Brugada Syndrome via the SLMAP 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 remain asymptomatic. 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 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 of Brugada syndrome (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).

SLMAP encodes a 828 amino acid protein, spans over 175 kb and is located at 3p14.3 (Wigle et al. 1997). Sarcolemmal membrane-associated protein encoded by SLMAP is one of the components of cardiac membranes involved in excitation-contraction (E-C) coupling. SLMAP can regulate excitation-contraction coupling at the level of the sarcoplasmic reticulum and its perturbation results in progressive deterioration of cardiac electrophysiology and function (Nader et al. 2012). To date, all reported pathogenic variants in SLMAP have been missense variants (Human Gene Mutation Database).

There is insufficient data to calculate clinical sensitivity.

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