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):Complete (Actionability curation complete.)

GENE/GENE PANEL: SCN5A
Condition: Brugada Syndrome
GENEDISEASE PAIRS: SCN5A601144
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
Clinical Features
(Signs / symptoms)
Brugada syndrome is characterized by a distinctive 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, which can result in syncope or sudden cardiac death. 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 AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome. Electrical storms, multiple episodes of ventricular arrhythmias over a short period of time, are malignant but rare in patients.
4 3 5 2 1
Natural History
(Important subgroups & survival / recovery)
Brugada syndrome presents primarily during adulthood, with syncope as the most common presenting feature. Age at diagnosis ranges from 2 days to 85 years. The mean age of sudden death is approximately 40 years. Both sexes are at a high risk for ventricular arrhythmias and sudden death, though the vast majority of those affected are male. Patients who have easily induced sustained ventricular arrhythmias, a spontaneous type 1 ECG pattern (compared to pharmacologically-induced), and a history of syncope have a worse prognosis.
1 3 4 5 6
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
An implantable cardioverter defibrillator (ICD) is reasonable for patients with Brugada syndrome, though some guidelines only recommend ICD implantation for those with certain risk factors such as a history of syncope and/or documented ventricular tachycardia that has not resulted in cardiac arrest. ICD should also be considered in patients with a spontaneous type 1 ECG pattern. In the absence of a spontaneous type 1 ECG pattern, an implantable loop recorder (ILR) should be considered. A cohort study of 220 patients with Brugada and a history of syncope reported an appropriate ICD shock rate of 10% over 3 years. (Tier 2)
7 5 6
Two additional cohort studies reported appropriate shock rates of 19%, 16%, and 12% for patients with a history of syncope, patients with a type 1 ECG pattern, and asymptomatic patients, respectively. (Tier 5)
8 9
Treatment of asymptomatic individuals is controversial and recommendations vary, but include observation until the first symptom develops and placement of an ICD in individuals with a family history of sudden cardiac death or when electrophysiological study indicates a likelihood of arrhythmias. (Tier 3)
1
Quinidine is recommended to prevent primary symptoms, and has been shown to restore ST-segment elevation and decrease the incidence of arrhythmias. In one study, of 19 patients treated for 6 to 219 months and followed 0.5 to 22 years, none had an arrhythmic event. In another study, syncope occurred in 2 of 21 patients treated an average of 17 months. (Tier 3)
1
Women experiencing arrhythmic events due to hormone changes during pregnancy can be treated with quinidine to normalize the ECG pattern. In a case study of a young pregnant woman, oral quinidine inhibited the recurrence of ventricular tachyarrhythmia. (Tier 3)
1
Because perioperative pharmacological and physiological changes may precipitate malignant arrhythmias, specific management is required for patients under anesthesia. (Tier 3)
3
Surveillance
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
At-risk patients with a family history or a known pathogenic variant should undergo ECG monitoring every one to two years. (Tier 3)
1
Family Management
Serial ECGs and a pharmacological drug challenge can assist in risk stratification in individuals with a family history of Brugada syndrome. (Tier 2)
3
If the pathogenic variant is known, relatives at risk should undergo genetic testing to identify those who should undertake preventive measures as well as rule out risk for those not carrying the pathogenic variant. (Tier 3)
1
Circumstances to Avoid
Patients should avoid certain antiarrhythmic, psychotropic, and anesthetic drugs that can induce cardiac arrhythmias. Other agents to avoid include acetylcholine, alcohol toxicity, cocaine, and ergonovine. (Tier 2)
2
Patients should also avoid or quickly mitigate high fever and electrolyte disturbances. (Tier 3)
1
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
Pathogenic mutations in SCN5A account for 15-30% of Brugada syndrome cases. (Tier 3)
1 3
Penetrance
OR
Relative Risk
(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
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.
 
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, resulting in sudden death in 8-12% of affected individuals. (Tier 3)
1

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Sudden cardiac death / ICD implantation
3
2C
2B
2
9CB
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. R Brugada, O Campuzano, P Brugada, J Brugada, K Hong. Brugada syndrome. 2005 Mar 31 [Updated 2014 Apr 10]. 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/NBK1517
2. Postema PG, Wolpert C, Amin AS, Probst V, Borggrefe M, Roden DM, Priori SG, Tan HL, Hiraoka M, Brugada J, Wilde AA. Drugs and brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org). Heart Rhythm. (2009) 6(9):1335-41.
3. Carey SM, Hocking G. Brugada syndrome--a review of the implications for the anaesthetist. Anaesth Intensive Care. (2011) 39(4):571-7.
4. Brugada syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=130
5. 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.
6. 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.
7. Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure. Nice. (2014) Website: https://www.nice.org.uk/guidance/ta314
8. Conte G, Sieira J, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis G, Di Giovanni G, La Meir M, Wellens F, Czapla J, Wauters K, Levinstein M, Saitoh Y, Irfan G, Julia J, Pappaert G, Brugada P. Implantable cardioverter-defibrillator therapy in brugada syndrome: a 20-year single-center experience. J Am Coll Cardiol. (2015) 65(9):879-88.
9. Sacher F, Probst V, Maury P, Babuty D, Mansourati J, Komatsu Y, Marquie C, Rosa A, Diallo A, Cassagneau R, Loizeau C, Martins R, Field ME, Derval N, Miyazaki S, Denis A, Nogami A, Ritter P, Gourraud JB, Ploux S, Rollin A, Zemmoura A, Lamaison D, Bordachar P, Pierre B, Jais P, Pasquie JL, Hocini M, Legal F, Defaye P, Boveda S, Iesaka Y, Mabo P, Haissaguerre M. Outcome after implantation of a cardioverter-defibrillator in patients with brugada syndrome: a multicenter study-part 2. Circulation. (2013) 128(16):1739-47.
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