Brugada Syndrome via the KCND3 Gene

Brugada syndrome (BrS) is a potentially life-threating arrhythmia disorder without structural abnormalities. BrS is 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. BrS is much more common in men than in women, and many people who have BrS 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). BrS is treatable 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 BrS have inherited a disease-causing variant from a parent as de novo pathogenic variants in BrS are rare (Hedley et al. 2009). The majority of causative variants in KCND3 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 these genes associated with Brugada syndrome (GPD1L, CACNA1C, CACNB2B, SCN1B, SCN3B, KCNE3, KCNJ8, KCND3, CACNA2D1, MOG1 and HCN4) have together been identified in approximately 5% of patients with BrS (Kapplinger et al. 2010; Crotti et al. 2012).

This test provides full coverage of all coding exons of the KCND3 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).