Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released - Under Revision 1.0.1
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: KCNQ1, KCNH2, SCN5A
• Condition: Long QT Syndrome, types 1, 2, and 3
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• KCNQ1 ⇔ 0008646 (long qt syndrome 1; lqt1): Strong Actionability
• KCNH2 ⇔ 0013367 (long qt syndrome 2; lqt2): Strong Actionability
• SCN5A ⇔ 0011377 (long qt syndrome 3; lqt3): Strong Actionability

Actionability Rationale

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

Final Consensus Scores

Gene Condition Pairs: KCNQ1 ⇔ 0008646 (OMIM:192500) KCNH2 ⇔ 0013367 (OMIM:613688)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the 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

Gene Condition Pairs: SCN5A ⇔ 0011377 (OMIM:603830)

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of long QT syndrome (LQTS) has been estimated at 1:2,500. [1, 2, 3, 4, 5]

Clinical Features

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. [1, 2, 3, 5, 6, 7, 8]

Natural History

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. [1, 2, 3, 4, 9]

2. How effective are interventions for preventing harm?

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) [5]

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) [2, 9, 10]

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) [7]

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) [2, 6, 9, 10]

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) [2, 9]

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) [5]

Women with LQT2 are at higher risk of postpartum SCA/SCD and should receive prepregnancy counseling. (Tier 1) [9]

Surveillance

No surveillance recommendations have been provided for the Pediatric context.

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) [1]

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) [9, 10]

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) [11]

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) [1, 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) [1, 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) [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) [8]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

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

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) [5]

However, the yield of genetic testing has been as high as 90% for these three genes in some LQTS cohorts. (Tier 5) [12]

Penetrance

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) [5]

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) [2, 13]

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) [1]

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) [14]

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) [12]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Considerable phenotypic variability within families has been reported. (Tier 3) [5]

4. What is the Nature of the 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). [1, 5, 6, 9, 15]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

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. (Tier 4) [10]

Date of Search: 08.28.2019

Reference List

1. Waddell-Smith KE, Skinner JR. Update on the Diagnosis and Management of Familial Long QT Syndrome. Heart Lung Circ. (2016) 25(8):769-76.

2. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace. (2015) 17(11):1601-87.

3. Romano-Ward syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=101016

4. Familial long QT syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=768

5. M Alders, I Christiaans. Long QT Syndrome. 2003 Feb 20 [Updated 2015 Jun 18]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1129

6. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes NA 3rd, Ferguson TB Jr, Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. (2013) 61(3):e6-75.

7. Ahn J, Kim HJ, Choi JI, Lee KN, Shim J, Ahn HS, Kim YH. Effectiveness of beta-blockers depending on the genotype of congenital long-QT syndrome: A meta-analysis. PLoS One. (2017) 12(10):e0185680.

8. Friederich P, Pfitzenmayer H. Anaesthesia recommendations for patients suffering from Long QT syndrome. Orphananesthesia. (2014) Accessed: 2019-08-28. Website: https://www.orpha.net/data/patho/Ans/en/Long_QT_EN.pdf

9. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. Circulation. (2018) 138(13):e272-e391.

10. Shen WK, Sheldon RS, Benditt DG, Cohen MI, Forman DE, Goldberger ZD, Grubb BP, Hamdan MH, Krahn AD, Link MS, Olshansky B, Raj SR, Sandhu RK, Sorajja D, Sun BC, Yancy CW. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. (2017) 136(5):e25-e59.

11. Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C, Crotti L, Piippo K, Lupoglazoff JM, Villain E, Priori SG, Napolitano C, Zhang L. High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment "failures". Circulation. (2009) 119(2):215-21.

12. Adler A, Sadek MM, Chan AY, Dell E, Rutberg J, Davis D, Green MS, Spears DA, Gollob MH. Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. Circ Arrhythm Electrophysiol. (2016) 9(1):e003440.

13. Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli A, Fedorowski A, Furlan R, Kenny RA, Martin A, Probst V, Reed MJ, Rice CP, Sutton R, Ungar A, van Dijk JG. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. (2018) 39(21):1883-1948.

14. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. (2003) 348(19):1866-74.

15. Olde Nordkamp LR, Postema PG, Knops RE, van Dijk N, Limpens J, Wilde AA, de Groot JR. Implantable cardioverter-defibrillator harm in young patients with inherited arrhythmia syndromes: A systematic review and meta-analysis of inappropriate shocks and complications. Heart Rhythm. (2016) 13(2):443-54.