Brugada Syndrome Panel

Brugada syndrome (BrS) is a potentially life-threating cardiac arrhythmia disorder without structural abnormalities, characterized by dizziness, syncope, nocturnal agonal respiration and sudden death. The classic electrocardiographic findings associated with Brugada Syndrome include ST segment elevation in leads V1 to V3, right bundle branch block, first degree AV block, and intraventricular conduction delay. Brugada syndrome is much more common in men than in women, and many people who have Brugada syndrome don't have symptoms. Symptoms usually manifest during adulthood, but they may appear any time between two days and 80 years of age (Antzelevitch et al. 2005). Brugada syndrome is treatable with preventive measures such as reducing fever, avoiding certain medications and using an implantable cardiac defibrillator (Francis et al. 2005).

Brugada syndrome is an autosomal dominant or X-linked dominant genetic disorder with variable expression, resulting from pathogenic variants within genes that encode cardiac ion channels. BrS is also referred to as a “cardiac channelopathy.” Pathogenic variants in 16 genes (CACNA1C, CACNB2, CACNA2D1, GPD1L, KCND3, KCNE3, KCNE5, KCNJ8, HCN4, RANGRF, SCN5A, SCN1B, SCN2B, SCN3B, SLMAP, and TRPM4) influencing sodium and calcium currents in the heart are associated with BrS and account for at least 26%-41% of cases (Kapplinger et al 2010; Crotti et al. 2012). Most patients with Brugada syndrome have inherited a disease-causing variant from a parent, as de novo pathogenic variants in BrS are rare (Hedley et al. 2009). See individual gene test descriptions for information on molecular biology of gene products, and spectra of pathogenic variants.

Pathogenic variants in SCN5A cause 15%-30% of Brugada syndrome cases based on clinical diagnosis. Pathogenic variants within other genes associated with Brugada syndrome (GPD1L, CACNA1C, CACNB2B, SCN1B, SCN3B, KCNE3,KCNJ8, KCND3,CACNA2D1, MOG1, and HCN4) have been identified in a total of approximately 5% of patients (Kapplinger et al 2010; Crotti et al. 2012). KCNE5, SCN2B, SLMAP and TRPM4 are newly identified genes associated with Brugada syndrome. There is insufficient data to calculate their clinical sensitivities.

Gross deletions or duplications not detectable by Sanger sequencing have been reported in CACNB2, CACNA2D1 and SCN5A as individual cases, but no statistical data is available yet (Human Gene Mutation Database). To date, no gross deletions or duplications have been reported in CACNA1C, GPD1L, KCND3, KCNE3, KCNE1L (KCNE5), KCNJ8, HCN4, RANGRF, SCN1B, SCN2B, SCN3B, SLMAP and TRPM4 (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).