Brugada Syndrome via the SCN3B Gene

Brugada syndrome (BrS) is a potentially life-threating 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 managed with preventive measures such as reducing fever, avoiding certain medications and using implantable cardiac defibrillator when necessary (Francis et al. 2005).

Brugada syndrome is an autosomal 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 mutation from a parent, as de novo mutation in BrS is rare (Hedley et al. 2009).

Sodium channels consist of α subunits and β subunits, which could be classified as “voltage-gated” or “ligand-gated” based on the triggers. SCN3B encodes protein Navβ3, a β3 subunit of the voltage-gated sodium channel (Morgan et al. 2000). In the heart, the function Navβ3 is to modify the function of Nav1.5, which regulates Inward sodium current (INa) and alternate cardiac action potential. Functional alterations of INa caused by gene mutations have been reported in a wide range of arrhythmias (Ishikawa et al. 2013). So far, all causative variants reported in SCN3B are missense variants (Human Gene Mutation Database).

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, CACNB2, SCN1B, SCN3B, KCNE3, KCNJ8, KCND3,CACNA2D1, MOG1, and HCN4) have together been identified in approximately 5% of patients with Brugada syndrome (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 estimate their clinical sensitivities at this time.

No gross deletions or duplications have been reported to date in SCN3B (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SCN3B gene 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 full 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).