TEC Assessment Index
Genetic Testing for Long QT Syndrome
Assessment Program
Volume 22, No. 9
November 2007
Executive Summary
Background
A genetic test is currently commercially available for mutations associated with the long QT syndrome (LQTS). The Romano-Ward syndrome (RWS), which is the most common type of LQTS and lacks noncardiac manifestations, can be difficult to diagnose by clinical methods. Genetic testing for RWS may improve the accuracy of the diagnostic work-up and lead to treatment that is efficacious at reducing the incidence of sudden death and/or other cardiovascular symptoms in affected patients.
Objective
Review evidence to determine if genetic testing for LQTS improves health outcomes for patients with known or suspected LQTS.
Search Strategy
MEDLINE® was searched (via PubMed) using the terms “long QT syndrome” OR “LQTS,” cross-referenced with the terms “genetics” OR “gene” from 1990 through October 2007, limited to English-language articles on human subjects. Electronic search was supplemented with hand-search of relevant bibliographies.
Selection Criteria
Studies were selected that included primary data on patients with LQTS and relevant evidence on the diagnostic accuracy of clinical or genetic methods for LQTS; the differential prognosis of LQTS by specific syndrome and/or LQTS subtype; or the outcomes of treatment with beta-blocker medications or implantable cardioverter-defibrillator (ICD) therapy.
Main Results
The commercially available genetic test for LQTS is accurate in identifying a mutation that is present, and in excluding mutations that are not present. The diagnostic accuracy of genetic testing for detecting the clinical syndrome of LQTS cannot be determined with certainty due to the lack of a true gold standard for the clinical diagnosis. In patients with a known clinical diagnosis of LQTS, approximately 70% are found to have a deleterious mutation associated with LQTS, indicating that other genetic mutations may exist that have not been identified.
Of all patients found to have a genetic mutation, only a minority meet the clinical criteria for LQTS. Therefore, genetic testing will identify additional 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 either the pathophysiologic channelopathy associated with LQTS or the true clinical syndrome of LQTS. It is possible to conclude that 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.
Treatment with beta blockers is likely to reduce the rate of adverse cardiovascular outcomes, including sudden death. Beta-blocker therapy appears to be effective in reducing adverse outcomes both for patients diagnosed by clinical criteria and for patients diagnosed by genetic testing.
Genetic testing for LQTS can identify the specific syndrome present, and/or the subtype of Romano-Ward syndrome. However, the evidence is not sufficient to conclude that information on LQTS subtypes obtained from genetic testing leads to important changes in clinical management.
Author's Conclusions and Comments
There is no direct evidence that use of genetic testing for LQTS improves outcomes. Although there are limitations in the evidence on analytic validity, clinical validity, and clinical utility, nonetheless, the overall case that genetic testing will improve outcomes in selected patient populations is compelling. Conventionally, diagnosis of LQTS is based on clinical criteria. There is no gold standard for diagnosis; however, the Schwartz score has been commonly used. Two large (n>500) studies compared diagnostic performance of clinical criteria against genetic testing and genetic testing against clinical criteria, respectively. Both show that genetic testing will identify more individuals with a LQTS mutation compared to the number of patients diagnosed with LQTS by clinical methods. These findings are consistent with what is well known clinically: that there is substantial risk of underdiagnosing LQTS, with results that may be catastrophic.
Despite uncertainties in the diagnostic accuracy of genetic testing, the clinical utility of testing is high. This is due to the catastrophic outcomes associated with LQTS and the availability of low-risk treatments that are efficacious in reducing adverse outcomes. The risk of undertreatment of such individuals is therefore likely to far outweigh the risk of overtreatment of such individuals.
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 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 was 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. The table provides an overview of the potential benefit of genetic testing in the spectrum of clinical populations that are encountered in practice.
Table. Potential Patient Indications for Genetic Testing
|
Meets Clinical Criteria for LQTS |
Some Signs or Symptoms of LQTS; Does Not Meet Clinical Criteria |
No Signs or Symptoms of LQTS |
| Family history positive and known mutiation in family |
-(?) |
++ |
+ |
| Family history positive but familiy mutation status unknown |
-(?) |
+ |
+ |
| Family history negative |
- |
+(?) |
- |
++ 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 (other definitions possible as well)
FH positive: family history positive for sudden death at age<30; or clinical diagnosis of LQTS in family (without known mutation)
Signs/symptoms LQTS: long QT interval on EKG; syncope; aborted cardiac arrest
Genetic testing has not been demonstrated to improve the outcomes of those individuals who already meet clinical criteria for LQTS. Once diagnosed with LQTS, all patients should be treated with beta blocker therapy and lifestyle modifications. There is no evidence to suggest that genetic testing influences clinical decisions on whether or not to treat with an implantable cardioverter-defibrillator (ICD). While many experts consider LQT3 to be less responsive to therapy with beta blockers, studies that address this question differ in their results, with some indicating a similar response to beta blockers for LQT3 genotype and others indicating a lack of benefit. Therefore, it is not possible to conclude that genetic testing for LQTS improves outcomes when used to direct therapy or determine prognosis.
However, if individuals who meet the clinical criteria for LQTS have immediate family members with indications for genetic testing, genetic testing of the index patient (i.e., clinically diagnosed patient) can be instrumental in interpreting results of genetic testing for family members. If a known mutation is found in the index patient, then genetic testing of family members can be targeted and both positive and negative results can be interpreted with greater certainty. Therefore, the family member will benefit from genetic testing of the index patient.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether genetic testing for LQTS meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
There are no assay kits approved by the U.S. Food and Drug Administration (FDA) for genetic testing for LQTS, 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 such oversight. Home-brew tests may be developed using reagents prepared in-house or, if available, commercially manufactured analyte-specific reagents (ASRs). ASRs are single biological 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.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
Although there are limitations in the evidence on analytic validity, clinical validity, and clinical utility, the overall case that genetic testing will improve outcomes in selected patient populations is compelling. For patients with a moderate-to-high pretest likelihood, the positive predictive value (PPV) of genetic testing will be high, and few patients will be misclassified as having LQTS when they do not. However, for patients with a low pretest likelihood of LQTS, the PPV of testing will be lower and the utility of testing less certain.
For determining prognosis and directing therapy, the evidence is sufficient to conclude that genetic testing offers some information on risk stratification above that provided by clinical evaluation. However, genetic testing has not identified subgroups of patients with risk low enough to forego treatment, nor has testing identified subgroups with risk high enough to justify more aggressive treatment, such as prophylactic implantation of an ICD. Similarly, while there is some evidence that certain LQTS subtypes may respond differently to beta-blocker therapy, the evidence on this is not consistent and therefore, it is not possible to conclude that genetic testing to direct therapy improves outcomes.
3. The technology must improve the net health outcome
For patients with a moderate-to-high pretest likelihood of LQTS, in whom the diagnosis cannot be made after clinical evaluation, genetic testing will improve health outcomes. In these individuals, genetic testing will correctly identify patients with LQTS who cannot be diagnosed by other methods, and lead to appropriate treatment.
Patients who are identified as having LQTS by purely genetic testing have a lower risk for cardiovascular events compared to patients with a clinical diagnosis. However, the risk of cardiovascular events and sudden death in patients identified by genetic testing remains high enough to warrant treatment with lifestyle modifications and beta-blocker therapy. Observational studies show a large decrease in the incidence of cardiovascular events reported after treatment with beta blockers.
For risk stratification, the evidence is not sufficient to conclude that health outcomes are improved. Although the evidence suggests that genetic testing will aid in risk stratification, there is no evidence to suggest that testing will lead to meaningful changes in clinical management that improve health outcomes.
4. The technology must be as beneficial as any established alternatives.
The alternative to the use of genetic testing for diagnosing LQTS is using clinical methods alone for diagnosis. As discussed above, clinical methods are insensitive compared to genetic testing. When used in the correct population with a moderate-to-high pretest probability of disease, genetic testing is more beneficial than diagnosis by clinical criteria alone.
For risk stratification, the use of genetic testing for LQTS has not been demonstrated to improve outcomes.
5. The improvement must be attainable outside the investigational settings.
At least one commercially available genetic test for LQTS is on the market, and can be ordered by any treating physician in the U.S. However, the interpretation of this test may be complex and require some expertise in genetics. Therefore, it is most appropriate that genetic testing be undertaken in clinical environments where expertise in genetic testing is available, and genetic counseling provided to patients in order to assist in complex clinical decision-making.
Based on the above, genetic testing for LQTS meets the TEC criteria for establishing the diagnosis of LQTS, in the following populations:
1. 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.
2. An individual who meets the clinical criteria for LQTS and who has a close relative at risk for LQTS with an indication for genetic testing. In this circumstance, testing of the individual with LQTS is intended to inform genetic testing options for at-risk relatives.
Genetic testing for LQTS does not meet the TEC criteria for determining prognosis and/or directing therapy in patients with known LQTS who do not have close relative(s) with indications for genetic testing.
* 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.
TEC Assessment Index
NOTICE OF PURPOSE:TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.
KEYWORDS: analyte specific reagents; Anderson-Tawil; arrhythmia; ASR; autosomal dominant; beta blocker; beta-blocker; calcium; cardiac; cardiac arrest; cardiovascular; cardiovert; cardioverter; carrier; carriers; channelopathy; CLIA; clinical laboratory; congenital; defibrillator; diagnosis; diagnostic; DNA sequencing; EGAPP; EKG; Familion; fibrillation; genetic testing; heart; ICD; ICDs; implant; implantation; interval, long QT; ions; Jervell; Keating criteria; Lange-Nielsen; likelihood; LQT; LQT3; LQTS; mutation; periodic paralysis; PGx Health; polymorphic; potassium; pretest; proband; QT; QTc; risk stratification; Romano-Ward; RWS; Schwartz score; sudden death; syncope; syndrome; tachycardia; Timothy syndrome; torsades de pointes; ventricular arrhythmia;
