Long QT Syndrome, types 1, 2, and 3

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: KCNQ1 (HGNC:6294) KCNH2 (HGNC:6251) SCN5A (HGNC:10593)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 08/28/2019
• Curation Status: Released (1.0.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
KCNQ1	long QT syndrome 1 (0100316)	192500	Strong Actionability
KCNH2	long QT syndrome 2 (0013367)	613688	Strong Actionability
SCN5A	long QT syndrome 3 (0011377)	603830	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Sudden cardiac death / Beta blockers	3	2C	3A	3	11CA
Sudden cardiac death / Avoidance of QT-prolonging medications	3	2C	2N	3	10CN
Sudden cardiac death / Beta blockers	3	2C	2A	3	10CA
Sudden cardiac death / Avoidance of QT-prolonging medications	3	2C	3N	3	11CN

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of long QT syndrome (LQTS) has been estimated at 1:2,500.

Clinical Features (Signs / symptoms)

This report focuses on LQTS types 1, 2, and 3 (LQT1, LQT2, and LQT3, respectively) which are not associated with extracardiac manifestations (historically termed Romano-Ward syndrome) and account for the majority of cases. LQTS is a cardiac electrophysiological disorder characterized by QT interval prolongation and torsade de pointes (TdP) ventricular tachycardia in the absence of structural heart disease. TdP may be self-terminating, resulting in a syncopal event, which is the most common symptom in individuals with LQTS. Such cardiac events typically occur without warning. TdP can degenerate into a malignant ventricular arrhythmia which may result in sudden cardiac arrest (SCA) or sudden cardiac death (SCD). The precipitating conditions associated with arrhythmic events vary with subtype with most arrhythmic events occurring during exercise in LQT1; at rest, during emotional stress, and with sudden noises in LQT2; and at rest or during sleep in LQT3.

Natural History (Important subgroups & survival / recovery)

LQTS has been identified in all ethnic groups. The mean age at presentation of LQTS is 14 years. Cardiac events may occur at any age, but are most common from the pre-teen years through the 20s. Cardiac events are often triggered by administration of a QT-prolonging drug or hypokalemia. It has been estimated that 50% or fewer of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. Of individuals who die of complications of LQTS, death is the first sign of the disorder in an estimated 10-15%. LQTS patients at the highest risk for cardiac events include those with QTc >500 ms, LQT2 and LQT3, females with LQT2, onset of symptoms at <10 years of age, and patients with prior cardiac arrest or recurrent unexplained syncope. For asymptomatic males with LQTS, the risk of cardiac events is highest in childhood. Adult females with LQT2 and QTc>500 ms are at increased risk of SCA/SCD, especially in the 9 months postpartum. The prognosis of the disease is usually excellent in patients that are correctly diagnosed and treated.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

The prevalence of pathogenic variants associated with LQT1, 2 and 3 was not available.

Unknown

It has been estimated that 60-75% of LQTS can be attributed to pathogenic variants in KCNQ1, KCNH2, and SCN5A (all gain of function for SCN5A).

Tier 3

Unknown

However, the yield of genetic testing has been as high as 90% for these three genes in some LQTS cohorts.

Tier 5

Penetrance (Includes any high-risk racial or ethnic subgroups)

5-39 %

LQTS exhibits reduced penetrance of the ECG changes and symptoms. ). It has been estimated that 50% or fewer of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. Overall, approximately 25% of individuals with a pathogenic variant have a normal QTc on baseline ECG. The percentage of genetically affected individuals with a normal QTc was higher in LQT1 (36%) than in LQT2 (19%) or LQT3 (10%). Registry data (can include patients, individuals with a pathogenic variant [mostly treated], and also relatives who died suddenly) show a cumulative mortality before age 40 years of 6-8% in LQT1, LQT2, and LQT3. In individuals between age 0 and 18 years, those with LQT1, LQT2, or LQT3 had a cumulative mortality of 2%, 3%, and 7%, respectively. From age 19 to 40 years, mortality rates were 5%, 7%, and 5%, respectively.

Tier 3

Syncopal events in LQTS are associated with an increased risk of subsequent cardiac arrest. The annual rate of SCD in patients with untreated LQTS is between 0.33 and 0.9% overall and estimated to be 5% for those with syncope.

Tier 3

Risk of life-threatening arrhythmia in asymptomatic genotype positive individuals is 4% by age 40 years, compared to 0.4% in genotype negative family controls.

Tier 3

An evaluation of 647 patients reported that the incidence of a first cardiac event (defined as syncope, cardiac arrest, or SCD) before the age of 40 was lower among patients with LQT1 (30%) compared to patients with LQT2 (46%) and LQT3 (42%). Looking at just cardiac arrest or SCD, the incidence was still lower in LQT1 (37/386 or 10%) compared to LQT2 (41/206 or 20%) and LQT3 (9/55 or 16%).

Tier 5

In a longitudinal care study of 88 patients with definite or probable LQTS treated in a specialized inherited arrhythmia clinic, 29 patients (33%) had a history of a cardiac event (SCA, documented torsade de pointes, syncope, or seizure). No patients experienced SCD or arrhythmic syncope during long-term follow-up (median of 4.6 years) and mortality remained at 0 during a follow-up of 520 patient-years.

Tier 5

Expressivity

Considerable phenotypic variability within families has been reported.

Tier 3

Intervention Effectiveness

Patient Management

To establish the extent of disease and needs in an individual diagnosed with LQTS, the main focus in the management of individuals with LQTS is to identify the subset of individuals at high risk for cardiac events. For this risk stratification the following evaluations are recommended:

• ECG evaluation for QTc interval

• Medical history: for syncope or cardiac arrest

• Other: consultation with a clinical geneticist and/or genetic counselor.

Tier 3

In patients with LQTS with a resting QTc greater than 470ms, a beta blocker is recommended. In asymptomatic patients with LQTS and a resting QTc less than 470ms, chronic therapy with a beta blocker is considered reasonable. Beta blockers reduce adverse cardiac events for LQT1 (>95%), LQT2 (>75%), and females with LQT3 (>60%). There are limited data regarding efficacy of beta blockers in males with LQT3 but, in selected patients, beta blockers can be protective against SCA. Asymptomatic adult (male) LQTS patients with normal QTc intervals may choose to decline beta-blocker therapy.

Tier 1

A meta-analysis of 10 studies (7 registry-based cohort studies [Cohort] and 3 interrupted time series studies [ITS]) involving 9,727 patients with LQTS investigated the use of beta-blockers and cardiac events (syncope, aborted cardiac arrest [ACA], and SCD). Using Cohort data, the use of a beta-blocker was associated with significant risk reduction of all cardiac events (HR=0.49, p<0.001) and serious cardiac events (ACA or SCD) (HR=0.47, p<0.001). For LQTS subtypes, beta-blocker therapy reduced cardiac events in LQT1 (HR=0.59, p<0.001) and LQT2 (HR=0.39, p<0.001). Using ITS data, 870 events occurred before beta-blocker therapy, which was reduced significantly by 61% (352 events) after taking beta-blockers (RR=0.39, 95% CI: 0.32-0.46). Risk of cardiac events was reduced in LQT1 by 71% (RR=0.29, 95% CI: 0.20-0.41) and in LQT2 by 52% (RR=0.48, 95% CI: 0.30-0.77). In LQT3, however, there was no significant difference in reduction of risk for cardiac events between before and after use of a beta-blocker. The authors note that the lack of sufficient data for beta-blocker use in LQT3 does not imply that beta-blockers should be prohibited in this subtype and cite a prior study of 403 patients with LQT3 that reported that beta-blocker therapy was associated with an 83% reduction in cardiac events in females (p=0.015) but not males.(

Tier 1

Implantation with an implantable cardioverter defibrillator (ICD) can be effective in reducing SCD in LQTS patients. ICD implantation is recommended for high risk LQTS patients (where high risk is defined as patients with a previous SCA, recurrent unexplained syncope and/or ventricular tachycardia, and in whom beta blocker use is ineffective or not tolerated). In one study of high-risk LQT patients, 1.3% mortality was reported in ICD-treated (n=73) vs. 16 % in untreated (n=161) patients, but the difference was not significant at p=0.07. Two additional smaller studies of patients with ICD treatment reported no mortality over an average 3 year follow-up. Cohort studies have reported appropriate ICD therapy rates from 37-65% and inappropriate therapy rates from 11-33%.

Tier 1

Use of additional medications is guided by LQTS type. In LQT3 sodium channel blockers (ranolazine, mexiletine, and flecainide) may shorten the QTc and have been used to reduce recurrent arrhythmias in case reports.

Tier 1

Although the incidence of arrhythmias during elective interventions such as surgery, endoscopies, childbirth, or dental work is low, it is prudent to monitor the ECG during such interventions and to alert the appropriate medical personnel for prevention (e.g. avoidance of epinephrine during dental procedures, anti-emetics post-surgery such as Zofran) and in case intervention is needed.

Tier 4

Women with LQT2 are at higher risk of postpartum SCA/SCD and should receive prepregnancy counseling.

Tier 1

Circumstances to Avoid

With all forms of LQTS, a degree of caution with sporting activity is recommended. There is increasing evidence that the risk is low if patients adhere to beta blocker therapy. Exercise precautions are more imperative with LQT1, or in those who have already experienced events during exercise, than in LQT2 and LQT3. Such individuals should generally be advised away from becoming professional athletes.

Tier 2

Because the risk of adverse events increases in patients with LQTS with prolongation of the QTc >500 ms, QT-prolonging medications and electrolyte depleting medications (e.g. diuretics) should not be used in patients with LQTS unless there is no suitable alternative. Episodes of torsades de pointes can be precipitated by exposure to a QT prolonging medication, or hypokalemia induced by diuretics or gastrointestinal illness.

Tier 1

A retrospective study of cardiac events in 216 genotyped LQT1 patients found that, prior to the initiation of beta blocker therapy, the use of QT-prolonging drugs was associated with a markedly increased risk of cardiac arrest compared with patients not on these drugs (53%; 95% CI, 28-77% vs. 8.5%; 95% CI, 5-13%, respectively; unadjusted odds ratio, 12.0; 95% CI, 4.1 to 35.3; P<0.001). QT-prolonging and other potentially proarrhythmic medications used by the study population encompassed almost all drug classes that should be avoided by LQTS patients.

Tier 5

In LQT1 patients, and other LQTS patients with a history of exercise induced syncope, swimming and diving are generally contraindicated. However, many patients choose to continue with swimming, and these are sometimes managed by the use of an advisory defibrillator with a supervisor at the pool-side, and adjuvant cardiac sympathectomy may be used.

Tier 2

LQT2 patients, or other LQTS patients who have experienced auditory-evoked cardiac events, should avoid exposure to acoustic stimuli especially during sleep (removing loud alarm clocks and turning down the volume on the phone at night).

Tier 2

Patients with LQTS should avoid or rapidly correct any electrolyte abnormalities (hypokalemia, hypomagnesaemia, hypocalcemia) that may occur during diarrhea, vomiting, metabolic conditions, or imbalanced diets for weight loss.

Tier 2

Epinephrine must be avoided as an adjuvant medication in regional anesthesia because it could provoke life-threatening arrhythmias. Atropine should also always be avoided because of its effect on heart rate and because it removes the cholinergic-adrenergic antagonism.

Tier 4

Nature of Intervention

Nature of Intervention

The identified interventions include beta-blockers and avoidance of QT prolonging drugs in all patients. Implantation of an ICD is an uncommon primary intervention which would involve invasive surgery and device maintenance, potentially starting at a young age. Inappropriate ICD shocks and device complications are reported in 8-35%, which can be minimized with concurrent beta-blocker therapy, optimal device programming, and appropriate lead selection. A meta-analysis of 462 LQTS patients from 7 studies reported that 13% (2.8% rate per year [95% CI 2.0-3.6]) experienced inappropriate shocks, and 26% (7% rate per year [95% CI 4.4-9.7]) experienced ICD-related complications including a 0.6% rate of ICD-related mortality. In addition, the use of ICD therapy carriers a risk for psychological consequences due to fear of being shocked, particularly among patients who have experienced a shock. Once started, beta blockers should not be stopped suddenly; there is a period of high risk after cessation due to up-regulation of beta-receptors on treatment. Certain disorders may be exacerbated by treatment with beta blockers (e.g. asthma, orthostatic hypotension, depression, and diabetes mellitus).

Context: Adult Pediatric

Chance to Escape Clinical Detection

Given that syncope is often the result of an arrhythmic event in patients with LQTS, early recognition and treatment are needed to avoid recurrences, which could present as cardiac arrest or SCD.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			KCNQ1			192500	0100316	0019171, 0002442
KCNH2			613688	0013367	0019171, 0002442
SCN5A			603830	0011377	0019171, 0002442

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