Brugada Syndrome via the CACNA2D1 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, and intraventricular conduction delay. 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 (Francis and Antzelevitch 2005).

Brugada syndrome is an autosomal dominant 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 , 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 variant from a parent, as de novo mutations in BrS are rare (Hedley et al. 2009).The preproprotein encoded by the CACNA2D1 gene is posttranslationally processed into 2 peptides, an alpha-2 subunit and a delta subunit, which help form voltage-dependent calcium channels. CACNA2D1 genetic variants could reduce L-type calcium channel current, shorten repolarization QT intervals and trigger cardiac arrhythmias (Burashnikov et al. 2010; Bourdin et al. 2015). So far, all pathogenic CACNA2D1 variants reported to cause BrS are missense variants (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the CACNA2D1 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Pathogenic variants 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). Gross deletions or duplications not detectable by sequencing have been reported in CACNA2D1 as individual cases associated with epilepsy and intellectual disability, but not with Brugada Syndrome (Human Gene Mutation Database).