BlueCross and BlueShield of Montana Medical Policy/Codes
Genetic Testing for Cardiac Disorders
Chapter: Genetic Testing
Current Effective Date: February 01, 2014
Original Effective Date: November 07, 2008
Publish Date: January 15, 2014
Revised Dates: March 1, 2010; March 16, 2011; April 17, 2012; August 20, 2012; September 24, 2013; January 14, 2014
Description

Arrhythmogenic Disorders

Long QT syndrome (LQTS) is caused by a mutation in one of the genes that controls cellular sodium and potassium ion channels. Testing for this mutation may assist in the diagnosis of LQTS and/or may identify patients at risk for LQTS when there is a family member diagnosed with the disorder.

Congenital long QT syndrome is an inherited disorder characterized by the lengthening of the repolarization phase of the ventricular action potential, increasing the risk for arrhythmic events, such as torsades de pointes, which may in turn result in syncope and sudden cardiac death. Management has focused on the use of beta blockers as first-line treatment, with pacemakers or implantable cardiac defibrillators (ICD) as second-line therapy.

Congenital LQTS usually manifests before the age of 40 years and may be suspected when there is a history of seizure, syncope, or sudden death in a child or young adult; this history may prompt additional testing in family members. It is estimated that more than one half of the 8,000 sudden unexpected deaths in children may be related to LQTS. The mortality rate of untreated patients with LQTS is estimated at 1–2% per year, although this figure will vary with the genotype, discussed further here. (1) Frequently, syncope or sudden death occurs during physical exertion or emotional excitement, and thus LQTS has received publicity regarding evaluation of adolescents for participation in sports. In addition, LQTS may be considered when a long QT interval is incidentally observed on an electrocardiogram (EKG). Diagnostic criteria for LQTS have been established, which focus on EKG findings and clinical and family history (i.e., Schwartz criteria, see following section, “Clinical Diagnosis”). (2) However, measurement of the QT interval is not well-standardized, and in some instances, patients may be considered borderline cases. (3)

In recent years, LQTS has been characterized as an “ion channel disease,” with abnormalities in the sodium and potassium channels that control the excitability of the cardiac myocytes. A genetic basis for LQTS has also emerged, with 7 different subtypes recognized, each corresponding to mutations in different genes as indicated here. (4) In addition, typical ST-T wave patterns are also suggestive of specific subtypes. (5)

Clinical Diagnosis

The Schwartz criteria are commonly used as a diagnostic scoring system for LQTS. (2) The most recent version of this scoring system is shown Table 1. A score of 4 or greater indicates a high probability that LQTS is present; a score of 2–3, a moderate-to-high probability; and a score of 1 or less indicates a low probability of the disorder. Prior to the availability of genetic testing, it was not possible to test the sensitivity and specificity of this scoring system; and since there is still no perfect gold standard for diagnosing LQTS, the accuracy of this scoring system remains ill-defined.

Table 1. Diagnostic Scoring System for LQTS (Adapted from reference 3)

Diagnostic Scoring System for LQTS 

Criteria

Points

Electrocardiographic findings:

---

 

Corrected QT (QTc) >480 millisecond (msec) 

3

 

QTc 460-470 msec 

2

 

QTc <450 msec 

1

History of torsades de pointes 

2

T-wave alternans 

1

Notched T-waves in three leads 

1

Low heart rate for age 

0.5

Clinical history:

---

 

Syncope brought on by stress 

2

 

Syncope without stress 

1

 

Congenital deafness 

0.5

Family history:

---

 

Family members with definite LQTS 

1

 

Unexplained sudden death in immediate family members younger than 30 years of age 

0.5

Genetic Testing

For example, if a family member has been diagnosed with LQTS based on clinical characteristics, complete analysis of all LQTS-associated genes can be performed to both identify the specific mutation and identify the subtype of LQTS. If a mutation is identified, then additional family members can undergo targeted genetic analysis for the identified mutation.

There are more than 1,200 unique mutations on at least 13 genes that have been associated with LQTS. The pathophysiologic significance of each of the discrete mutations is an important part of the interpretation of genetic analysis. Laboratories that test for LQTS keep a database of known pathologic mutations; however, these are mainly proprietary and may vary among different laboratories. The probability that a specific mutation is pathophysiologically significant is greatly increased if the same mutation has been reported in other cases of known LQTS. In other cases, a mutation may be found that has not definitely been associated with LQTS and therefore may or may not be pathologic. Variants are classified as to their pathologic potential; an example of such a classification system is as follows:

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

In addition to single mutations, some cases of LQTS are associated with deletions or duplications of genes. (6) This may be the case in up to 5% of total cases of LQTS. These types of mutations may not be identified by gene sequence analysis. They can be more reliably identified by chromosomal microarray analysis (CMA), also known as array comparative genomic hybridization (aCGH). Some laboratories that test for LQTS are now offering detection of LQTS-associated deletions and duplications by this testing method. This type of test may be offered as a separate test and may need to be ordered independently of gene sequence analysis when testing for LQTS.

The absence of a mutation does not imply the absence of LQTS; it is estimated that mutations are only identified in 70-75% of patients with a clinical diagnosis of LQTS. (7) A negative test is only definitive when there is a known mutation identified in a family member and targeted testing for this mutation is negative. Other laboratories have investigated different testing strategies. For example, Napolitano and colleagues propose a 3-tiered approach, first testing for a core group of 64 codons that have a high incidence of mutations, followed by additional testing of less frequent mutations. (8)

Another factor complicating interpretation of the genetic analysis is the penetrance of a given mutation or the presence of multiple phenotypic expressions. For example, approximately 50% of carriers of mutations never have any symptoms. There is variable penetrance for the LQTS, and penetrance may differ for the various subtypes. While linkage studies in the past indicated that penetrance was 90% or greater, more recent analysis by molecular genetics has challenged this number, (9) and suggested that penetrance may be as low as 25% for some families.

Cardiomyopathy

Background

Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular condition, with a phenotypic prevalence of approximately 1 in 500 adults (0.2%). (33) It is the most common cause of sudden cardiac death (SCD) in adults younger than 35 years of age and is probably also the most the most common cause of death in young athletes. (34) The overall death rate for patients with HCM is estimated to be 1% per year in the adult population. (35-36)

The genetic basis for HCM is a defect in the cardiac sarcomere, which is the basic contractile unit of cardiac myocytes composed of a number of different protein structures. (37) Nearly 1,400 individual mutations in at least 18 different genes have been identified to date. (38-40) Approximately 90% of pathogenic mutations are missense (i.e., one amino acid is replaced for another), and the strongest evidence for pathogenicity is available for 11 genes coding for thick filament proteins (MYH7, MYL2, MYL3), thin filament proteins (TNNT2, TNNI3, TNNC1, TPM1, ACTC), intermediate filament proteins (MYBPC3), and the Z-disc adjoining the sarcomere (ACTN2, MYOZ2). Mutations in myosin heavy chain (MYH7) and myosin binding protein C (MYBPC3) are the most common and account for roughly 80% of sarcomeric HCM. These genetic defects are inherited in an autosomal dominant pattern with rare exceptions. (37) In patients with clinically documented HCM, genetic abnormalities can be identified in approximately 60%. (39, 41) Most patients with clinically documented disease are demonstrated to have a familial pattern, although some exceptions are found presumably due to de novo mutations. (41)

The clinical diagnosis of HCM depends on the presence of left ventricular hypertrophy (LVH), measured by echocardiography or magnetic resonance imaging (MRI), in the absence of other known causative factors such as valvular disease, long-standing hypertension, or other myocardial disease. (39) In addition to primary cardiac disorders, there are systemic diseases that can lead to LVH and thus “mimic” HCM. These include infiltrative diseases such as amyloidosis, glycogen storage diseases such as Fabry disease and Pompe disease, and neuromuscular disorders such as Noonan’s syndrome and Friederich’s ataxia. (41) These disorders need to be excluded before a diagnosis of familial HCM is made.

HCM is a very heterogenous disorder. Manifestations range from subclinical, asymptomatic disease to severe life-threatening disease. Wide phenotypic variability exists among individuals, even when an identical mutation is present, including among affected family members. (34) This variability in clinical expression may be related to environmental factors and modifier genes. (42) A large percentage of patients with HCM, perhaps the majority of all HCM patients, are asymptomatic or have minimal symptoms. (41-42)  These patients do not require treatment and are not generally at high risk for SCD. A subset of patients has severe disease that causes a major impact on quality of life and life expectancy. Severe disease can lead to disabling symptoms, as well as complications of HCM, including heart failure and malignant ventricular arrhythmias.

Diagnostic screening of first-degree relatives and other family members is an important component of HCM management. Guidelines have been established for clinically unaffected relatives of affected individuals. Screening with physical examination, electrocardiography, and echocardiography is recommended every 12-18 months for individuals between the ages of 12 to 18 years and every 3 to 5 years for adults. (42) Additional screening is recommended for any change in symptoms that might indicate the development of HCM. (42)

Genetic testing has been proposed as a component of screening at-risk individuals to determine predisposition to HCM among those patients at risk. Patients at risk for HCM are defined as individuals who have a close family member with established HCM. Results of genetic testing may influence management of at-risk individuals, which may in turn lead to improved outcomes. Furthermore, results of genetic testing may have implications for decision making in the areas of reproduction, employment, and leisure activities.

Regulatory Status

There are no assay kits approved by the U.S. Food and Drug Administration (FDA) for genetic testing for HCM, nor are any kits being actively manufactured and marketed for distribution. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing. While the FDA has technical authority to regulate home-brew tests, there is currently no active oversight nor any known plans to begin oversight. Home-brew tests may be developed using reagents prepared in-house or, if available, commercially manufactured analyte-specific reagents (ASRs). ASRs are single reagents “intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens” and must meet certain FDA criteria but are not subject to premarket review.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Arrhythmogenic Disorders

Genetic testing in patients with suspected congenital long QT syndrome (LQTS) may be considered medically necessary for individuals who do not meet the clinical criteria for LQTS, but who have:

  • First- or second- or third-degree relative* with a known LQTS mutation; or
  • First- or second- or third-degree relative* diagnosed with LQTS by clinical means whose genetic status is unavailable; or
  • Signs or symptoms indicating a moderate-to-high pretest probability** of LQTS.

*  NOTE:  

  • First-degree relative:  Any relative who is one meiosis away from a particular individual in a family; a relative with whom one-half of an individual’s genes are shared, a 50% genetic link to the patient (i.e., parent, sibling, offspring).
  • Second-degree relative:  Any relative who is two meioses away from a particular individual in a family; a relative with whom one-quarter of an individual's genes are shared, a 25% genetic link to the patient (i.e., grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling).
  • Third-degree relative:  Any relative who is three meioses away from a particular individual in a family; a relative with whom one-eighth of an individual’s genes are shared, a 12.5% genetic link to the patient (i.e., great-grandparent, great-grandchild, great-uncle, great-aunt, grand-nephew, grand-niece, first cousin).

** NOTE:   Determining the pretest probability of LQTS is not standardized. An example of a patient with a moderate to high pretest probability of LQTS is a patient with a Schwartz score of 2-3. Refer to “Diagnostic Scoring System for LQTS” table in Description Section for scoring.

Genetic testing for LQTS to determine prognosis or to direct therapy in patients with known LQTS is considered experimental, investigational and/or unproven.

Cardiomyopathy

Genetic testing for predisposition to inherited hypertrophic cardiomyopathy (HCM) may be considered medically necessary for individuals who are at risk for development of HCM, defined as having a first-degree relative with established HCM, when there is a known pathogenic gene mutation present in that affected relative.

Genetic testing for predisposition to inherited hypertrophic cardiomyopathy (HCM) is considered not medically necessary for patients with a family history of HCM in which a first degree relative has tested negative for pathologic mutations.

Genetic testing for predisposition to inherited hypertrophic cardiomyopathy (HCM) is considered experimental, investigational and/or unproven for all other patient populations, including but not limited to:

  • Individuals who are at-risk for development of HCM, defined as having a first-degree relative*** with established HCM, when there is no known pathogenic gene mutation present in that affected relative. This includes:
    • Patients with a family history of HCM, with unknown genetic status of affected relative(s); and
    • Patients with a family history of HCM, when a pathogenic gene mutation has not been identified in affected relatives.

*** NOTE:   First-degree relative:  Any relative who is one meiosis away from a particular individual in a family; a relative with whom one-half of an individual’s genes are shared, a 50% genetic link to the patient (i.e., parent, sibling, offspring).

Other Conditions and Risks

All other genetic tests for any cardiac conditions or risks are considered experimental, investigational and/or unproven.

Policy Guidelines

Long QT Syndrome

Tier 1 CPT Codes:

81280 (full sequence analysis)

81281 (known familial Sequence variant)

81282 (duplication/deletion variants)

Tier 2 CPT Codes:

81403

  • KCNJ2 (potassium inwardly-rectifying channel, subfamily J, member 2)

81405

  • CASQ2 (calseqestrin 2 [cardiac muscle])

81406

  • KCNH2 (potassium voltage-gated channel, subfamily H [eag-related], member 1)
  • KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1)

81407

  • SCN5A (sodium channel, voltage-gated, type V, alpha subunit)

81408

  • RYR2 (ryanodine receptor 2 [cardiac])

HCPCS

S3861 Genetic testing, sodium channel, voltage-gated, type V, alpha subunit (SCN5A) and variants for Brugada syndrome

Cardiomyopathy

Tier 2 CPT Codes:

81405

  • ACTC1 (actin, alpha, cardiac muscle 1) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • MYL2 (myosin, light chain 2, regulatory, cardiac, slow) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • MYL3 (myosin, light chain 3, alkali, ventricular, skeletal, slow) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • TNNI3 (troponin I, type 3 [cardiac]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • TPM1 (tropomyosin 1 [alpha]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence

81406

  • TNNT2 (troponin T, type 2 [cardiac]) (e.g., familial hypertrophic cardiomyopathy), full gene sequence

81407

  • MYBPC3 (myosin binding protein C, cardiac) (e.g., familial hypertrophic cardiomyopathy), full gene sequence
  • MYH7 (myosin, heavy chain 7, cardiac muscle, beta) (e.g., familial hypertrophic cardiomyopathy, Liang distal myopathy), full gene sequence

81479

  • (unlisted, would be used to report TNNC1, ACTN2 and MYOZ2 testing)

HCPCS:

S3865 Comprehensive gene sequence for hypertrophic cardiomyopathy

S3866 Genetic analysis for a specific mutation in an individual with a known HCM mutation in the family

Rationale

Arrhythmogenic Disorders

The following discussion of the evidence is based on a 2007 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment, “Genetic Testing for Long QT Syndrome.” (10)

Validation of the clinical use of any genetic test focuses on 3 main principles: Validation of the clinical use of any genetic test focuses on three main principles:

  • The analytic validity of the test, which refers to the technical accuracy of the test in detecting a mutation that is present or excluding a mutation that is absent;
  • The clinical validity of the test, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and
  • The clinical utility of the test, i.e., how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.

Analytic Validity

Information on analytic sensitivity and specificity for gene sequence analysis was obtained from the website of Transgenomics (formerly PGxHealth) (New Haven, CT). Additional unpublished data were supplied by Transgenomics in response to a list of structured questions.

The website states that the analytic sensitivity of the test is greater than 99%: This analytic sensitivity is based on an independent analysis of 21 “unknown” samples, which had been previously characterized and supplied to the company by a research lab at the University of Rochester, NY. Of these 21 samples, 20 contained various types of mutations, including nonsense, missense, splice site, and insertions/deletions, and one sample was a “wild type,” containing no mutations. According to the manufacturer, all of the mutations were correctly identified, thus leading to their reporting of analytic sensitivity of greater than 99%.

The website states the following concerning the analytic specificity of the test: “The chance of a falsely detected genetic variant is minimized by requiring that each variant be seen in sequence traces for both forward and reverse directions and that two trained technicians independently examine each trace. Chances of false positives are minimized by the use of a validated sample tracking system that uses robotics and barcodes. For each positive finding of a Class I or Class II variant, a second round of PCR amplification and sequencing is performed to confirm the initial finding.”

Abnormal results from the commercial test are reported as Class I or Class II mutations, and the analytic specificity for each class of mutations will differ. Approximately 75% of all reported deleterious mutations are Class I, and the remaining 25% are Class II mutations. For Class I mutations, data from the validation sample reported by the manufacturer indicate that false positive results are expected to be extremely uncommon, so that analytic specificity will approach 100%. For Class II mutations, false positive results are more likely to occur. Analysis of non-long QT syndrome (LQTS) patients revealed that variants reported as Class II mutations are found in approximately 5% of patients without LQTS. Therefore, the analytic specificity of Class II mutations is expected to be approximately 95%.

Kapa et al. (11) examined the likelihood that sequence variations were benign versus pathogenic mutations by comparing variations found in patients with definite LQTS with those from normal patients. This study compared gene sequence variations found in 388 definite cases of LQTS with sequence variations from approximately 1,300 unaffected individuals. Sequence variations in unaffected individuals, which presumably represent non-pathologic changes, were missense mutations in more than 99% of cases. Therefore, variations that were not missense mutations had a very high predictive value for pathologic mutations. For missense mutations, the location appeared to be critical in predicting whether they are pathogenic. Missense mutations in certain areas of the KCNQ1 gene, such as the transmembrane, linker and pore regions, had a high probability of being pathogenic.

Clinical Validity

The true clinical sensitivity and specificity of genetic testing for LQTS cannot be determined with certainty, as there is no independent gold standard for the diagnosis of LQTS. The clinical diagnosis can be compared to the genetic diagnosis, and vice versa, but neither the clinical diagnosis nor the results of genetic testing can be considered an adequate gold standard.

Hofman et al. (12) performed the largest study, comparing clinical methods with genetic diagnosis using registry data. This study compared multiple methods for making the clinical diagnosis, including the Schwartz score, the Keating criteria, and the absolute length of the corrected QT (QTc) with genetic testing. These data indicate that only a minority of patients with a genetic mutation will meet the clinical criteria for LQTS. Using the most common clinical definition of LQTS, a Schwartz score of 4 or greater, only 19% of patients with a genetic mutation met the clinical criteria. Even at lower cutoffs of the Schwartz score, the percentage of patients with a genetic mutation who met clinical criteria was still relatively low, improving to only 48% when a cutoff of 2 or greater was used. When the Keating criteria were used for clinical diagnosis, similar results were obtained. Only 36% of patients with a genetic mutation met the Keating criteria for LQTS.

The best overall accuracy was obtained by using the length of the QTc as the sole criterion; however, even this criterion achieved only modest sensitivity at the expense of lower specificity. Using a cutoff of 430 msec or longer for the QT interval, a sensitivity of 72% and a specificity of 86% was obtained.

Tester et al. (13) completed the largest study to evaluate the percent of individuals with a clinical diagnosis of LQTS that are found to have a genetic mutation. The population in this study was 541 consecutive patients referred for evaluation of LQTS. A total of 123 patients had definite LQTS on clinical grounds, defined as a Schwartz score of 4 or greater, and 274 patients were found to have a LQTS mutation. The genetic diagnosis was compared to the clinical diagnosis, defined as a Schwartz score of 4 or greater. Of all 123 patients with a clinical diagnosis of LQTS, 72% (89/123) were found to have a genetic mutation.

The evidence on clinical specificity focuses on the frequency and interpretation of variants that are identified that are not known to be pathologic. If a mutation is identified that is previously known to be pathologic, then the specificity of this finding is high. However, many variants are discovered on gene sequencing that are not known to be pathologic, and the specificity of these types of findings are lower. The rate of identification of variants is estimated to be in the range of 5% for patients who do not have LQTS. (11)

A publication from the National Heart, Lung, and Blood Institute (NHLBI) GO exome sequencing project (ESP) reported on the rate of sequence variations in a large number of patients without LQTS. (14) The ESP sequenced all genome regions of protein-coding in a sample of 5,400 persons drawn from various populations, none of which included patients specifically with heart disease and/or channelopathies. Exome data were systematically searched to identify sequence variations that had previously been associated with LQTS, including both nonsense variations that are generally pathologic and missense variations that are less likely to be pathological. A total of 33 such sequence variations were identified in the total population, all of them being missense variations. The percent of the population that had at least one of these missense variations was 5.2%. There were no nonsense variations associated with LQTS found among the entire population.

Conclusions. This evidence indicates that genetic testing will identify more individuals with possible LQTS compared with clinical diagnosis alone. It may often not be possible to determine with certainty whether patients with a genetic mutation have the true clinical syndrome of LQTS. The data also demonstrate that approximately 30% of patients with a clinical diagnosis will not be found to have a known mutation, suggesting that there are additional mutations associated with LQTS that have not been identified to date. Therefore, a negative genetic test is not definitive for excluding LQTS at the present time.

The clinical specificity varies according to the type of mutation identified. For nonsense mutations, which have the highest rate of pathogenicity, there are very few false positives among patients without LQTS, and therefore a high specificity. However, for missense mutations, there is a rate of approximately 5% among patients without LQTS; therefore the specificity for these types of mutation is less and false positive results do occur.

Clinical Utility

Diagnosis. For diagnosing LQTS, the clinical utility of genetic testing is high. LQTS is a disorder that may lead to catastrophic outcomes, i.e., sudden cardiac death in otherwise healthy individuals. Diagnosis using clinical methods alone may lead to underdiagnosis of LQTS, thus exposing undiagnosed patients to the risk of sudden cardiac arrest. For patients in whom the clinical diagnosis of LQTS is uncertain, genetic testing may be the only way to further clarify whether LQTS is present. Patients who are identified as genetic carriers of LQTS mutations have a non-negligible risk of adverse cardiac events even in the absence of clinical signs and symptoms of the disorder. Therefore, treatment is likely indicated for patients found to have a LQTS mutation, with or without other signs or symptoms.

Treatment with beta blockers has been demonstrated to decrease the likelihood of cardiac events, including sudden cardiac arrest. Although there are no controlled trials of beta blockers, there are pre-post studies from registry data that provide evidence on this question. Two such studies reported large decreases in cardiovascular events and smaller decreases in cardiac arrest and/or sudden death after starting treatment with beta blockers. (15, 16) These studies reported a statistically significant reduction in cardiovascular events of greater than 50% following initiation of beta-blocker therapy. There was a reduction of similar magnitude in cardiac arrest/sudden death, which was also statistically significant.

Treatment with an implantable cardioverter-defibrillator (ICD) is available for patients who fail or cannot take beta-blocker therapy. One published study reported on outcomes of treatment with ICDs. (17) This study identified patients in the LQTS registry who had been treated with an ICD at the discretion of their treating physician. Patients in the registry who were not treated with an ICD, but had the same indications, were used as a control group. The authors reported that patients treated with an ICD had a greater than 60% reduction in cardiovascular outcomes.

One study reported on changes in management that resulted from diagnosing LQTS by testing relatives of affected patients with known LQTS (cascade testing). (18) Cascade testing of 66 index patients with LQTS led to the identification of 308 mutation carriers. After a mean follow-up of 69 months, treatment was initiated in 199/308 (65%) of carriers. Beta-blockers were started in 163 patients, a pacemaker was inserted in 26 patients, and an ICD was inserted in 10 patients. All carriers received education on lifestyle issues and avoidance of drugs that can cause QT prolongation.

Two studies evaluated the psychological effects of genetic testing for LQTS. Hendriks et al. studied 77 patients with a LQTS mutation and their 57 partners. (19) Psychologic testing was performed after the diagnosis of LQTS had been made and repeated twice over an 18-month period. Disease-related anxiety scores were increased in the index patients and their partners. This psychologic distress decreased over time but remained elevated at 18 months. Andersen et al. conducted qualitative interviews with 7 individuals found to have LQTS mutations. (20) They reported that affected patients had excess worry and limitations in daily life associated with the increased risk of sudden death, which was partially alleviated by acquiring knowledge about LQTS. The greatest concern was expressed for their family members, particularly children and grandchildren.

Prognosis. For determining LQTS subtype or specific mutation, the clinical utility is less certain. The evidence suggests that different subtypes of LQTS may have variable prognosis, thus indicating that genetic testing may assist in risk stratification. Several reports have compared rates of cardiovascular events in subtypes of LQTS. (1, 16, 21, 22) These studies report that rates of cardiovascular events differ among subtypes, but there is not a common pattern across all studies. Three of the 4 studies (16, 21, 22) reported that patients with LQT2 have higher event rates than patients with LQT1, while Zareba and colleagues (1) reported that patients with LQT1 have higher event rates than patients with LQT2.

More recent research has identified specific sequence variants that might be associated with higher risk of adverse outcomes. Albert et al. (23) examined genetic profiles from 516 cases of LQTS included in 6 prospective cohort studies. The authors identified 147 sequence variations found in 5 specific cardiac ion channel genes and tested the association of these variations with sudden cardiac death. Two common intronic variations, one in the KCNQ1 gene and one in the SCN5A gene were most strongly associated with sudden death. Migdalovich et al. (24) correlated gender-specific risks for adverse cardiac events with the specific location of mutations (pore-loop vs. non pore-loop) on the KCNH2 gene in 490 males and 676 females with LQTS. They reported that males with pore-loop mutations had a greater risk of adverse events (hazard ratio [HR]: 2.18, p=0.01) than males without pore-loop mutations but that this association was not present in females. Costa et al. (25) combined information on mutation location and function with age and gender to risk-stratify patients with LQTS 1 by life-threatening events.

Other research has reported that the presence of genetic variants at different locations can act as disease “promoters” in patients with LQTS mutations. (26, 27) Amin et al. (26) reported that 3 single-nucleotide polymorphisms (SNPs) in the untranslated region of the KCNQ1 were associated with alterations in the severity of disease. Patients with these SNPs had less severe symptoms and a shorter QT interval compared to patients without the SNPs. Park et al. (27) examined a large LQTS kindred that had variable clinical expression of the disorder. Patients were classified into phenotypes of mild and severe LQTS. Two SNPs were identified that were associated with severity of disease, and all patients classified as having a severe phenotype also had one of these 2 SNPs present.

Conclusions. This evidence suggests that knowledge of the specific mutation present may provide some prognostic information but is not sufficient to conclude that knowledge of the specific mutation improves outcomes for a patient with known LQTS.

Management. There is not sufficient evidence to conclude that the information obtained from genetic testing on risk assessment leads to important changes in clinical management. Most patients will be treated with beta-blocker therapy and lifestyle modifications, and it has not been possible to identify a group with low enough risk to forego this conservative treatment. Conversely, for high-risk patients, there is no evidence suggesting that genetic testing influences the decision to insert an ICD and/or otherwise intensify treatment.

Some studies that report outcomes of treatment with beta blockers also report outcomes by specific subtypes of LQTS. (16, 22) Priori and colleagues (16) reported pre-post rates of cardiovascular events by LQTS subtypes following initiation of beta-blocker therapy. There was a decrease in event rates in all LQTS subtypes, with a similar magnitude of decrease in each subtype. Moss and colleagues (15) also reported pre-post event rates for patients treated with beta-blocker therapy. This study indicated a significant reduction in event rates for patients with LQT1 and LQT2 but not for LQT3. This analysis was also limited by the small number of patients with LQT3 and cardiac events prior to beta-blocker treatment (4 of 28). Sauer and colleagues (28) evaluated differential response to beta-blocker therapy in a Cox proportional hazards analysis. These authors reported an overall risk reduction in first cardiac event of approximately 60% (HR: 0.41, 95% confidence interval [CI]: 0.27-0.64) in adults treated with beta blockers and an interaction effect by genotype. Efficacy of beta-blocker treatment was worse in those with LQT3 genotype (p=0.04) compared with LQT1 or LQT2. There was no difference in efficacy between genotypes LQT1 and LQT2.

There is also some evidence on differential response to beta blockers according to different specific type and/or location of mutations. Barsheset et al. (29) examined 860 patients with documented mutations in the KCNQ1 gene and classified the mutations according to type and location. Patients with missense mutations in the cytoplasmic loop (c-loop mutations) had a more marked risk reduction for cardiac arrest following treatment with beta blockers compared to patients with other mutations (HR: 0.12, 95% CI: 0.02-0.73, p=0.02).

Conclusions. These data suggest that there may be differences in response to beta-blocker therapy, according to LQTS subtype and the type/location of the specific mutation. However, the evidence is not consistent in this regard; for example, one of the 3 studies demonstrated a similar response to beta-blockers for LQT3 compared to other subtypes. Although response to beta-blocker therapy may be different according to specific features of LQTS, it is unlikely that this evidence could be used in clinical decision making, since it is not clear how this information would influence management.

Indications for Testing

Indications for testing will depend on a variety of factors, including family history, presence or absence of a known mutation in the family, symptoms, length of the QTc interval on electrocardiogram (EKG), etc. For diagnostic testing, patients with a moderate-to-high pretest probability of LQTS, but in whom the diagnosis cannot be made by clinical methods, will derive the most benefit from testing. Table 2 provides a framework for categorizing patients into testing categories; however, as indicated in the table, there may be substantial uncertainty on the benefit of testing for a number of these categories.

For individuals with a known LQTS mutation in the family but who do not themselves meet the clinical criteria for LQTS, genetic testing will improve outcomes. These individuals have a high pretest probability of disease and LQTS can be diagnosed with certainty if the test is positive. Treatment of these individuals with beta blockers will reduce the incidence of subsequent cardiovascular events. Furthermore, because the specific mutation is known prior to testing, the disease can be ruled out with certainty if results are negative.

For diagnosis of LQTS in other patient populations, there may be a benefit as well. For patients who have some signs and symptoms of LQTS but no known mutation in the family, testing may be beneficial. In this situation, LQTS can be diagnosed with reasonable certainty if a Class I mutation is identified; however, the likelihood of false positive results is higher than if a known mutation were present in the family. In patients with lower pretest probabilities of disease, the utility of testing declines, although precise risk/benefit thresholds cannot be established.

Table 2. Potential Patient Indications for Genetic Testing

Family History:

 

Meets clinical criteria for LQTS

Some SS of LQTS; Does not meet clinical criteria

No SS of LQTS

FH positive and known mutation in family 

- (?) 

  ++ 

+

 

FH positive but family mutation status unknown 

- (?) 

+

 

FH negative

  - 

+ (?) 

-

  • Clinical criteria for LQTS:  Schwartz score 4 or greater (other definitions possible as well)
  • FH+:  family history positive for sudden death at age younger than 30; or clinical diagnosis of LQTS in family (without known mutation)
  • S/S of LQTS:  long QT interval on EKG; syncope; aborted cardiac arrest

KEY:

++   Definite benefit of genetic testing

+     Probable benefit of genetic testing

?     Uncertain benefit of genetic testing

-      No benefit of genetic testing

Clinical criteria for LQTS – Schwartz score 4 or greater (other definitions possible as well)

FH+ –  family history positive for sudden death at age younger than 30 years; or clinical diagnosis of LQTS in family (without known mutation)

S/S  Signs/symptoms of LQTS – long QT interval on EKG; syncope; aborted cardiac arrest

Genetic testing has also been proposed to determine LQTS subtype and/or the specific mutation present. For individuals who meet clinical criteria for LQTS, genetic testing for this purpose has not been demonstrated to improve the patient’s health outcomes. Once diagnosed with LQTS, most, if not all patients, should be treated with beta-blocker therapy and lifestyle modifications. For patients with known LQTS, there is no evidence to suggest that genetic testing influences clinical decisions whether to treat with beta-blocker therapy, nor does the evidence indicate that knowledge of genetic testing results influences the decision to implant an automated implantable cardioverter-defibrillator (AICD). Therefore, it is not possible to conclude that genetic testing for LQTS improves outcomes when used to direct therapy or determine prognosis.

Based on the above evidence, it can be concluded that genetic testing for LQTS improves health outcomes for the following patient groups:

  • Individuals who do not meet the clinical criteria for LQTS but who have:
    • a close relative (i.e., first-, second-, or third-degree relative) with a known LQTS mutation; or
    • a close relative diagnosed with LQTS by clinical means whose genetic status is unavailable; or
    • signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS.

Summary

A genetic mutation can be identified in approximately 70-75% of patients with LQTS. The majority of these are point mutations that are identified by gene sequencing analysis; however a small number are deletions/duplications that are best identified by chromosomal microarray analysis (CMA). The clinical validity of testing for point mutations by sequence analysis is high, while the clinical validity of testing for deletions/duplications by CMA is less certain.

The clinical utility of genetic testing for LQTS is high when there is a moderate to high pre-test probability of LQTS and when the diagnosis cannot be made with certainty by other methods. A definitive diagnosis of LQTS leads to treatment of LQTS with beta blockers in most cases, and sometimes to treatment with an ICD. As a result, confirming the diagnosis of LQTS will lead to a health outcome benefit by reducing the risk for ventricular arrhythmias and sudden cardiac death. The clinical utility of testing is also high for close relatives of patients with known LQTS, since these individuals should also be treated if they are found to have a pathologic LQTS mutation. Therefore, genetic testing for the diagnosis of LQTS is medically necessary for the following individuals who do not have a clinical diagnosis of LQTS but who have: 1) a close relative (i.e., first-, second-, or third-degree relative) with a known LQTS mutation, 2) a close relative diagnosed with LQTS by clinical means whose genetic status is unavailable, or 3) signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS. For all other indications, including prognosis and management of patients with known LQTS, genetic testing is considered experimental, investigational, and/or unproven.

Practice Guidelines and Position Statements

The Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) jointly published an expert consensus statement on genetic testing for channelopathies and cardiomyopathies. (30) This document made the following specific recommendations concerning testing for LQTS:

  • Class I (is recommended) (level of evidence C)
    • 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 (may be considered) (level of evidence C)
    • 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.

The American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) issued guidelines in 2006 on the management of patients with ventricular arrhythmias and the prevention of sudden death. (31) These guidelines made a general statement that “In patients affected by LQTS, genetic analysis is useful for risk stratification and therapeutic decisions.” These guidelines did not address the use of genetic testing for the diagnosis of LQTS.

Cardiomyopathy

Commercial testing has been available since May 2003, and there are numerous commercial companies that currently offer genetic testing for hypertrophic cardiomyopathy (HCM). (38, 43) Testing is performed either as comprehensive testing or targeted gene testing. Comprehensive testing, which is done for an individual without a known genetic mutation in the family, analyzes the genes that are most commonly associated with genetic mutations for HCM and evaluates whether any potentially pathogenic mutations are present. The number of HCM genes in the testing panel ranges between 12 and 18 genes, and additional testing characteristics are presented in Table 3. (38) For a patient with a known mutation in the family, targeted testing is performed. Targeted mutation testing evaluates the presence or absence of a single mutation known to exist in a close relative.

Table 3. Characteristics of Commercial Testing for HCM

Company

 

Began HCM Testing (Year)

 

Number of HCM Genes in Panel

Turnaround Time (Weeks)

 

No of Probability Categories

GeneDX (Gaithersburg, Maryland)  

2008  

18  

8  

5  

Transgenomic-FAMILION  

2008  

12  

4-6  

3  

Correlagen Diagnostics (Waltham, Massachusetts)  

2007  

16  

6-8  

7  

Partners (Cambridge, Massachusetts)  

2003  

18  

5  

5  

Adapted from Maron et al. (38)

The rationale for this policy statement is based primarily on a 2009 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (44) that considered whether genetic testing for patients at risk for HCM improves outcomes. This Assessment reviewed the evidence on the accuracy of genetic testing in identifying patients who will subsequently develop HCM. Seven studies were identified that met the inclusion criteria for review. (45-51) These peer-reviewed articles were supplemented by data on analytic validity available through the manufacturers’ websites. (43, 52)

Analytic and Clinical Validity. For predispositional genetic testing, the analytic validity (ability to detect or exclude a specific mutation identified in another family member) and clinical validity (ability to detect any pathologic mutation in a patient with HCM and exclude a mutation in a patient without HCM) were evaluated. The analytic validity is more relevant when there is a known mutation in the family, whereas the clinical validity is more relevant for individuals without a known mutation in the family.

The analytic sensitivity (ability to detect a specific mutation that is present) of sequence analysis for detecting mutations that cause HCM is likely to be very high based on what is known about the types of mutations that cause HCM and the limited empiric data provided by the manufacturer and detailed description of the testing methodology. (52) There are scant data available on the analytic specificity of HCM testing. The available information on specificity, mainly from series of patients without a personal or family history of HCM, suggests that false-positive results for known pathologic mutations are uncommon. (47, 51) However, the rate of false-positive results is likely to be higher for classification of previously unknown variants.

Therefore, for a patient with a known mutation in the family, the high analytic validity means that targeted genetic testing for a familial mutation has high predictive value for both a positive (mutation detected) and a negative (mutation not detected) test result. A negative test indicates that the individual is free of the mutation, while a positive test indicates that the patient has the mutation and is at risk for developing HCM in the future.

Multiple pathologic mutations are found in 1-5% of patients with HCM and are associated with more severe disease and a worse prognosis. (39) For these patients, targeted mutation analysis may miss mutations other than the one tested for. Some experts recommend comprehensive testing of all individuals for this reason; however, the number of patients with multiple pathologic mutations that will be missed through targeted testing is small.

However, a positive genetic test result does not indicate that the individual has clinical HCM. The other important component to clinical validity in this context is penetrance, or the probability that an individual with a pathogenic mutation will eventually develop the condition of concern. There is reduced penetrance in HCM (i.e., not everyone with a deleterious mutation will develop manifestations of HCM). (53) In addition, penetrance varies among different mutations and may even vary among different families with an identical pathologic mutation. (54) As a result, it is not possible to estimate accurately the penetrance for any given mutation in a specific family.

A study by Page and colleagues attempted to identify the disease expression and penetrance of MYBPC3 mutations in a cohort of HCM patients and their relatives. Their findings support that clinical disease expression among carriers of HCM mutation is heterogenous with mutation type (e.g., missense, nonsense, etc.) or specific mutation. In addition, demographic characteristics such as older patient age or male gender resulted in an increased disease penetrance. (55)

The clinical validity of genetic testing for HCM is considerably lower than the analytic validity. Evidence on clinical sensitivity, also called the mutation detection rate, consists of several case series of patients with established HCM. To date, the published mutation detection rate ranges from 33–63%. (45-46, 48-50) The less-than-perfect mutation detection rate is due in part to the published studies having investigated some, but not all, of the known genes that underlie HCM, and investigators in these studies using mutation scanning methods such as single-strand conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE) that will miss certain deleterious mutations. Presumably more comprehensive mutation analysis methods (e.g., sequence analysis with or without deletion duplication analysis) could identify additional mutations. Another reason for the less-than-perfect mutation detection rate is that other, as yet unidentified, genes may be responsible for HCM. Finally, there may be unknown, nongenetic factors that mimic HCM.

Therefore, for patients without a known mutation in the family, a negative test is not sufficient to rule out HCM because of the suboptimal clinical sensitivity. A positive genetic test in a patient without a known family history of disease increases the likelihood that an individual carries a pathologic mutation but is not sufficient for establishing the presence of clinical disease.

Clinical Utility. There are benefits to predisposition genetic testing for at-risk individuals when there is a known mutation in the family. Inheritance of the predisposition to HCM can be ruled out with near certainty when the genetic test is negative (mutation not detected) in this circumstance. A positive test result (mutation detected) is less useful. It confirms the presence of a pathologic mutation and an inherited predisposition to HCM but does not establish the presence of the disease. It is possible that surveillance for HCM may be increased after a positive test, but the changes in management are not standardized, and it is also possible that surveillance will be essentially the same following a positive test.

Because of the suboptimal clinical sensitivity relating to less-than-perfect mutation detection, the best genetic testing strategy for predisposition testing for HCM begins with comprehensive testing (e.g., sequence analysis) of a DNA sample from an affected family member. Comprehensive mutation analysis in an index patient is of importance by informing and directing the subsequent testing of at-risk relatives. If the same mutation is identified in an at-risk relative, then it confirms the inheritance of the predisposition to HCM and the person is at risk for developing the manifestations of the disease. However, if the familial mutation is not identified in an at-risk relative, then this confirms that the mutation has not been inherited, and there is a very low likelihood (probably similar to or less than the population risk) that the individual will develop signs or symptoms of HCM. Therefore, clinical surveillance for signs of the disorder can be discontinued, and they can be reassured that their risk of developing the disease is no greater than the general population.

If a familial mutation is not known and an at-risk individual undergoes testing, a positive result (mutation detected) would confirm an inherited predisposition to HCM and an increased risk for clinical manifestations in the future. However, a negative result (no mutation detected) could not exclude the possibility that a mutation was inherited. In this case, risk assessment and surveillance for HCM would depend on the family history and other personal risk factors. Thus, in this situation, testing has limited utility in decision making. Moreover, if a familial mutation is not known, comprehensive mutation analysis would be the method of choice, and in addition to a positive or negative result, there is the possibility of detecting a variant of uncertain significance—a variant for which the association with clinical disease is not known.

Knowledge of the results of genetic testing may aid in decision making on such issues as reproduction by providing information on the susceptibility to develop future disease. Direct evidence on the impact of genetic information on this type of decision making is lacking, and the effect of such decisions on health outcomes is uncertain. A clinical trial affiliated with University of Pittsburgh (NCT00156429) is currently recruiting patients with HCM to assess genetic predictors of clinical outcomes. Targeted enrollment is 540 participants with an expected completion date of May 2020.

Additionally, rudimentary disease prevention based on assisted reproduction using preimplantation genetic diagnosis (PGD) is possible. PGD utilizes in vitro fertilization with a single cell removed from early-stage embryos and tested for the familial mutation. Only those embryos without the identified HCM mutation are used to initiate pregnancy. Disease-modifying studies are in development using animal models of HCM. In rodent models, sarcomere mutations have been implicated in early abnormal intracellular calcium handling far in advance of left ventricular hypertrophy (LVH). Treatment of this calcium handling by use of diltiazem appeared to attenuate the development of LVH when started in early life. The feasibility of this strategy in humans is being assessed by an ongoing randomized controlled trial (NCT00319982) which compares diltiazem to placebo in known sarcomere mutation carriers who have yet to develop LVH. (56)

Summary

For individuals at risk for hypertrophic cardiomyopathy (HCM) (first-degree relatives), genetic testing is most useful when there is a known mutation in the family. In this situation, genetic testing will establish the presence or absence of the same mutation in a close relative with a high degree of certainty. Absence of this mutation will establish that the individual has not inherited the familial predisposition to HCM and thus has a similar risk of developing HCM as the general population. These patients no longer need ongoing surveillance for the presence of clinical signs of HCM. Therefore, genetic testing may be considered medically necessary for first-degree relatives of individuals with a known pathologic mutation.

For at-risk individuals without a known mutation in the family, the evidence does not permit conclusions of the effect of genetic testing on outcomes, since there is not a clear relationship between testing and improved outcomes. Genetic testing is considered experimental, investigational, and/or unproven for this purpose. For at-risk individuals who have a family member with HCM who tests negative for pathologic mutations, genetic testing is not indicated. Genetic testing is considered not medically necessary in this situation.

Clinical Guidelines and Position Statements

The ACC Foundation and the AHA issued joint guidelines on the diagnosis and treatment of hypertrophic cardiomyopathy in 2011. (57) The following recommendations were issued concerning genetic testing:

Class I indications:

  • Evaluation of familial inheritance and genetic counseling is recommended as part of the assessment of patients with HCM (Level of Evidence: B)
  • Patients who undergo genetic testing should also undergo counseling by someone knowledgeable in the genetics of cardiovascular disease so that results and their clinical significance can be appropriately reviewed with the patient (Level of Evidence: B)
  • Screening (clinical, with or without genetic testing) is recommended in first-degree relatives of patients with HCM (Level of Evidence: B)
  • Genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of HCM or when another genetic condition is suspected to be the cause (Level of Evidence: B)

Class IIa indications:

  • Genetic testing is reasonable in the index patient to facilitate the identification of first-degree family members at risk for developing HCM (Level of Evidence: B)

Class IIb indications:

  • The usefulness of genetic testing in the assessment of risk of SCD in HCM is uncertain (Level of Evidence: B)

Class III indications: No Benefit

  • Genetic testing is not indicated in relatives when the index patient does not have a definitive pathogenic mutation (Level of Evidence: B)
  • Ongoing clinical screening is not indicated in genotype-negative relatives in families with HCM (Level of Evidence: B)

The Heart Rhythm Society and the European Heart Rhythm Association published recommendations for genetic testing for cardiac channelopathies and cardiomyopathies in 2011. (58) For hypertrophic cardiomyopathy, the following recommendations were made:

  • Comprehensive or targeted 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 testing is recommended for family members and appropriate relatives following the identification of the HCM-causative mutation in an index case.

Coding

Disclaimer for coding information on Medical Policies.

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.   

ICD-9 Codes

425.1, 425.4, 426.82, 746.89, V17.41, V17.49, V82.71-V82.79

ICD-10 Codes

I42.1, I42.2, I45.81, Z13.6, Z13.79, Z13.71, Z31.430, Z31.440, Z82.41, Z82.49

Procedural Codes: 81280, 81281, 81282, 81403, 81405, 81406, 81407, 81408, 81479, S3861, S3865, S3866
References

Arrhythmogenic Disorders (1-32); Cardiomyopathy (33-59)

  1. Zareba W, Moss AJ, Schwartz PJ et al. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med 1998; 339(14):960-5.
  2. Schwartz PJ, Moss AJ, Vincent GM et al. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993; 88(2):782-4.
  3. Al-Khatib SM, LaPointe NM, Kramer JM et al. What clinicians should know about the QT interval. JAMA 2003; 289(16):2120-7.
  4. Khan IA. Long QT syndrome: diagnosis and management. Am Heart J 2002; 143(1):7-14.
  5. Zhang L, Timothy KW, Vincent GM et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation 2000; 102(23):2849-55.
  6. Eddy CA, MacCormick JM, Chung SK et al. Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome. Heart Rhythm 2008; 5(9):1275-81.
  7. Chiang CE. Congenital and acquired long QT syndrome. Current concepts and management. Cardiol Rev 2004; 12(4):222-34.
  8. Napolitano C, Priori SG, Schwartz PJ et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA 2005; 294(23):2975-80.
  9. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999; 99(4):529-33.
  10. Genetic Testing for Long QT Syndrome. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program 2007; 22(9):1-36.
  11. Kapa S, Tester DJ, Salisbury BA et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation 2009; 120(18):1752-60.
  12. Hofman N, Wilde AA, Kaab S et al. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? Eur Heart J 2007; 28(5):575-80.
  13. Tester DJ, Will ML, Haglund CM et al. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol 2006; 47(4):764-8.
  14. Refsgaard L, Holst AG, Sadjadieh G et al. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet 2012 [Epub ahead of print].
  15. Moss AJ, Zareba W, Hall WJ et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 2000; 101(6):616-23.
  16. Priori SG, Napolitano C, Schwartz PJ et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004; 292(11):1341-4.
  17. Zareba W, Moss AJ, Daubert JP et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol 2003; 14(4):337-41.
  18. Hofman N, Tan HL, Alders M et al. Active cascade screening in primary inherited arrhythmia syndromes: does it lead to prophylactic treatment? J Am Coll Cardiol 2010; 55(23):2570-6.
  19. Hendriks KS, Hendriks MM, Birnie E et al. Familial disease with a risk of sudden death: a longitudinal study of the psychological consequences of predictive testing for long QT syndrome. Heart Rhythm 2008; 5(5):719-24.
  20. Andersen J, Oyen N, Bjorvatn C et al. Living with long QT syndrome: a qualitative study of coping with increased risk of sudden cardiac death. J Genet Couns 2008; 17(5):489-98.
  21. Priori SG, Schwartz PJ, Napolitano C et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348(19):1866-74.
  22. Schwartz PJ, Priori SG, Spazzolini C et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103(1):89-95.
  23. Albert CM, MacRae CA, Chasman DI et al. Common variants in cardiac ion channel genes are associated with sudden cardiac death. Circ Arrhythm Electrophysiol 2010; 3(3):222-9.
  24. Migdalovich D, Moss AJ, Lopes CM et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm 2011; 8(10):1537-43.
  25. Costa J, Lopes CM, Barsheshet A et al. Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome. Heart Rhythm 2012; 9(6):892-8.
  26. Amin AS, Giudicessi JR, Tijsen AJ et al. Variants in the 3' untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J 2012; 33(6):714-23.
  27. Park JK, Martin LJ, Zhang X et al. Genetic variants in SCN5A promoter are associated with arrhythmia phenotype severity in patients with heterozygous loss-of-function mutation. Heart Rhythm 2012 [Epub ahead of print].
  28. Sauer AJ, Moss AJ, McNitt S et al. Long QT syndrome in adults. J Am Coll Cardiol 2007; 49(3):329-37.
  29. Barsheshet A, Goldenberg I, O-Uchi J et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation 2012; 125(16):1988-96.
  30. Ackerman MJ, Priori SG, Willems S et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace 2011; 13(8):1077-109.
  31. Zipes DP, Camm AJ, Borggrefe M et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006; 48(5):e247-346.
  32. Genetic Testing for Congenital Long QT Syndrome. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 July) Medicine: 2.04.43.
  33. Ramaraj R. Hypertrophic cardiomyopathy: etiology, diagnosis, and treatment. Cardiol Rev 2008; 16(4):172-80.
  34. Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. J Cardiovasc Electrophysiol 2008; 19(1):104-10.
  35. Marian AJ. Genetic determinants of cardiac hypertrophy. Curr Opin Cardiol 2008; 23(3):199-205.
  36. Roberts R, Sigwart U. Current concepts of the pathogenesis and treatment of hypertrophic cardiomyopathy. Circulation 2005; 112(2):293-6.
  37. Keren A, Syrris P, McKenna WJ. Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nat Clin Pract Cardiovasc Med 2008; 5(3):158-68.
  38. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 2012; 60(8):705-15.
  39. Cirino AL HC. Hypertrophic Cardiomyopathy: the genetic determinants of clinical disease expression. GeneReviews 2008. Available online at: http://www.ncbi.nlm.nih.gov Last accessed November 18, 2009.
  40. Ghosh N, Haddad H. Recent progress in the genetics of cardiomyopathy and its role in the clinical evaluation of patients with cardiomyopathy. Curr Opin Cardiol 2011; 26(2):155-64.
  41. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet 2004; 363(9424):1881-91.
  42. Maron BJ, McKenna WJ, Danielson GK et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003; 42(9):1687-713.
  43. Arya A, Bode K, Piorkowski C et al. Catheter ablation of electrical storm due to monomorphic ventricular tachycardia in patients with nonischemic cardiomyopathy: acute results and its effect on long-term survival. Pacing Clin Electrophysiol 2010; 33(12):1504-9.
  44. Genetic testing for predisposition to inherited hypertrophic cardiomyopathy. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program 2009; Volume 24, Tab 11.
  45. Harvard CardioGenomics website. 2010. Available online at: http://cardiogenomics.med.harvard.edu Accessed November 20, 2013.
  46. Erdmann J, Daehmlow S, Wischke S et al. Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. Clin Genet 2003; 64(4):339-49.
  47. Niimura H, Bachinski LL, Sangwatanaroj S et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998; 338(18):1248-57.
  48. Olivotto I, Girolami F, Ackerman MJ et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc 2008; 83(6):630-8.
  49. Richard P, Charron P, Carrier L et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation 2003; 107(17):2227-32.
  50. Van Driest SL, Ellsworth EG, Ommen SR et al. Prevalence and spectrum of thin filament mutations in an outpatient referral population with hypertrophic cardiomyopathy. Circulation 2003; 108(4):445-51.
  51. Watkins H, McKenna WJ, Thierfelder L et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 1995; 332(16):1058-64.
  52. Familion™ genetic tests for inherited cardiac syndromes: technical specifications. PGxHealth Website (now Transgenomics Health) 2009. Available online at: http://pgxhealth.com Last accessed January, 2009.
  53. Charron P, Carrier L, Dubourg O et al. Penetrance of familial hypertrophic cardiomyopathy. Genet Couns 1997; 8(2):107-14.
  54. Fananapazir L, Epstein ND. Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations. Circulation 1994; 89(1):22-32.
  55. Page SP, Kounas S, Syrris P et al. Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circ Cardiovasc Genet 2012; 5(2):156-66.
  56. Ho CY. Genetic considerations in hypertrophic cardiomyopathy. Prog Cardiovasc Dis 2012; 54(6):456-60.
  57. Gersh BJ, Maron BJ, Bonow RO et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011.
  58. Ackerman MJ, Priori SG, Willems S et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011; 8(8):1308-39.
  59. Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 July) Medicine: 2.02.28.
History
March 2011  Policy updated with literature search; policy statements unchanged. Reference numbers 28 to 32 added.  Added investigational indication. 
April 2012  New CPT codes added to policy. Policy updated with literature search; policy statements unchanged. Ten references removed, list renumbered; references 17, 22, 23 & 25 added.
August 2012 Policy updated with literature search, references 14, 25-27, 29, 30 added. No change to policy statement.
October 2013 Policy formatting and language revised.  Combined the "Genetic Testing for Congenital Long QT Syndrome" and "Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy" policies.  Title changed to "Genetic Testing for Cardiac Disorders".  Removed codes S3820 and S3862.  Policy statement unchanged.
February 2014 Document reviewed and updated. The following changes were made in Coverage:  1) Third degree relative was added to criteria for testing for arrhythmogenic disorders; 2) Definition of first-, second-, and third-degree relatives was modified; 3) Genetic testing for predisposition to inherited hypertrophic cardiomyopathy (HCM) is considered not medically necessary for patients with a family history of HCM in which a first degree relative has tested negative for pathologic mutations; 4) The term “predisposition to” was added to testing for cardiomyopathy.
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Genetic Testing for Cardiac Disorders