Laboratory Section - Genetic Testing for Congenital Long QT Syndrome

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

Congenital long QT syndrome (LQTS) is an inherited disorder characterized by the lengthening of the repolarization phase of the ventricular action potential, increasing the risk 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 implantation cardioverter defibrillators (ICD) as second-line therapy.

Congenital LQTS usually manifests itself before the age of 40 years, and may be suspected when there is a history of seizure, syncope, or sudden death in a child or young adult; this history may prompt additional testing in family members. It is estimated that more than one half of the 8,000 sudden unexpected deaths in children may be related to LQTS. The mortality of untreated patients with LQTS is estimated at 1%–2% per year, although this figure will vary with the genotype, discussed further below. (2) Frequently, syncope or sudden death occurs during physical exertion or emotional excitement, and thus LQTS has received some publicity regarding evaluation of adolescents for participation in sports. In addition, LQTS may be considered when a long QT interval is incidentally observed on an EKG. Diagnostic criteria for LQTS have been established, which focus on EKG findings and clinical and family history. (3) However, measurement of the QT interval is not well standardized, and in some cases, patients may be considered borderline cases. (4)

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 seven different variants recognized, each corresponding to mutations in different genes as indicated below (5):

• LQT1 is associated with mutations in the gene KNQ1 located on chromosome 11. LQT1 is responsible for about 50% of all LQTS, and arrhythmic events prompted by exercise may occur most commonly in this subtype. Therefore, patients with LQT1 may be advised to minimize exercise.
• LQT2 is associated with mutations in the gene KCNH2 located on chromosome 7 and is seen in 45% of patients with LQTS. Arrhythmic events appear to be precipitated by auditory stimuli and these patients may be advised to avoid clock alarms, etc.
• LQT3 is associated with mutations in the gene SCN5A located on chromosome 3. This subtype is seen in 3%–4% of patients with LQTS. In this subtype, the majority of cardiac events occur during sleep. LQT3 variant is also known as the Brugada syndrome.
• LQT 4-7 involve KCN genes located on chromosomes 21 and 17. These variants each account for less than 1% of LQTS.

In addition to the above, typical ST-T-wave patterns are also suggestive of specific subtypes. (6)

The Familion Test describes the analysis of the genes responsible for subtypes LQT 1-5. The test is offered in a variety of ways. For example, if a family member has been diagnosed with LQTS based on clinical characteristics, complete analysis of all five 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 a focused genetic analysis for the identified mutation. If a specific type of LQTS is suspected based on the EKG abnormalities, genetic testing can focus on the individual gene. For example, subjects with suspected Brugada syndrome can undergo genetic analysis of the SCN5a gene.

All of the LQTS genes are large, and genetic testing has revealed multiple different mutations along their length. The pathophysiologic significance of each of the discrete mutations is an important part of the interpretation of genetic analysis. Genaissance, the laboratory offering the Familion test, compares the results to the Genaissance Cardiac Ion Channel Variant Database, which includes data from over 750 individuals of diverse ethnic backgrounds. Therefore, the chance that a specific mutation is pathophysiologically significant is increased if it is the same mutation as that reported in several other cases of known LQTS. However, there may be many instances when the detected mutations are of unknown significance. Also, the absence of a mutation does not imply the absence of LQTS; it is estimated that mutations are only identified in 60%–70% of patients with a clinical diagnosis of LQTS. (7) For these reasons, the most informative result of testing would probably occur when a family member undergoes genetic testing for a specific genetic mutation that has been identified in symptomatic relatives known to have LQTS. Interpretation of the results will likely be improved as the database grows.  For example, Napolitano and colleagues propose a three-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 mutation never have any symptoms.

Policy/Criteria

Genetic testing in patients with known or suspected congenital long QT syndrome is considered investigational.

Scientific Background

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

1. The technical feasibility of the test
2. The diagnostic performance of the test, such as sensitivity, specificity, and positive and negative predictive value in different populations of patients and compared to the gold standard; and
3. The clinical utility of the test, i.e., how the results of the diagnostic test will be used to improve the management of the patient.

Technical Feasibility

Genetic analysis of the entire length of the various identified genes or specific genetic analysis of an isolated mutation are established laboratory procedures.

Diagnostic Performance

The diagnostic performance is related to the interpretation of the results of the genetic analysis. As noted in the policy Description, the absence of an identified mutation does not imply absence of disease, since other mutations on different genes could potentially be involved. More complex is understanding the clinical significance of an identified mutation. The ion channel genes are quite large, with numerous mutations discovered along their entire length. When a mutation is identified, it can be compared to a growing database of discovered mutations, with the presumption that there is an increased risk that a mutation is pathogenic if it is similar to one that has already been identified in an affected patient. However, due to varying penetrance of mutations, there is not necessarily a strong correlation between the genotype and phenotype. For example, if the database is derived from families with highly penetrant disease, the clinical significance of a given mutation may be overestimated in the general population. These considerations are similar to those raised early on regarding the interpretation of BRCA 1 and BRCA 2 mutations for hereditary breast cancer.

Clinical Implications

While genetic testing for LQTS is recognized as an important research tool, its clinical use will depend on whether the results of the genetic analysis can be used to improve patient management. At present, the initial treatment is typically beta blocker therapy, although this strategy has never been tested in controlled trials, and several authors caution that there is still a high rate of cardiac events in patients on beta blocker therapy.  (9,10) Other treatment options include left-sided cardiac sympathetic denervation, pacemakers, or ICD. A search of the published scientific literature through September 5, 2006 did not identify any articles in which the genotypic analysis was used in the management of the patient. The bulk of the literature consists of retrospective studies. However, several different clinical situations may be considered:

• Symptomatic patients with clinically diagnosed LQTS, in whom genetic testing is performed to determine the subtype
  

  In some instances the subtype, i.e., LQT1-5, can be identified based on characteristic EKG findings. However, genotyping has been suggested as a technique to further categorize patients and potentially identify an underlying mutation that could serve as the basis of focused testing for other family members. However, treatment with beta blockers as a first-line therapy is recommended in all clinically diagnosed and symptomatic patients (i.e., syncope, torsade de pointes), and the management impact for the individual patient is unclear in this situation. Currently, treatment does not vary with the genetic subtype.

• Asymptomatic patients with a borderline or prolonged QT interval, not meeting the clinical diagnosis of LQTS, in the absence of a family history
  

  While the presence of genetic mutations might suggest that the patient is at higher risk for arrhythmic events, the lack of clarity regarding the pathophysiologic consequences of individual mutations in the absence of a family history and the variable penetrance and multiple phenotypic expressions limit the clinical interpretation of genotyping in these settings.

• Asymptomatic family member with a relative with LQTS with a known genotype.

  In this scenario, patients might be offered treatment if a mutation found in an asymptomatic family member matched that of an affected relative. In other words, treatment would be based primarily on the presence of a mutation alone. Priori and colleagues have used the genotype to risk stratify patients with LQTS. (11) The authors studied the genotypes of 580 patients along with their history of syncope, cardiac arrest or sudden death. The risk of a first cardiac death below the age of 40 was lowest among those with LQT-1 subtype compared to LQT-2 or LQT-3. The authors proposed a risk stratification scheme that suggested, for example, prophylactic treatment be offered to patients considered at high or intermediate risk based on genotype, gender, and QT interval. However, as noted in an accompanying editorial, risk prediction is still fraught with uncertainty; several subjects considered at low risk still died suddenly, and given this risk, it is uncertain whether information regarding the LQTS subtype could be used to defer treatment. (12)

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.04.43
2. Zareba W, Moss AJ, Schwartz PJ et al. Influence of genotype on the clinical course of the long QT syndrome. N Engl J Med 1998;339(14):960-5
3. Schwartz PJ, Moss AJ, Vincent GM et al. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993;88(2):782-4
4. Al-Khatib SM, LaPointe NM, Kramer JM et al. What clinicians should know about the QT interval. JAMA 2003;289(16):2120-8
5. Khan IA. Long QT syndrome: diagnosis and management. Am Heart J 2002;143(1):7-14
6. 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
7. Chiang CE. Congenital and acquired long QT syndrome. 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. 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
10. 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
11. Priori S, Schwartz PJ, Napolitano C et al. Risk stratification in the long QT-syndrome. N Engl J Med 2003;348(19):1866-74
12. Vincent GM. The long-QT syndrome - bedside to bench to bedside. N Engl J Med 2003;348(19):1837-8

Cross References

Genetic Testing, TRG Medical Policy, Laboratory, No. 20

Laboratory Section Table of Contents