishing clinical validity for assessing polymorphisms of inherited cardiac conditions, as well as evaluating the strength of association between genotype and phenotype, from a logical argument. Clinical validity of a gene is established when a gene is known to cause disease; since a specific variant must be responsible for causing the disease, a gene variant must be known to cause that disease. Conversely, if no variants can be established to cause disease, the clinical validity association has not been established. Variants of unknown significance (VUS) would, therefore, not have established clinical validity. Garcia et al. (2016) proposed three categories of strength of association: strong, suggested, and emerging.

• “Strong” refers to “cases where there exists at least one clinically observed variant supported by sufficient evidence to classify that variant as pathogenic. “Strong” indicates that the relationship has been proven.”
• “Suggested” is used in cases where some preliminary evidence exists suggesting a causal relationship, but the relationship has not yet been formally proven.”
• “Emerging” is used to describe a growing suspicion that a specific condition is caused by a gene that has already been proven to cause disease.

The authors go on to state that if one “strong” relationship exists, then clinical validity has been established. If not, the gene should be considered of “uncertain significance” (Garcia et al., 2016).

The authors also provide recommendations for gene panels to test for certain conditions. 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”) (Garcia et al., 2016).

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) (Hofman et al., 2013).

Le Scouarnec et al. (2015) et al. examined 167 index cases presenting with a Brugada pattern on the electrocardiogram as well as 167 individuals aged over 65-years 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. No significant enrichment was observed for any other arrhythmia-susceptibility gene, including SCN10A and CACNA1C. These results indicate that, except for SCN5A, rare coding 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 rare coding variants were observed in a similar extent among cases versus controls, for most previously reported BrS-susceptibility genes” (Le Scouarnec et al., 2015).

Tester et al. (2012) examined 173 cases of sudden unexplained death that were referred for cardiac channel molecular autopsy. The mutational analysis included the long QT syndrome genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) and a catecholaminergic polymorphic ventricular tachycardia (CPVT) type 1–associated gene (RYR2). Overall, 45 putative pathogenic mutations absent in 400 to 700 controls were identified in 45 autopsy-negative SUD cases (26.0%) (Tester et al., 2012).

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 with a success rate of 26.5% (53/200 patients). This compares to 18% (36/200) that would have been diagnosed using commercially available genetic panels; although, this finding was not statistically significant. The authors concluded, “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” (Seidelmann et al., 2017).

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. Seventy cases were examined, which were then sequenced for a custom panel of 35 genes. One putative pathogenic variant was found, and several novel variants of uncertain significance resulting in cardiac channelopathies was identified in some cases of otherwise unexplained stillbirth. The authors concluded “these variants may have a role in fetal demise” (Munroe et al., 2018).

Wang et al. (2017) examined the “genetic spectrum” of LVNC. The authors sequenced 73 cardiomyopathy-related genes in 102 patients, and 43 pathogenic variants were identified in 16 genes in 39 patients. Sarcomeric variants accounted for 63% of these variants whereas variants associated with channelopathies accounted for 12%. MYH7 and TAZ pathogenic variants were the most common, and patients with pathogenic variants showed more severe symptoms such as earlier age of onset (Wang et al., 2017).

van Lint et al. (2019) evaluated the detection rates for variants of unknown (class 3), likely (class 4), and certain (class 5) pathogenicity in cardiogenetic gene panels. The study included 936 patients that were evaluated with the arrhythmia panels (four versions), and 1970 patients were evaluated with the cardiomyopathy panels (six versions). The arrhythmia panels detected class 3 variants in 34.8% of patients, class 4 variants in 4.2% of patients, and class 5 variants in 4.6% of patients. The cardiomyopathy panels detected class 3 variants in 40.8% of patients, class 4 variants in 7.9% of patients, and class 5 variants in 12% of patients. Overall, the arrhythmia panels detected variants of interest in 44% of patients, and the cardiomyopathy panels detected variants of interest in 61% of patients. The authors concluded that “larger gene panels can increase the detection rate of likely pathogenic and pathogenic variants, but mainly increase the frequency of variants of unknown pathogenicity” (van Lint et al., 2019).

Guidelines and Recommendations

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

In 2017 (Al-Khatib Sana et al., 2018) 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 that recommends the following:

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.

Arrhythmogenic Right Ventricular Cardiomyopathy

• “Selected first-degree relatives refers to relatives who are willing to undergo further testing and who could benefit from further screening and testing (and not the terminally ill patients or those who do not want to be screened and tested).”
• “Arrhythmogenic right ventricular cardiomyopathy is detected clinically in approximately 35% to 40% of first-degree relatives, most commonly in siblings or symptomatic first-degree relatives”
• “The proband with arrhythmogenic right ventricular cardiomyopathy is usually diagnosed by the presence of clinical symptoms along with the presence of arrhythmogenic right ventricular cardiomyopathy Task Force criteria”
• “A pathogenic genetic mutation was added to the major Task Force criteria in 2010. The yield of genetic testing in probands with suspected arrhythmogenic right ventricular cardiomyopathy is generally 30% to 54% and is up to 58% among patients with a strong family history of SCD in multiple members. A negative genetic test for arrhythmogenic right ventricular cardiomyopathy does not exclude the disease, and a positive genetic test currently does not guide therapy.”

Hypertrophic Cardiomyopathy

• “In first-degree relatives of patients with HCM due to a known causative mutation, genetic counseling and mutation-specific genetic testing are recommended.”
• “In patients with clinically suspected or diagnosed HCM, genetic counseling and genetic testing are reasonable.”
• “When genetic testing reveals a mutation in the index patient, ascertainment of genetic status in first- and second-degree relatives can be predictive of risk for developing HCM. Relatives with overt HCM will have the same pathogenic HCM mutation as the index patient.”

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 (CPVT)

• 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, including in KCNH2 (SQT1), KCNQ1 (SQT2), and KCNJ2 (SQT3).

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)
• For 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 (Al-Khatib Sana et al., 2018).

American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) Guideline for the Management of Heart Failure

These 2022 guidelines provide guidelines on genetic evaluation and testing for the management of heart failure. The relevant recommendations are captured below:

• “In first-degree relatives of selected patients with genetic or inherited cardiomyopathies, genetic screening and counseling are recommended to detect cardiac disease and prompt consideration of treatments to decrease HF progression and sudden death.”
• “In select patients with nonischemic cardiomyopathy, referral for genetic counseling and testing is reasonable to identify conditions that could guide treatment for patients and family members.”

These joint recommendations also urge that “In patients in whom a genetic or inherited cardiomyopathy is suspected, a family history should be performed, including at least 3 generations and ideally diagrammed as a family tree pedigree” (Heidenreich et al., 2022).

American College of Cardiology Foundation (ACCF)/American College of Cardiology (ACC) and American Heart Association (AHA)

In 2020, the AHA released a joint guideline with the ACC for the diagnosis and treatment of patients with hypertrophic cardiomyopathy (Ommen et al., 2020). This guideline replaced the 2011 guideline released jointly by the ACCF and the AHA. The updated 2020 guideline has also been endorsed by the Heart Rhythm Society (HRS). With relation to genetic testing, they released the following with a level B-NR quality of evidence, signifying “moderate-quality evidence from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies; meta-analyses of such studies”:

Class 1 (Benefit >>> Risk)

• “In patients with HCM, evaluation of familial inheritance, including a 3-generation family history, is recommended as part of the initial assessment 
• In patients with HCM, genetic testing is beneficial to elucidate the genetic basis to facilitate the identification of family members at risk for developing HCM (cascade testing) 
• In patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause, a work-up including genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy (“HCM phenocopies”) is recommended 
• In patients with HCM who choose to undergo genetic testing, pre- and post-test genetic counseling by an expert in the genetics of cardiovascular disease is recommended so that risks, benefits, results, and their clinical significance can be reviewed and discussed with the patient in a shared decision-making process 
• When performing genetic testing in an HCM proband, the initial tier of genes tested should include genes with strong evidence to be disease-causing in HCM* 
• In first-degree relatives of patients with HCM, both clinical screening (ECG and 2D echocardiogram) and cascade genetic testing (when a pathogenic/likely pathogenic variant has been identified in the proband) should be offered 
• In families where a sudden unexplained death has occurred with a postmortem diagnosis of HCM, postmortem genetic testing is beneficial to facilitate cascade genetic testing and clinical screening in first-degree relatives
• In patients with HCM who have undergone genetic testing, serial reevaluation of the variant(s) identified is recommended to assess for variant reclassification, which may impact diagnosis and cascade genetic testing in family members
• In affected families with HCM, preconception and pre-natal reproductive and genetic counseling should be offered”
• NOTE: “Strong evidence HCM genes include, at the time of this publication, MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1”

Class 2b (Benefit ≥ Risk)

• “In patients with HCM, the usefulness of genetic testing in the assessment of risk of SCD [sudden cardiac death] is uncertain
• In patients with HCM who harbor a variant of uncertain significance, the usefulness of clinical genetic testing of phenotype-negative relatives for the purpose of variant reclassification is uncertain”

No benefit

• “For patients with HCM who have undergone genetic testing and were found to have no pathogenic variants (i.e., harbor only benign/likely benign variants), cascade genetic testing of the family is not useful
• Ongoing clinical screening is not indicated in genotype-negative relatives in families with genotype-positive HCM, unless the disease-causing variant is downgraded to variant of uncertain significance, likely benign, or benign variant during follow-up” (Ommen et al., 2020).

The ACCF and AHA also published a joint guideline, regarding the “Management of Heart Failure”, which states that “Increasingly, it is recognized that many (20% to 35%) patients with an idiopathic DCM have a familial cardiomyopathy (defined as 2 closely related family members who meet the criteria for idiopathic DCM).” “Advances in technology permitting high-throughput sequencing and genotyping at reduced costs have brought genetic screening to the clinical arena” and refers to the 2009 and 2011 published guidelines. The guidelines further note that genetic testing may be considered in conjunction with counseling in familial DCM (Yancy et al., 2013).

American Heart Association (AHA)

The AHA published a guideline regarding cardiomyopathy in children. In it, they state that “genetic testing should first be performed in the individual known to have a specific cardiomyopathy phenotype and should be informed by the child’s overall presentation, with a detailed examination looking for dysmorphic features, muscle weakness, scoliosis, or specific laboratory findings.” They also state that indications for genetic testing include “determining the cause of HCM, predicting the clinical course and severity, screening first-degree relatives, and determining recurrence risk.”

This guideline addresses HCM, DCM, RCM, LVNC, Arrhythmogenic Ventricular Cardiomyopathy (both right and left ventricles), as well as cardiomyopathy caused by channelopathies such as Long-QT syndrome (Lipshultz et al., 2019). However, though it addresses the many manifestations of cardiomyopathy, few suggestions for clinical practice are made due to “the lack of evidence and consensus in the classification and diagnosis of children with cardiomyopathy,” such that the document takes the form of a scientific statement instead of clinical guidelines.

In a 2023 scientific statement regarding cardiomyopathy in children, the AHA goes on to state that when “cardiomyopathy is identified in a child without a known preexisting risk, panel genetic testing or whole exome sequencing is recommended. A pathogenic or likely pathogenic variant in the proband should prompt cascade genetic testing of first-degree relatives who are at risk for cardiomyopathy” (Bogle et al., 2023).

The AHA also published a guideline discussing early repolarization. In it, they remark that the biological basis for early repolarization pattern “remains incompletely understood.” Therefore, the AHA proposes “large-scale, unbiased (e.g., genome-wide association studies), family-guided genetic discovery approaches, as well as efforts aimed at understanding both the mechanisms underlying ER and the associated arrhythmogenesis” (Patton et al., 2016).

In a 2020 statement from the AHA titled “Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement from the American Heart Association”, the AHA pointed towards a 2018 conjoint guideline by the HFSA with the ACMG for guidance for genetic testing of cardiomyopathies. The pertinent recommendations were extracted and are presented below:

“A family history of at least 3 generations should be obtained for all patients with a primary cardiomyopathy. Second, clinical screening for cardiomyopathy is recommended for at-risk first-degree relatives. Third, patients with genetic, familial, or other unexplained forms of cardiomyopathy should be referred to expert centers. Genetic counseling is recommended for all patients with cardiomyopathy and their family members.

In a family, testing should be directed to the most clearly affected family member. If that individual is found to have a gene variant that is judged to be pathogenic or likely pathogenic, then cascade genetic testing for that variant should be offered to at-risk family members. For infants with cardiomyopathy, in addition to any routine newborn screening tests that might have been performed, the specialized evaluation is likely to include genetic testing and should also include an evaluation for syndromic or metabolic conditions for which a specific intervention or therapy might be warranted” (Musunuru et al., 2020).

Finally, the guideline notes that the management of certain conditions may benefit or otherwise be influenced by the results of genetic testing. Long-QT syndrome, HCM, DCM, and RCM are listed as having variants that may be specifically targeted with certain treatments (Musunuru et al., 2020).

Heart Failure Society of American and American College of Medical Genetics and Genomics (ACMG)

In 2018, the Heart Failure Society of America and the American College of Medical Genetics and Genomics published a clinical practice resource for the genetic evaluation of cardiomyopathy. There,

“Recommendation 1. Genetic testing is recommended for patients with cardiomyopathy

1. Genetic testing is recommended for the most clearly affected family member. 
2. Cascade genetic testing of at-risk family members is recommended for pathogenic and likely pathogenic variants.
3. In addition to routine newborn screening tests, specialized evaluation of infants with cardiomyopathy is recommended, and genetic testing should be considered.”

On the point of whom to test, the societies have the following to say:

“To yield the most conclusive, informative results, diagnostic genetic testing is optimally initiated on a confirmed affected individual. Furthermore, as there are sometimes multiple genetic variants contributing to disease in a single family, the testing should ideally be initiated on the person who is most likely to harbor the disease-causing variant or variants. This is frequently the individual in the family with the most severe disease and/or the earliest disease onset. This is a well established principle in clinical genetics, as selecting the individual with the most evident disease increases the likelihood of finding a genetic cause. If the ideal person for initiation of genetic testing in a family is unavailable or unwilling to proceed, then comprehensive genetic testing should be considered for another unequivocally affected family member.”

As for when to test, ACMG “recommend[s] genetic testing at the time a new cardiomyopathy diagnosis is made, but it can be conducted at any time following diagnosis. Education and counseling regarding genetic testing options are a key component of the process. For those who have had genetic testing in the past, retesting may be appropriate if the previous testing produced negative or inconclusive results and the test’s detection rate has improved. This latter point is particularly relevant for DCM as the gene panels have rapidly expanded (e.g., TTN and others) and are anticipated to continue” (Hershberger et al., 2018). A chart of selected genes implicated in various cardiomyopathies is included below.

Table 1 Selected genes in association with cardiomyopathy

^aCore gene lists represent genes with the highest diagnostic yield and/or strongest evidence of the gene in association with the listed phenotype; the genes listed are not exhaustive and should be considered illustrative for the type of cardiomyopathy. Considerable overlap of genes between cardiomyopathy phenotypes is well established. Genes known to cause metabolic disease or genetic syndromes are often included in testing panels, but vary depending on the clinical laboratory. Gene lists therefore need to be reviewed carefully before ordering testing. Metabolic and genetic syndrome columns provide examples only and are not intended to be comprehensive

^bOnly TTN truncating variants are thought relevant for cardiomyopathy HCM hypertrophic cardiomyopathy, DCM dilated cardiomyopathy. ARVC arrhythmogenic right ventricular cardiomyopathy, RCM restrictive cardiomyopathy, LVNC left ventricular noncompaction, ACMG American College of Medical Genetics and Genomics

Table 1 above appropriated from (Hershberger et al., 2018)

The specific cardiomyopathy comments are as follows:

HCM

• “Beyond sarcomeric genes, core genes to screen in patients with HCM include GLA, PRKAG2, and LAMP2.”
• “Consultation with a geneticist is indicated.”

DCM

• “Core genes to be tested in individuals with DCM include genes encoding sarcomeric and cytoskeletal proteins.”
• “Genetic testing is important in mothers of individuals with Duchenne or Becker to determine carrier status because carrier females may develop DCM in the third to fifth decade of life.”

LVNC

• “Genetic testing is not recommended when the LVNC phenotype is identified serendipitously in asymptomatic individuals with otherwise normal cardiovascular structure and function.” 

As such, these genes may form an important backdrop upon which the following is performed:

“Recommendation 2. Focused cardiovascular phenotyping is recommended when pathogenic or likely pathogenic variants in cardiomyopathy genes, designated for reporting of secondary findings by the ACMG, are identified in an individual.

1. If a cardiovascular phenotype is identified as would be predicted by currently available knowledge of the gene/ variant pair, all usual approaches described in this document for a genetic evaluation, including family-based approaches, are recommended.
2. If no cardiovascular disease phenotype is identified in the individual, recommendations for surveillance screening at intervals should be considered.
3. If no cardiovascular phenotype is identified in the individual, cascade evaluation of at-risk relatives may be considered, tempered by the strength of evidence supporting the pathogenicity of the variant, the usual age of onset of the gene/variant pair, and pedigree information (e.g., the ages of at-risk family members, other previously known cardiovascular clinical data in the pedigree, and related information)” (Hershberger et al., 2018).

American College of Medical Genetics and Genomics (ACMG)

In 2023 version 3.2, ACMG referenced several myopathies and channelopathies in their “minimum” list of genes for which mutations should be reported when whole genome sequencing is performed for other primary purposes (incidental findings). Those genes are listed below:

• FBN1, TGFBR1, TGFBR2, SMAD3, ACTA2, MYH11 for aortopathies
• PKP2, DSP, DSC2, TMEM43, and DSG2 for ARVC
• RYR2, CASQ2, and TRDN for Catecholaminergic polymorphic ventricular tachycardia (CPVT)
• TNNT2, LMNA, FLNC, TTN, BAG3, DES, RBM20, and TNNC1 for DCM
• COL3A1 for Ehlers-Danlos syndrome, vascular type 
• LDLR, APOB, and PCSK9 for Familial hypercholesterolemia 
• MYH7, MYBP3, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, and MYL2 for HCM
• KCNQ1 and KCNH2 for Long QT syndrome types 1 and 2
• SCN5A for Long QT syndrome 3; Brugada syndrome 
• CALM1, CALM2, CALM3 for Long QT syndrome types 14-16 (Miller et al., 2023)

In an erratum published in 2021, the authors appended a series of new gene-phenotype pairings, each associated with the cardiovascular phenotype “Risk of sudden death with preventive interventions available”: CASQ2/catecholaminergic polymorphic ventricular tachycardia (CPVT), TRDN/catecholaminergic polymorphic ventricular tachycardia (CPVT) & long QT syndrome, FLNC/cardiomyopathy, and TTN/cardiomyopathy (Miller et al., 2021).

The Heart Rhythm Society (HRS)/The European Heart Rhythm Association (EHRA) Expert Consensus Statement

Hypertrophic Cardiomyopathy (HCM)

Class I recommendations (is recommended):

• “Comprehensive or targeted (MYBPC3, MYH7, TNNI3, TNNT2, TPM1) HCM genetic testing is recommended for any patient in whom a cardiologist has established a clinical diagnosis of HCM based on examination of the patient's clinical history, family history, and electrocardiographic/echocardiographic phenotype.”
• “Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the HCM-causative mutation in an index case.”

Dilated Cardiomyopathy (DCM)

Class I recommendations:

• “Comprehensive or targeted (LMNA and SCN5A) DCM genetic testing is recommended for patients with DCM and significant cardiac conduction disease (i.e., first-, second-, or third- degree heart block) and/or with a family history of premature unexpected sudden death.”
• “Mutation-specific testing is recommended for family members and appropriate relatives following the identification of a DCM-causative mutation in the index case.”

Class IIa (can be useful) recommendations:

• Genetic testing can be useful for patients with familial DCM to confirm the diagnosis, to recognize those who are highest risk of arrhythmia and syndromic features, to facilitate cascade screening within the family, and to help with family planning.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Class I recommendations:

• “Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the ACM/ARVC- causative mutation in an index case.”

Class II recommendations:

• “Comprehensive or targeted (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43) ACM/ARVC genetic testing can be useful for patients satisfying task force diagnostic criteria for ACM/ARVC.” (II-A, can be useful)
• “Genetic testing may be considered for patients with possible ACM/ARVC (1 major or 2 minor criteria) according to the 2010 task force criteria (European Heart Journal).” (II-B, may be considered)

Left Ventricular Noncompaction (LVNC)

Class I recommendations:

• “Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of a LVNC-causative mutation in the index case.”

Class IIa recommendations:

• LVNC genetic testing can be useful for patients in whom a cardiologist has established a clinical diagnosis of LVNC based on examination of the patient's clinical history, family history, and electrocardiographic/echocardiographic phenotype. (II-A)

Restrictive Cardiomyopathy (RCM)

Class I recommendations:

• “Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of a RCM-causative mutation in the index case.”

Class IIb (may be considered) recommendations:

• “RCM genetic testing may be considered for patients in whom a cardiologist has established a clinical index of suspicion for RCM based on examination of the patient's clinical history, family history, and electrocardiographic/echocardiographic phenotype.”

Long-QT Syndrome

Class I recommendations:

• “Comprehensive or LQT1-3 (KCNQ1, KCNH2, and 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, and 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., i.e., 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.”

Class IIb recommendations:

• “Comprehensive or LQT1-3 (KCNQ1, KCNH2, and 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.”

Catecholaminergic polymorphic ventricular tachycardia (CPVT)

Class I recommendations:

• Comprehensive or CPVT1 and CVPT2 (RYR2 and 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.

Brugada Syndrome

Class I recommendations:

• Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the BrS-causative mutation in an index case.

Class IIa recommendations:

• 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

Genetic testing is not indicated in the setting of an isolated type 2 or type 3 Brugada ECG pattern.

Short QT syndrome

Class I recommendations:

• Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the SQTS-causative mutation in an index case.

Class IIb recommendations:

• Comprehensive or SQT1-3 (KCNH2, KCNQ1, and 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.

Sinus Node Dysfunction (SND)

• “In idiopathic sinus node dysfunction (SND), mutations in the cardiac pacemaker channel gene HCN4 and in sodium channel genes can be identified in an unknown portion. However, because non-genetic causes appear more frequently in idiopathic SND, genetic testing for idiopathic SND should be considered on an individual basis”.

Progressive Cardiac Conduction Disease (CCD)

• “Genetic testing may be considered as part of the diagnostic evaluation for patients with either isolated CCD or CCD with concomitant congenital heart disease, especially when there is documentation of a positive family history of CCD.”
• “Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the CCD-causative mutation in an index case.”
• “Taken together, tiered genetic testing for patients with CCD and congenital heart disease or cardiomyopathies is useful because other cardiac and non-cardiac disease features may be present or may develop; individual genes should be considered after discussion of clinical features with an experienced cardiogenetic center”.

Post-Mortem Genetic Testing in Sudden Unexpected Death Cases

• “In the setting of autopsy-negative SUDS, comprehensive or targeted (RYR2, KCNQ1, KCNH2, and SCN5A) ion channel genetic testing may be considered in an attempt to establish probable cause and manner of death and to facilitate the identification of potentially at-risk relatives and is recommended if circumstantial evidence points toward a clinical diagnosis of LQTS or CPVT specifically (such as emotional stress, acoustic trigger, drowning as the trigger of death).”
• “Mutation-specific genetic testing is recommended for family members and other appropriate relatives following the identification of a SUDS-causative mutation in the decedent” (Ackerman et al., 2011; M.J. Ackerman et al., 2011).

Heart Rhythm Society (HRS), European Heart Rhythm Association (EHRA), and Asia Pacific Heart Rhythm Society (APHRS)

In an international consensus statement released by the HRS, EHRA, and APHRS, the three medical societies provide expert recommendations for diagnosing “inherited primary arrhythmia syndromes.” The pertinent guidelines are listed below:

• “Expert Consensus Recommendations on LQTS Diagnosis
  1. LQTS is diagnosed:
     1. In the presence of an LQTS risk score ≥3.5 in the absence of a secondary cause for QT prolongation and/or
     2. In the presence of an unequivocally pathogenic mutation in one of the LQTS genes or 
     3. In the presence of a QT interval corrected for heart rate using Bazett’s formula (QTc) ≥500 ms in repeated 12-lead electrocardiogram (ECG) and in the absence of a secondary cause for QT prolongation.
  2. LQTS can be diagnosed in the presence of a QTc between 480-499 ms in repeated 12-lead ECGs in a patient with unexplained syncope in the absence of a secondary cause for QT prolongation and in the absence of a pathogenic mutation.”
• “Expert Consensus Recommendations on Brugada Syndrome Diagnosis
  1. BrS is diagnosed in patients with ST-segment elevation with type 1 morphology ≥2 mm in ≥1 lead among the right precordial leads V1, V2, positioned in the 2nd, 3rd or 4th intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of Class I antiarrhythmic drugs.
  2. BRS is diagnosed in patients with type 2 or type 3 ST-segment elevation in ≥1 lead among the right precordial leads V1, V2 positioned in the 2nd, 3rd or 4th intercostal space when a provocative test with intravenous administration of Class I antiarrhythmic drugs induces a type I ECG morphology.”
• “Expert Consensus Recommendations on [Catecholaminergic Polymorphic Ventricular Tachycardia] Diagnosis
  1. CPVT is diagnosed in the presence of a structurally normal heart, normal ECG, and unexplained exercise or catecholamine-induced bidirectional VT or polymorphic ventricular premature beats or VT in an individual < 40 years of age.
  2. CPVT is diagnosed in patients (index case or family member) who have a pathogenic mutation.
  3. CPVT is diagnosed in family members of a CPVT index case with a normal heart who manifest exercise-induced premature ventricular contractions (PVCs) or bidirectional/ polymorphic VT.
  4. CPVT can be diagnosed in the presence of a structurally normal heart and coronary arteries, normal ECG, and unexplained exercise or catecholamine-induced bidirectional VT or polymorphic ventricular premature beats or VT in an individual >40 years of age.”
• “Expert Consensus Recommendations on Short QT Syndrome Diagnosis
  1. SQTS is diagnosed in the presence of a QTc ≤330 ms.
  2. SQTS can be diagnosed in the presence of a QTc <360 ms and one or more of the following: a pathogenic mutation, family history of SQTS, family history of sudden death at age ≤40, survival of a VT/VF episode in the absence of heart disease.”
• “Expert Consensus Recommendations on Early Repolarization Diagnosis
  1. ER syndrome is diagnosed in the presence of J-point elevation ≥1mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG in a patient resuscitated from otherwise unexplained VF/polymorphic VT.
  2. ER syndrome can be diagnosed in an SCD victim with a negative autopsy and medical chart review with a previous ECG demonstrating J-point elevation ≥1mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG
  3. ER syndrome can be diagnosed in the presence of J-point elevation ≥1mm in ≥2 contiguous inferior and/or lateral leads of a standard 12-lead ECG.”
• “Expert Consensus Recommendations on Progressive Cardiac Conduction Disease Diagnosis
  1. Progressive cardiac conduction disease (PCCD) is diagnosed in the presence of unexplained progressive conduction abnormalities in young (<50 years) individuals with structurally normal hearts in the absence of skeletal myopathies, especially if there is a family history of PCCD.”
• “Unexplained Cardiac Arrest:
  1. Expert Consensus Recommendations on Idiopathic Ventricular Fibrillation (IVF) Diagnosis
     1. IVF is defined as a resuscitated cardiac arrest victim, preferably with documentation of VF, in whom known cardiac, respiratory, metabolic and toxicological etiologies have been excluded through clinical evaluation.
  2. Expert Consensus Recommendations on Idiopathic Ventricular Fibrillation Evaluation
     1. Class IIa - Genetic testing in IVF can be useful when there is a suspicion of a specific genetic disease following clinical evaluation of the IVF patient and/or family members.
     2. Class III - 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.
• “Unexplained Sudden Cardiac Death: Expert Consensus Recommendations on Sudden Unexplained Death Syndrome Evaluation
  1. Class I – Collection of blood and/or suitable tissue for molecular autopsy/postmortem genetic testing is recommended in all SUDS victims.
  2. Class IIa – An arrhythmia syndrome focused molecular autopsy/postmortem genetic testing can be useful for all SUDS victims” (Priori et al., 2013).

Heart Rhythm Society (HRS)

Arrhythmogenic Cardiomyopathies

The HRS published an “Expert Consensus Statement” on “Evaluation, Risk Stratification, and Management of Arrhythmogenic Cardiomyopathy.” In it, they include recommendations on genetic testing for this set of cardiac disorders.

“For individuals and decedents with either a clinical or necropsy diagnosis of ACM, genetic testing of the established ACM-susceptibility genes is recommended.”

“For genetic testing of the established ACM-susceptibility genes, comprehensive analysis of all established genes with full coverage is recommended.”

“When a likely pathogenic or pathogenic genetic variant has been identified in the proband, cascade genetic testing can be offered to first-degree at-risk relatives… Cascade genetic testing is therefore only offered to family members where a likely pathogenic or pathogenic variant in a known disease-associated gene is identified in the proband…” (Towbin et al., 2019).

Canadian Cardiovascular Society/Canadian Heart Rhythm Society

Long QT Syndrome

Genetic testing is recommended in the cardiac arrest survivor with LQTS for the primary purpose of screening first-degree relatives, in the patient with syncope and QTc prolongation that is attributed to LQTS, and in the asymptomatic patient with consistent QTc prolongation that is clinically suspected to represent LQTS.

Brugada Syndrome

Genetic testing in the cardiac arrest survivor, patient with syncope, or asymptomatic patient with a persistent or provocable type 1 Brugada ECG pattern is recommended for the primary purpose of screening of family members. However, patients with types 2 or 3 Brugada ECG patterns are not recommended for genetic testing.

CPVT

Genetic testing is recommended for the primary purpose of screening family members (Gollob et al., 2011).

European Society of Cardiology (ECS)

Genetic counselling is recommended for all HCM patients when the HCM is not explained solely by a non-genetic cause.

Genetic testing is recommended for patients fulfilling the diagnostic criteria for HCM, both as a confirmatory test and to enable genetic testing for relatives. Both cascade genetic screening and a clinical evaluation are recommended for first-degree relatives that carry the same mutation as the HCM patient (“proband”). Even if a mutation is absent, relatives should consider reassessment should symptoms appear or other clinical data emerges. A genetic analysis, such as pedigree analysis and high-throughput sequencing, should include the most implicated sarcomere protein genes. If a rarer condition is suspected, the analysis should include the gene responsible for that condition.

Pre-natal genetic testing is not recommended due to phenotypic variability (Elliott et al., 2014).

In 2023, the ESC released clinical practice guidelines delineating the management of cardiomyopathies. The pertinent recommendations from this update are listed below:

• “Recommendations for diagnostic work-up in cardiomyopathies:
  • It is recommended that all patients with suspected or established cardiomyopathy undergo systematic evaluation using a multiparametric approach that includes clinical evaluation, pedigree analysis, ECG, Holter monitoring, laboratory tests, and multimodality imaging (Class I recommendation, evidence level C)
  • It is recommended that all patients with suspected cardiomyopathy undergo evaluation of family history and that a three- to four-generation family tree is created to aid in diagnosis, provide clues to underlying aetiology, determine inheritance pattern, and identify at-risk relatives (Class I recommendation, evidence level C)”
• “Recommendations for genetic counselling and testing in cardiomyopathies
  • Genetic counselling, provided by an appropriately trained healthcare professional and including genetic education to inform decision-making and psychosocial support, is recommended for families with an inherited or suspected inherited cardiomyopathy, regardless of whether genetic testing is being considered (Class I recommendation, evidence level B)
  • It is recommended that genetic testing for cardiomyopathy is performed with access to a multidisciplinary team, including those with expertise in genetic testing methodology, sequence variant interpretation, and clinical application of genetic testing, typically in a specialized cardiomyopathy service or in a network model with access to equivalent expertise (Class I recommendation, evidence level B)
  • Pre- and post-test genetic counselling is recommended in all individuals undergoing genetic testing for cardiomyopathy (Class I recommendation, evidence level B)
  • If pre-natal diagnostic testing is to be pursued by the family, it is recommended that this is performed early in pregnancy, to allow decisions regarding continuation or co-ordination of pregnancy to be made (Class I recommendation, evidence level C)
  • For index patients:
    • Genetic testing is recommended in patients fulfilling diagnostic criteria for cardiomyopathy in cases where it enables diagnosis, prognostication, therapeutic stratification, or reproductive management of the patient, or where it enables cascade genetic evaluation of their relatives who would otherwise be enrolled into long-term surveillance (Class I recommendation, evidence level B)
    • Genetic testing is recommended for a deceased individual identified to have cardiomyopathy at post-mortem if a genetic diagnosis would facilitate management of surviving relatives (Class I recommendation, evidence level C)
    • Genetic testing may be considered in patients fulfilling diagnostic criteria for cardiomyopathy when it will have a net benefit to the patient, considering the psychological impact and preference, even if it does not enable diagnosis, prognostication, or therapeutic stratification, or cascade genetic screening of their relatives (Class IIb recommendation, evidence level C)
    • Genetic testing in patients with a borderline phenotype not fulfilling diagnostic criteria for a cardiomyopathy may be considered only after detailed assessment by specialist teams (Class IIb recommendation, evidence level C
  • For family members:
    • It is recommended that cascade genetic testing, with pre- and post-test counselling, is offered to adult at-risk relatives if a confident genetic diagnosis (i.e. a P/LP variant) has been established in an individual with cardiomyopathy in the family (starting with first-degree relatives if available, and cascading out sequentially) (Class I recommendation, evidence level B)
    • Cascade genetic testing with pre- and post-test counselling should be considered in paediatric at-risk relatives if a confident genetic diagnosis (i.e. a P/LP variant) has been established in an individual with cardiomyopathy in the family (starting with first-degree relatives, if available, and cascading out sequentially), considering the underlying cardiomyopathy, expected age of onset, presentation in the family, and clinical/legal consequences (Class IIa recommendation, evidence level B)
    • Testing for the presence of a familial variant of unknown significance, typically in parents and/or affected relatives, to determine if the variant segregates with the cardiomyopathy phenotype should be considered if this might allow the variant to be interpreted with confidence (Class IIa recommendation, evidence level C)
    • Diagnostic genetic testing is not recommended in a phenotype-negative relative of a patient with cardiomyopathy in the absence of a confident genetic diagnosis (i.e. a P/LP variant) in the family (Class III recommendation, evidence level C)” (Arbelo et al., 2023).

State and Federal Regulations, as applicable

Food and Drug Administration (FDA)

Many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (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. 

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81401, 81403, 81404, 81405, 81406, 81407, 81408, 81413, 81414, 81439, 81479, S3861, S3865, S3866, 0237U

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

For policy titled: Genetic Testing for Cardiac Ion Channelopathies:

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

Bezzina, C. R., Lahrouchi, N., & Priori, S. G. (2015). Genetics of Sudden Cardiac Death. doi:10.1161/CIRCRESAHA.116.304030

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

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

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

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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 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

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Nerbonne, J. M., & Kass, R. S. (2005). Molecular physiology of cardiac repolarization. Physiol Rev, 85(4), 1205-1253. doi:10.1152/physrev.00002.2005

Priori, S. G., silvia.priori@fsm.it, Maugeri Foundation IRCCS, P., Italy, Department of Molecular Medicine, University of Pavia, Pavia, Italy and New York University, New York, New York, Wilde, A. A., Department of Cardiology, A. M. C., Amsterdam, Netherlands, Princess AlJawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia, Horie, M., George Washington University Medical Center, W., DC, United States. (2013). HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes. Heart Rhythm, 10(12), 1932-1963. doi:10.1016/j.hrthm.2013.05.014

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

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 Schwartz, P. J., Stramba-Badiale, M., Crotti, L., Pedrazzini, M., Besana, A., Bosi, G., Spazzolini, C. (2009). Prevalence of the congenital long-QT syndrome. Circulation, 120(18), 1761-1767. doi:10.1161/circulationaha.109.863209

Seidelmann, S. B., Smith, E., Subrahmanyan, L., Dykas, D., Abou Ziki, M. D., Azari, B., Mani, A. (2017). Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. Circ Cardiovasc Genet, 10(1). doi:10.1161/circgenetics.116.001573

Spoonamore, K. G., & Johnson, N. M. (2016). Who Pays? Coverage Challenges for Cardiovascular Genetic Testing in U.S. Patients. Front Cardiovasc Med, 3. doi:10.3389/fcvm.2016.00014

Tester, D. J., & Ackerman, M. J. (2011). Genetic Testing for Potentially Lethal, Highly Treatable Inherited Cardiomyopathies/Channelopathies in Clinical Practice. Circulation, 123(9), 1021- 1037. doi:10.1161/circulationaha.109.914838

Tester, D. J., Medeiros-Domingo, A., Will, M. L., Haglund, C. M., & Ackerman, M. J. (2012). Cardiac Channel Molecular Autopsy: Insights From 173 Consecutive Cases of Autopsy-Negative Sudden Unexplained Death Referred for Postmortem Genetic Testing. In Mayo Clin Proc (Vol. 87, pp. 524-539).

Voorhees, A. P., & Han, H. C. (2015). Biomechanics of Cardiac Function. Compr Physiol, 5(4), 1623-1644. doi:10.1002/cphy.c140070

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For policy titled: Genetic Testing for Inherited Cardiomyopathies and Channelopathies:

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Specialty Matched Consultant Advisory Panel review 4/2020

Medical Director review 4/2020

Specialty Matched Consultant Advisory Panel review 4/2021

Medical Director review 4/2021

Medical Director review 11/2022

Medical Director review 4/2023

Medical Director review 1/2025

Policy Implementation/Update Information

For policy titled: Genetic Testing for Cardiac Ion Channelopathies:

1/1/2019 BCBSNC will provide coverage for genetic testing for cardiac ion channelopathies when it is determined to be medically necessary because criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)

For policy titled: Genetic Testing for Inherited Cardiomyopathies and Channelopathies:

10/1/2019 Reviewed by Avalon 2nd Quarter 2019 CAB. Policy extensively revised to include description and guidelines for cardiomyopathies. Policy statement revised to include “cardiomyopathies” and as follows: to the When Covered section added items #8-14; When Not Covered section added 2 additional “not medically necessary” statements and 1 “investigational” statement regarding HCM; Added the following to the 2nd to last statement regarding Genetic testing for Early Repolarization “J-wave” Syndrome, Sinus Node Dysfunction (SND) and/or other rhythm disorders is considered investigational. Related Policies added to Description section. References updated. Medical Director review 9/2019. (jd)

10/29/19 Wording in the Policy, When Covered, and/or Not Covered section(s) changed from Medical Necessity to Reimbursement language, where needed. (hb)

4/28/20 Specialty Matched Consultant Advisory Panel review 4/2020. Medical Director review 4/2020. (jd)

7/28/20 Reviewed by Avalon 2nd Quarter 2020 CAB. Policy guidelines and references updated. The following codes were added to the Billing/Coding section: S3865, S3866. Medical Director review 7/2020. (jd)

7/1/21 Reviewed by Avalon 1st Quarter 2021 CAB. Added the following to the When Covered section - item 5, a and b: “Patients have a” for clarity. Added CPT code 0237U to Billing/Coding section for PPA effective 7/1/21. Specialty Matched Consultant Advisory Panel review 4/2021. Medical Director review 4/2021. (jd)

5/17/22 Reviewed by Avalon 1st Quarter 2022 CAB. to the following revisions were made to the When Covered section, under item 2, wrote out “long QT syndrome (LQTS) for clarity along with item 7, wrote out “short QT syndrome”. Added items 14 and 17. Policy guidelines and references updated; added Table of Terminology. Medical Director review 4/2022. (jd)

12/13/22 Off-cycle review by Avalon 3rd Quarter 2022 CAB. Related Policies, Policy Guidelines and References updated. When Covered and When Not Covered sections edited for clarity and consistency, no change to policy statement. Coverage criteria 16 removed due to redundancy with coverage criteria 14. These coverage criteria previously read: "14. Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) is considered medically necessary for patients who meet the diagnostic criteria for HCM in order to facilitate cascade screening of first-degree relatives. 16. Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) is considered medically necessary for individuals who meet the diagnostic criteria for HCM to assist treatment decisions or to facilitate cascade screening of their first-degree relatives." Coverage criteria 14 now reads "For patients who meet the diagnostic criteria for hypertrophic cardiomyopathy (HCM), genetic testing for predisposition to HCM is considered medically necessary." Added new Note 1 to define closer relatives: Note 1: Close blood relatives include 1st-degree relatives (e.g., parents, siblings, and children), 2nd-degree relatives (e.g., grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings), and 3rd-degree relatives (great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins)." Medical Director review 11/2022. (tm)

5/16/23 Reviewed by Avalon 1st Quarter 2023 CAB. Related Policies section removed. Minor edits to When Covered section for clarity, no change in policy statement. Policy Guidelines and References updated. Medical Director review 4/2023. (tm)

12/31/24 Annual policy review. No updates from lab benefit manager, no change to policy statement. (tm)

4/1/25 Reviewed by Avalon 4^th Quarter 2024 CAB. Description, Policy Guidelines and References updated. Related Policy section added, Table of Terminology removed. Updates to When Covered section: Reimbursement language regarding genetic counseling removed from criteria 1, criteria 2a edited and now reads “For individuals who have had a syncopal event and who have a Schwartz score greater than 1.” Added new coverage criteria 2b and 2c, 2b “For individuals for whom a cardiologist has a strong clinical suspicion of LQTS based on the individual’s clinical history, family history, and electrocardiogram (ECG) findings (e.g., Schwartz score greater than or equal to 3.5).” 2c “For individuals with QT prolongation (QTc greater than 480 ms for prepubescent individuals, QTc greater than 500 ms for postpubescent individuals) in the absence of other clinical conditions that might prolong the QT interval (e.g., electrolyte abnormalities, hypertrophy, bundle branch block).” Removed “asymptomatic” from former criteria 2b and is now criteria 2d. Criteria 4 edited to remove “>1” and changed to “greater than 1” for clarity. Criteria 7 edited to include genetic testing indications for SQTS affected individuals, now reads “Sequencing of short QT syndrome (SQTS)-associated genes is considered medically necessary for the following: a. For individuals for whom a cardiologist has a strong clinical suspicion of SQTS based on the individual’s clinical history, family history, and ECG findings (e.g., abnormally short QT intervals [less than or equal to 360 ms in males; less than or equal to 370 ms in females], an increased propensity to develop atrial and ventricular tachyarrhythmia in the absence of structural heart disease). b. Testing for the known familial likely pathogenic or pathogenic variant in asymptomatic individuals with a close relative (see Note 1) with a known SQTS likely pathogenic or pathogenic variant.” Criteria 3, 5a, 6b, 7b, 9, 10b, 11, 12, 13b, 15, and 16, changed “mutations” to “likely pathogenic or pathogenic variant”. Coverage criteria 14 changed “patients” to “individuals” for clarity. Updates to Not Covered section: criteria 1 changed “mutations” to “likely pathogenic or pathogenic variant”. Coverage criteria 1, 3 and 8 changed “patients” to “individuals” for clarity. Changed “1^st-degree”, “2^nd-degree”, and “3^rd-degree” to “first-degree”, “second-degree”, and “third-degree” in Note 1. Removed CPT code 96040, S0265 from Billing/Coding section. Medical Director review 1/2025. (tm)