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Brugada syndrome (BrS) is a potentially life-threatening cardiac disorder characterized by ST segment elevation in right precordial leads (V1 to V3) on ECG, incomplete or complete right bundle branch block, and susceptibility to syncope, ventricular tachyarrhythmia and sudden cardiac death.
Brugada syndrome occurs worldwide and is estimated to affect 5 per 10,000 individuals of all ethnicities, with some regional differences.   BrS is a genetic cardiac channelopathy resulting from loss-of-function mutations causing changes in sodium and calcium ion flux.  It is inherited as an autosomal dominant trait, occurring in males and females equally, although males are more likely to be symptomatic. Family history suggestive of BrS is an important diagnostic factor, as spontaneous mutation occurs rarely and most affected individuals are expected to have an affected parent.

Clinical presentation/course

BrS has variable and diverse clinical manifestations. The most common clinical symptoms are syncope and cardiac arrest that occur at rest or during sleep. Some patients with BrS have supraventricular arrhythmias. Most individuals with BrS are asymptomatic. The diagnostic significance of a ‘Brugada-type’ ECG pattern in asymptomatic individuals is uncertain and is an area of ongoing study. Most symptomatic individuals present between ages 20 to 40, but symptoms have been reported from infancy through late life. Males are 8-10 times more likely than females to develop symptoms of Brugada syndrome for unclear reasons.

Figure 1: Brugada ECG pattern, Type 1, 2 and 3. (Click on the image to see enlarged figure.)

It is strongly recommended that structural abnormalities of the heart be excluded before a conclusive diagnosis of BrS is made.  The Brugada ECG pattern can be an early sublinical manifestation of arrhythmogenic right ventricular cardiomyopathy (ARVC).  Other factors that could account for either the ECG findings or syncope should also be excluded. These include atypical right bundle branch block, left ventricular hypertrophy, early repolarization, acute myocardial infarction, acute pericarditis, and the ECG changes sometimes seen in the right precordial leads in well-trained athletes.


Genetics of Brugada Syndrome

BrS is a genetic disorder with autosomal dominant transmission. Mutations in at least 5 genes influencing sodium and calcium currents in the heart are associated with BrS and account for at least 26%-41% of cases with Brugada syndrome. Genetic testing to predict the syndrome in asymptomatic at-risk family members of a patient with Brugada syndrome first requires identification of the disease-causing mutation in the family. If a disease-causing mutation is found in an affected individual, genetic testing of relatives may be appropriate, allowing for evaluation and treatment of only the family members at risk of arrhythmias. Most patients with Brugada syndrome have inherited a disease-causing mutation from a parent as de novo mutation in BrS is rare. Children of a patient diagnosed with BrS have a 50% chance of inheriting the mutation associated with the syndrome. As individuals with BrS may be asymptomatic, the lack of a family history does not rule out a heritable disease.

Gene Symbol Alpha-1C subunit of the L-type voltage-dependent calcium channel CACNA1C Beta-2 subunit of the voltage-dependent L-type calcium channel CACNB2 NAD-dependent glycerol-3-phosphate dehydrogenase GPD1L Voltage-gated sodium channel type 1 beta subunit SCN1B Sodium channel, voltage gated, type V beta subunit SCN5A

Genetic testing for Brugada Syndrome and its utility:
Diagnostic genetic testing can be considered for patients who clinically manifest with symptoms of BrS and for patients who are asymptomatic but are within a family with a known mutation. Testing should be performed first on the family member who is symptomatic, i.e. has clinical manifestations of BrS.  Preferably, the youngest of most severely affected family member should be tested first.  The three possible outcomes of genetic testing are: positive, negative, and variant of unknown clinical significance (VOUS).  Identification of a mutation in the family can lead to genetic identification of at risk family members who are clinically asymptomatic and who may have normal electrocardiograms.  Family members who test positive for the familial mutation should receive baseline electrocardiogram and annual ECG screening exams.  Alternatively, a negative genetic test result for the familial mutation would obviate the need for repeated follow-up examinations. Genetic testing can be used for prenatal diagnosis.  All patients who undergo genetic testing should receive pre-test and post-test genetic counseling to understand the implications of testing

Resources for Patients

• GeneDx cardiology page: www.genedx.com/cardiology
• Gene Reviews, a database of genetic diseases: www.geneclinics.org
• National Society of Genetic Counselors, to help you find a counselor near you: www.nsgc.org
• Ramon Brugada Senior Foundation www.brugada.org
• Sudden Arrhythmia Death Syndrome (SADS), a patient support organization: www.sads.org
• Cardiac Arrhythmias Research and Education Foundation (C.A.R.E.), a patient support organization: www.longqt.org
• The Canadian Sudden Arrhythmia Death Syndromes (SADS) Foundation, a patient support organization in Canada:  www.sads.ca
• Sudden Cardiac Arrest Association, a patient support organization:  www.suddencardiacarrest.org
• Genetic Heart Disease Program: www.geneticheartdisease.org

References

1. Brugada P and Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome - a multicenter report. J Amer Coll Cardiol 1992; 20: 1391-1396. PMID: 1309182
2. Antzelevitch C et al. Brugada syndrome: report of the second consensus conference. Heart Rhythym 2005; 4:429-40. PMID: 15898165
3. Fowler SJ and Priori SG. Clinical spectrum of patients with a Brugada ECG. Curr Opin Cardiol 2009: 24; 74-81. PMID: 19102039
4. Ekhardt L. Gender differences in Brugada Syndrome. J Cardiovasc Electrophysiol 2008: 18: 422-424. PMID: 17286563
5. Napolitano C, Priori SG. Brugada syndrome. Orphanet J Rare Dis. 1, 35. 2006. doi:10.1186/1750-1172-1-35. PMID: 16972995
6. Hong, K et al. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations.  Circulation 2004; 110: 3023-7. PMID: 15520322
7. Hedley, P. et al. The genetic basis of Brugada syndrome: a mutation update. Hum Mutation. 2009; 30:1-11. PMID: 19606473
8. Benito B, Brugada R, Brudaga J, Brugada P. Brugada Sydrome. Progress in Cardiovascular Diseases 2008: 51(1); 1-22. PMID: 18634914
9. Tan HL, Meregalli PG. Lethal ECG changes hidden by therapeutic hypothermia. Lancet 2007: 369; 78. PMID: 17208645
10. Bebarta VS, Phillips S, Eberhardt A et al. Incidence of Brugada ECG pattern and outcomes after intentional tricyclic antidepressant ingestion. Am J Cardiol 2007: 100; 656-660. PMID: 17697824
11. GeneReviews: Brugada syndrome. Brugada R, Brugada P, Brugada J & Hong K. at: http://www.ncbi.nlm.gov/bookshelf/br.fcgi?book=gene&part=brugada