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 here.  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.  However, measurement of the QT interval is not well standardized, and in some cases, patients may be considered borderline cases.

 

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 variants recognized, each corresponding to

mutations in different genes as indicated here.  In addition, typical ST-T-wave patterns are also suggestive of specific subtypes.

 

The long QT syndrome (LQTS, also known as Jervell syndrome, Lange-Neilson syndrome, and Romano-Ward syndrome) is associated with sudden death (and congenital deafness), and has been found to result from mutations in fundamental cardiac ion channels that “orchestrate the action potential of the human heart”.  More than 35 mutations in four cardiac ion channel genes have been identified in LQTS:

 

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.

 

A number of papers, many from Dr. M.J. Ackerman at Mayo Clinic, have documented the genetic findings, but none of these papers describe how this knowledge changes the therapeutic options for patients with LQTS.

 

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 5 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. (6) 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.

 

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.

 

There are no specific codes for this testing.  Genetic testing code  modifier '8C' may be added to CPT codes to indicate testing for long QT.

Genetic testing for long QT syndrome must meet primary coverage criteria:

 

Genetic testing for long QT syndrome is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

 

Genetic testing for asymptomatic patients is a specific contract exclusion in most member benefit contracts and is not covered.  This includes cardiac ion channel genetic testing.

 

For contracts without primary coverage criteria, genetic testing for long QT syndrome is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit contract.

 

 

Validation of the clinical use of any diagnostic test focuses on 3 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.

 

Genetic analysis, of the entire length of the various identified genes or specific genetic analysis of an isolated mutation, is an established laboratory procedure.

 

The diagnostic performance is related to the interpretation of the results of the genetic analysis. As noted in the Description section, 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.

 

While genetic testing for LQTS is recognized as an important research tool, its clinical use  depends  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.  Other treatment options include left-sided cardiac sympathetic denervation, pacemakers, or ICD. A search of the literature did not identify any articles in which the genotypic analysis was used in the management of the patient. The bulk of the published literature consists of retrospective studies. However, several different clinical situations may be considered:

 

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.

 

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, the variable penetrance and multiple phenotypic expressions limit the clinical interpretation of genotyping in these settings.

 

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.   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.