Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Incomplete (WARNING: Incomplete Stage 2 curation.)

GENE/GENE PANEL: KCNQ1, KCNH2, SCN5A
Condition: Romano-Ward Long QT Syndrome
GENEDISEASE PAIRS: KCNQ1192500 KCNH2613688 SCN5A603830
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Long QT Syndrome (LQTS) has prevalence estimates ranging from 1/2000 to 1/7000
1 2 3 4
Clinical Features
(Signs / symptoms)
LQTS is an electrophysiological disorder characterized by QT interval prolongation and torsade de pointes (TdP) ventricular tachycardia in the absence of structural heart disease. TdP is typically self-terminating, resulting in a syncopal event, which is the most common symptom in LQTS. TdP can degenerate into a malignant ventricular arrhythmia which may result in cardiac arrest or sudden cardiac death (SCD). The precipitating conditions associated with arrhythmic events are, to a large extent, gene-specific with most arrhythmic events occurring during physical or emotional stress in LQT1 (KCNQ1); at rest, during emotional stress , and with sudden noises in LQT2 (KCNH2); and at rest or during sleep in LQT3 (SCN5A).
1 2 3 5 6 7
Natural History
(Important subgroups & survival / recovery)
The mean age for the first manifestation of LQTS is 12 years, but can range from the first year of life to as late as the fifth or sixth decade. Subsequent cardiac events may occur from infancy through middle age, but are most common from the pre-teen years through the 20s. After age 40, cardiac events are uncommon for most genotypes. Among untreated patients, the natural history typically involves several syncopal events, eventually leading to SCD. For some, SCD is the first manifestation of the disease.
 
Prognosis in LQTS is often determined by the genetic defect, QT duration, gender, and prior events. LQT3 patients have the highest risk, compared to LQT1 and LQT2. A normal QT interval provides a good prognosis, while a QT interval exceeding 500ms provides the highest risk of symptoms. Males have a poorer prognosis than females in adulthood, though the reverse is true in childhood. A family history of SCD has not been shown to be a risk factor for SCD. However, patients who have been resuscitated from SCD have an especially poor prognosis, with a relative risk of 12.9 of experiencing another cardiac arrest. Risk of SCD is also increased during the immediate post-partum period, particularly in women with LQT2.
1 2 3 5 6 7
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Beta blockade should be initiated in those who have had symptoms, those with a definite long QT interval, and in those with a positive genetic diagnosis but a normal QT interval. In a study of LQT1 (n=549) and LQT2 (n=422) patients from an international registry, reduction of risk of cardiac arrest or SCD was 23% in LQT1 adult males, 34% in LQT1 adult females, 46% in LQT2 adult males and 71% in LQT2 adult females. (Tier 2)
1 5 7 8
Evidence regarding the effectiveness of beta blockers in patients with LQT3 is variable. One primary study reported that beta-blockers had statistically significant effects in preventing cardiac events in patients with LQT1 (HR=0.29, p<0.001) and LQT2 (HR=0.47, p=0.01) but not in patients with LQT3 (HR=1.67, p=0.44); sample size was particularly small for the LQT3 subset and lacked power. A second primary study reported that beta-blocker therapy significantly reduced the risk of cardiac arrest and sudden cardiac death in a large group of LQT3 patients (HR=0.34, p=0.02), but detailed information on study design and results were lacking. (Tier 5)
9 10
Implantation with an implantable cardioverter defibrillator (ICD) along with continued use of beta blockers can be effective in reducing SCD in LQTS patients. ICD implantation is recommended for high risk LQTS patients, such as those with a previous cardiac arrest, those who experience syncope and/or ventricular tachycardia while receiving beta blockers, and those with LQT2 and LQT3 which are associated with a high risk of cardiac arrest. 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)
5 6
Left cardiac sympathetic neural denervation (LCSD) may be considered for LQTS patients with syncope, TdP, or cardiac arrest while receiving beta blockers. No primary studies were cited; the level of evidence was rated as, “limited population risk strata evaluated” and “conflicting evidence from single randomized trial or non-randomized studies.” (Tier 1)
5
Surveillance
No surveillance recommendations have been provided.
 
Family Management
First degree relatives of patients with LQTS should undergo an ECG to determine QT interval and genetic testing for certainty of mutation status. (Tier 2)
1
Family members who have not been excluded for LQTS should avoid medications contra- indicated in LQTS, beta blockers should be proposed, and sensible limitations should be placed on sporting activities. (Tier 2)
1
Circumstances to Avoid
Patients with LQTS are recommended to avoid competitive sports activity, specifically those with LQT1 and those who have experienced cardiac events during exercise. However, among 60 LQTS athletes who did not follow recommendations in one study, only 1 experienced a sporting-related event: a 9-year-old boy with LQT1, extreme QT prolongation, a history of aborted cardiac arrest and non-compliance with beta-blockers. (Tier 2)
1 5
Patients with LQTS should avoid drugs known to prolong the QT interval, cause TdP, or deplete potassium and magnesium. (Tier 2)
1 5 7
LQT1 patients and other LQTS patients who have experienced exercise-induced syncope should avoid or limit swimming and diving. (Tier 2)
1 5
LQT2 patients and other LQTS patients who have experienced auditory-evoked cardiac events should avoid exposure to acoustic stimuli especially during sleep (e.g. avoidance of telephone and alarm clock on the night stand). (Tier 2)
5
Patients with LQTS should avoid or rapidly correct any electrolyte abnormalities that may occur during diarrhea, vomiting, metabolic conditions, or imbalanced diets for weight loss. (Tier 2)
7
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
Mutations in KCNQ1, KCNH2, and SCN5A (all gain of function for SCN5A) make up almost 100% of patients with genetically confirmed autosomal dominant LQTS. Note that only about 75% of clinically diagnosed patients will have a detectable mutation (Tier 3)
2
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Among all patients with LQTS, approximately 50% or fewer have symptoms, usually one to a few syncopal spells, while the remaining approximately 50% or more never show symptoms. Across LQTS subtypes, the penetrance of syncopal events varies: 63% in LQT1, 46% in LQT2, and 18% in LQT3. The incidence of SCD is 6-8% among all individuals with LQTS, which does not differ across subtypes. (Tier 3)
2
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)
11
Information on relative risk was not available.
 
 
Expressivity
The number of syncopal events in symptomatic patients with LQTS ranges from 1 to hundreds, indicating variable expressivity (Tier 4)
2
4. What is the Nature of the Intervention?
Nature of Intervention
The identified interventions include implantation of an ICD, which would involve invasive surgery and device maintenance, potentially starting at a young age. 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. Lifetime treatment with beta blockers may have side effects.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
LQTS is typically diagnosed with ECG, a screening procedure not typically recommended for asymptomatic adults with apparently low risk of coronary heart disease. Additionally, up to one- third of asymptomatic gene mutation carriers have results within the normal range. It is likely that this disorder could go unrecognized and present in a patient as TdP and cardiac arrest, potentially resulting in SCD. (Tier 4)
2

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Sudden cardiac death (KCNQ1, KCNH2) / Beta blockers
3
2C
2B
3
10CB
Sudden cardiac death (KCNQ1, KCNH2) / ICD implantation
3
2C
2A
2
9CA
Sudden cardiac death (SCN5A) / Beta blockers
3
2C
0D
3
8CD
Sudden cardiac death (SCN5A) / ICD implantation
3
2C
2A
2
9CA
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Skinner J. Cardiovascular genetic diseases council writing group. guidelines for the diagnosis and management of familial long qt syndrome. .. The cardiac society of australia and new zealand. (2011) Website: http://www.csanz.edu.au/documents/guidelines/clinical_practice/Familial_Long_QT_Syndrome.pdf
2. 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; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1129
3. Romano-Ward syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=101016
4. Beckmann BM, Wilde AA, Kaab S. Clinical utility gene card for: long-qt syndrome (types 1-13). Eur J Hum Genet. (2013) 21(10).
5. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B. Acc/aha/esc 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the american college of cardiology/american heart association task force and the european society of cardiology committee for practice guidelines (writing committee to develop guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death) developed in collaboration with the european heart rhythm association and the heart rhythm society. Europace. (2006) 8(9):746-837.
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. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. Hrs/ehra/aphrs expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by hrs, ehra, and aphrs in may 2013 and by accf, aha, paces, and aepc in june 2013. Heart Rhythm. (2013) 10(12):1932-63.
8. Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, Deharo JC, Gajek J, Gjesdal K, Krahn A, Massin M, Pepi M, Pezawas T, Ruiz Granell R, Sarasin F, Ungar A, van Dijk JG, Walma EP, Wieling W. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. (2009) 30(21):2631-71.
10. Sauer AJ, Moss AJ, McNitt S, Peterson DR, Zareba W, Robinson JL, Qi M, Goldenberg I, Hobbs JB, Ackerman MJ, Benhorin J, Hall WJ, Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long qt syndrome in adults. J Am Coll Cardiol. (2007) 49(3):329-37.
11. 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.
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