Brugada Syndrome via the CACNB2 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 BrS include ST segment elevation in leads V1 to V3, right bundle branch block, first degree AV block, intraventricular conduction delay, etc. Brugada syndrome is much more common in men than in women, and many people who have BrS don't have any symptoms. Symptoms usually manifest during adulthood, but they may appear any time between two days and 80 years of age (Antzelevitch et al. 2005). BrS is treatable with preventive measures such as reducing fever, avoiding certain medications and using an implantable cardiac defibrillator when necessary (Francis and Antzelevitch 2005).

Brugada syndrome is an autosomal dominant disorder with variable expression, resulting from mutations within genes that encode cardiac ion channels. BrS is also referred to as a “cardiac channelopathy.” Mutations in 16 genes ( CACNA1C , CACNB2, CACNA2D1 , GPD1L , KCND3 , K CNE3 , KCNE5, KC NJ8 , HCN4 , R ANGRF , SCN5A , SCN 1B , SCN2B , SCN3B , SLMAP, an d TRPM4) influencing sodium and calcium currents in the heart are associated with BrS and account for at least 26%-41% of cases of BrS (Kapplinger et al 2010; Crotti et al. 2012). Most patients with BrS have inherited a disease-causing mutation from a parent, as de novo mutations in BrS are rare (Hedley et al. 2009).

CACNB2 encodes the cardiac voltage-dependent L-type calcium channel (LTCC) Beta-2 subunit. L-type calcium channels (LTCC) regulate calcium entry into cardiomyocytes. CACNB2 protein LTCC auxiliary subunits traffic the pore-forming Alpha-1C subunit (CACNA1C) to the membrane, modulate channel kinetics and play important role in excitation-contraction coupling (Catterall et al. 2005). Most causative mutations reported in CACNB2 are missense mutations, including all reported to cause BrS (Human Gene Mutation Database).

Mutations in the SCN5A gene cause 15%-30% of Brugada syndrome based on clinical diagnosis. Another 5% of patients with BrS have pathogenic variants in one of the following genes: GPD1L, CACNA1C, CACNB2, SCN1B, SCN3B, KCNE3, KCNJ8, KCND3, CACNA2D1, MOG1 and HCN4 (Kapplinger et al. 2010; Crotti et al. 2012).

This test provides full coverage of all coding exons of the CACNB2 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).