ACTIONABILITY KNOWLEDGE REPOSITORY ACTIONABILITY CURATION INTERFACE

Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening P Current Version Rule-Out Dashboard Release History Status (Pediatric): Passed (Consensus scoring is Complete) Curation Status (Pediatric): Released Status (Adult): Passed (Consensus scoring is Complete) A

GENE/GENE PANEL: SCN5A
Condition: Brugada Syndrome
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
SCN5A0011001 (brugada syndrome 1; brgda1)
Strong Actionability
Actionability Rationale
Most scorers felt that the final assertion was between Moderate and Strong, but the majority of scorers chose Strong. Although there is strong evidence for the intervention that drives the score, there is another intervention (ICD placement) that is more invasive but with less evidence of effectiveness particularly in children.
Final Consensus Scoresa
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Gene Disease Pairs: SCN5A0011001
Sudden cardiac death / Avoidance of drugs with sodium channel blocking properties and high fever
3
2C
2B
3
10CB
Sudden cardiac death / Risk stratification (may include EPS) to guide ICD placement
3
2C
2D
2
9CD

 
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
The prevalence of Brugada syndrome is difficult to estimate due to the recent identification of the disorder and the difficulty in diagnosis. Available prevalence estimates vary around the world, from 1/700-1/800 in certain endemic areas of Asia to 1/3,300-1/10,000 in Europe and the United States.
1 2 3 4 5 6 7
Clinical Features
(Signs / symptoms)
Brugada syndrome is characterized by a distinctive electrocardiographic (ECG) pattern of sinus tachycardia (ST) segment elevation in the V1-V3 leads (termed “type 1 abnormality”) in the absence of gross structural abnormalities. Patients have a high risk for ventricular arrhythmias (VA), which can result in syncope or sudden cardiac death (SCD). Clinical presentations may also include sudden infant death syndrome (SIDS) and the sudden unexpected nocturnal death syndrome (SUNDS). Other conduction defects can include first-degree atrioventricular (AV) block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome. Electrical storms, multiple episodes of VA over a short period of time, are malignant but rare in patients. Symptoms include nocturnal agonal respiration, palpitations and chest discomfort, which often occur during rest, sleep, during a febrile state, or with vagotonic conditions, but rarely during exercise.
8 1 2 3 4 5 6 7 9
Natural History
(Important subgroups & survival / recovery)
Brugada syndrome presents primarily during adulthood, with syncope as the most common presenting feature. Age at diagnosis may range from infancy to late adulthood. The mean age of SCD is approximately 40 years. Both sexes are at a high risk for VA and SCD, though the vast majority of those affected are male. Patients who have easily induced sustained VA, a spontaneous type 1 ECG pattern (compared to pharmacologically-induced), and a history of syncope have a worse prognosis.
8 1 2 3 4 5 6 7 9
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish extent of disease and individual needs after initial diagnosis, patients are recommended to undergo an ECG, induction with sodium channel blockers among those with a type 2 or type 3 pattern on ECG, electrophysiological study, and medical genetics consultation. (Tier 4)
1
An implantable cardioverter defibrillator (ICD) is reasonable for patients with Brugada syndrome with certain risk factors such as a history of arrhythmic syncope and/or spontaneous type 1 ECG pattern, and/or documented ventricular tachycardia (VT) and/or are survivors of aborted cardiac arrest. One guideline recommends considering ICD implantation in those with Brugada syndrome who develop ventricular fibrillation (VF) during programmed ventricular stimulation (PVS) with two or three extrastimuli at two sites. (Tier 1)
6 8 9 10
ICD implantation has been shown to reduce mortality in symptomatic patients with Brugada syndrome. A systematic review reports that in patients with Brugada syndrome (who had already survived a sudden cardiac arrest event) randomized to ICD therapy, there was a nine-fold lower risk of mortality compared with people randomized to medical therapy (0% with ICD versus 18% with medical therapy; RR 0.11, 95% CI 0.01 to 0.83; 2 trials, 86 participants). A meta-analysis of 1539 patients with Brugada syndrome reported that during a mean follow-up of 4.9 years, 229 patients (18%) experienced appropriate ICD intervention. The appropriate ICD intervention rate was 3.1 per 100 person years. (Tier 1)
11 12
The following studies have been performed in clinically affected individuals. There is conflicting evidence regarding risk stratification based on electrophysiological study (EPS). A multicenter prospective study investigated risk stratification in individuals (N = 320) with type 1 ECG pattern for primary prevention of SCD and no previous cardiac arrest or documented VT/VF. EPS with PVS was performed in 245 patients and ICD placement occurred in 110. During follow-up (median = 40 months) major arrhythmic events occurred in 14% of patients with positive EPS, 0% patients with negative EPS, and 5.3% patients without EPS. (Tier 1)
9
However, another study evaluated a Brugada syndrome registry of 1029 consecutive patients with type 1 ECG pattern at baseline or after drug challenge. Cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients (median follow-up = 31.9 months), suggesting symptoms and spontaneous type 1 ECG were predictive of arrhythmatic events. Though not specifically noted in the recommendation for ICD placement, studies have assessed additional risk factors such as QRS fragmentation and SCN5A pathogenic variant status. A prospective study (N = 308) assessed predictors of arrhythmic events in patients with Brugada syndrome without history of VT/VF during a median follow-up of 34 months and found that arrhythmia inducibility was not a predictor while history of syncope, spontaneous type 1 ECG, ventricular refractory period <200 ms, and QRS fragmentation were significant predictors. In a large case series of patients with Brugada syndrome who experienced an arrhythmic event, SCN5A pathogenic variants were found in 30% of the cohort. Higher SCN5A pathogenic variant rates were observed in females in all age groups. (Tier 5)
13 14 15
A meta-analysis of 1780 patients with Brugada syndrome found that the presence of SCN5A pathogenic variants was associated with elevated risk of major arrhythmic events in both Asian (OR = 1.82, 95% CI 1.07-3.11; P=0.03) and white (OR 2.24, 95% CI 1.02-4.90; P=0.04) populations. (Tier 1)
16
Observation without therapy is recommended in asymptomatic patients with only inducible type 1 ECG pattern. Implantation of an ICD in an asymptomatic patient without a spontaneous type 1 ECG pattern has not been shown to confer any benefit. (Tier 1)
9
Women experiencing arrhythmic events due to hormone changes during pregnancy can be treated with quinidine to normalize the ECG pattern. (Tier 3)
1
Because perioperative pharmacological and physiological changes may precipitate syncope or sudden death, specific management is required for patients under anesthesia. (Tier 3)
2
Surveillance
Individuals with a known pathogenic variant in should undergo ECG monitoring every one to two years beginning at birth. (Tier 3)
1
Circumstances to Avoid
Patients should avoid certain antiarrhythmic, psychotropic, and anesthetic drugs that can induce or aggravate cardiac arrhythmias. Other agents to avoid include acetylcholine, alcohol toxicity, cocaine, cannabis, and ergonovine (Tier 2)
3 5 6 9
One retrospective study evaluated 74 adult cases of drug-induced type 1 Brugada pattern on ECG from noncardiac drugs (including psychotropic and anesthetic drugs); 77% were males, drug toxicity was involved in 46%, and mortality was 13%. These 74 patients more frequently had abnormal ECG in the absence of drugs than the ECG of controls (56% vs 33%, p=0.04). Fever was present in 10 cases (13.5%); 3 of these 10 febrile patients developed VF (Tier 2)
9
Patients should also avoid or quickly mitigate high fever with antipyretic drugs. (Tier 2)
5 6 9
One retrospective multicenter study evaluated fever related arrhythmic events in patients with Brugada syndrome (defined as a typical type 1 ECG either spontaneously or after IV administration of a sodium channel blocking drug). In 35 of 588 patients (6%) the arrhythmic event occurred during a febrile illness; 80% were male, 80% presented with aborted cardiac arrest and 17% with arrhythmic storm. An SCN5A pathogenic variant was found in 12 of 28 (43%) who underwent genetic testing. The highest proportion of fever-related arrhythmic events were observed in the pediatric population (age <16 years), with a disproportionately higher event rate in the very young (age 0-5 years; 65%). (Tier 5)
17
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
The population prevalence of pathogenic variants associated with Brugada syndrome was not available. However, it is estimated that 15-30% of Brugada syndrome cases can be attributed to pathogenic variants in SCN5A. (Tier 3) (Tier 3)
1 2 7 9
Penetrance
(Include any high risk racial or ethnic subgroups)
Among individuals with a pathogenic variant in SCN5A, approximately 20-30% have a type 1 ECG pattern and approximately 80% manifest the characteristic ECG change when challenged with a sodium channel blocker. (Tier 3)
1
The majority of patients remain asymptomatic, while 20-30% experience syncope and 8-12% experience at least one cardiac arrest (potentially leading to sudden death). (Tier 4)
4
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available.
 
 
Expressivity
Information on variable expressivity was not available.
 
4. What is the Nature of the Intervention?
Nature of Intervention
Identified interventions include the implantation of an ICD, which would involve invasive surgery and device management, potentially starting at a young age; those who are young will require multiple device replacements during their lifetime. In the pediatric patients, ICD implantation is more challenging and complications are more frequent due to the increased heart rates and activity of the population. Inappropriate ICD shocks and device complications can be minimized by optimal device programming and appropriate lead selection. A meta-analysis of 1037 Brugada syndrome patients from 17 studies reported that 21 (3.9% rate per year [95% CI 3.0-4.8]) experienced inappropriate shocks, and 21 (3.4% rate per year [95% CI 2.5-4.3]) experienced complications. In addition, the use of ICD therapy carries a risk for psychological consequences due to the fear of being shocked, particularly among patients who have experienced a shock.
5 7 8 9 18
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Brugada syndrome is typically diagnosed with ECG, a screening procedure not typically recommended for asymptomatic adults with apparently low risk of coronary heart disease. It is very likely this disorder could go unrecognized and present in a patient as ventricular arrhythmia and cardiac arrest, which may result in sudden death. (Tier 3)
1
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.

 
Gene Disease Associations
Gene
Disease Associations
Primary MONDO Identifier
Additional MONDO Identifiers
OMIM Identifier
Reference List
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4. Brugada syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=130
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6. 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. Rev Esp Cardiol (Engl Ed). (2016) 69(2):176.
7. Brugada J, Blom N, Sarquella-Brugada G, Blomstrom-Lundqvist C, Deanfield J, Janousek J, Abrams D, Bauersfeld U, Brugada R, Drago F, de Groot N, Happonen JM, Hebe J, Yen Ho S, Marijon E, Paul T, Pfammatter JP, Rosenthal E. Pharmacological and non-pharmacological therapy for arrhythmias in the pediatric population: EHRA and AEPC-Arrhythmia Working Group joint consensus statement. Europace. (2013) 15(9):1337-82.
8. 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.
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: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. (2018) 15(10):e73-e189.
10. 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.
11. McNamara DA, Goldberger JJ, Berendsen MA, Huffman MD. Implantable defibrillators versus medical therapy for cardiac channelopathies. Cochrane Database Syst Rev. (2015)
12. Dereci A, Yap SC, Schinkel AFL. Meta-Analysis of Clinical Outcome After Implantable Cardioverter-Defibrillator Implantation in Patients With Brugada Syndrome. JACC Clin Electrophysiol. (2019) 5(2):141-148.
13. Milman A, Gourraud JB, Andorin A, Postema PG, Sacher F, Mabo P, Conte G, Giustetto C, Sarquella-Brugada G, Hochstadt A, Kim SH, Juang JJM, Maeda S, Takahashi Y, Kamakura T, Aiba T, Leshem E, Michowitz Y, Rahkovich M, Mizusawa Y, Arbelo E, Huang Z, Denjoy I, Wijeyeratne YD, Napolitano C, Brugada R, Casado-Arroyo R, Champagne J, Calo L, Tfelt-Hansen J, Priori SG, Takagi M, Veltmann C, Delise P, Corrado D, Behr ER, Gaita F, Yan GX, Brugada J, Leenhardt A, Wilde AAM, Brugada P, Kusano KF, Hirao K, Nam GB, Probst V, Belhassen B. Gender differences in patients with Brugada syndrome and arrhythmic events: Data from a survey on arrhythmic events in 678 patients. Heart Rhythm. (2018) 15(10):1457-1465.
14. Probst V, Veltmann C, Eckardt L, Meregalli PG, Gaita F, Tan HL, Babuty D, Sacher F, Giustetto C, Schulze-Bahr E, Borggrefe M, Haissaguerre M, Mabo P, Le Marec H, Wolpert C, Wilde AA. Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation. (2010) 121(5):635-43.
15. Priori SG, Gasparini M, Napolitano C, Della Bella P, Ottonelli AG, Sassone B, Giordano U, Pappone C, Mascioli G, Rossetti G, De Nardis R, Colombo M. Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry. J Am Coll Cardiol. (2012) 59(1):37-45.
16. Chen C, Tan Z, Zhu W, Fu L, Kong Q, Xiong Q, Yu J, Hong K. Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta-analysis. Clin Genet. (2020) 97(1):198-208.
17. Michowitz Y, Milman A, Sarquella-Brugada G, Andorin A, Champagne J, Postema PG, Casado-Arroyo R, Leshem E, Juang JJM, Giustetto C, Tfelt-Hansen J, Wijeyeratne YD, Veltmann C, Corrado D, Kim SH, Delise P, Maeda S, Gourraud JB, Sacher F, Mabo P, Takahashi Y, Kamakura T, Aiba T, Conte G, Hochstadt A, Mizusawa Y, Rahkovich M, Arbelo E, Huang Z, Denjoy I, Napolitano C, Brugada R, Calo L, Priori SG, Takagi M, Behr ER, Gaita F, Yan GX, Brugada J, Leenhardt A, Wilde AAM, Brugada P, Kusano KF, Hirao K, Nam GB, Probst V, Belhassen B. Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada Syndrome. Heart Rhythm. (2018) 15(9):1394-1401.
18. 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.
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