Long QT Syndrome via the SCN4B Gene

Long QT syndrome (LQTS) is a heritable channelopathy characterized by an exceedingly prolonged cardiac repolarization that may trigger ventricular arrhythmias (torsade de pointes), recurrent syncopes, seizure, or sudden cardiac death (SCD) (Cerrone et al. 2012). The incidence of LQTS has been estimated between 1 in 2500 and 1 in 7000 in the general population. LQTS can manifest with syncope and cardiac arrest that is commonly triggered by adrenergic stress, often precipitated by emotion or exercise. Roughly 10% to 15% of patients experience symptoms at rest or during the night (Schwartz et al. 2001). The mean age of onset of symptoms is 12 years, and earlier onset usually is associated with a more severe form of the disease (Priori et al 2004). Inherited LQTS occurs due to mutations in multiple genes such as KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), ANK2(LQT4), KCNE1 (LQT5), KCNE2 (LQT6), KCNJ2(LQT7), CACNA1C(LQT8), CAV3(LQT9), SCN4B(LQT10), AKAP9(LQT11), SNTA1(LQT12) and KCNJ5 (LQT13), but it can also be acquired (acquired LQTS), usually as a result of pharmacological therapy. A small percentage of cases of LQTS occur in people who have an underlying variation in the SCN4B gene.

Pathogenic variants in SCN4B are associated with Long QT syndrome type 10 (LQT10) and are inherited in an autosomal dominant manner (Yu et al. 2003). The SCN4B gene is composed of five exons (228 amino acids) on Chromosome 3p23. Sodium channels consist of α subunits and β subunits, which could be classified as “Voltage-gated” or “ligand-gated” based on the triggers. SCN4B encodes protein Navβ4, a β4 subunit of the voltage-gated sodium channel. Navβ4 is expressed primarily in excitable tissues, including neuronal, muscular and cardiac tissues (Maier et al. 2004). The β4 subunit is covalently associated with sodium channel α subunit via a disulfide bond to constitute a functional ion channel complex. The β4 subunit modulates the channel's gating kinetics and voltage dependence. Pathogenic variants in SCN4B cause a dramatic eight-fold increase in the late sodium current, which interfere with cardiac electrophysiology (Meadows et al. 2005; Medeiros-Domingo et al. 2007). So far, all causative variants reported in SCN4B are missense (Human Gene Mutation Database).

Up to 70 % of patients with clinical diagnosis of Long QT syndrome have identifiable pathogenic variants (Beckmann et al. 2013). The majority of LQTS cases are caused by pathogenic variants in one of three genes: KCNQ1, KCNH2 and SCN5A. Approximately 5% of LQTS pathogenic variants were contributed together by following genes: ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, SNTA1 and KCNJ5 (Lieve et al. 2013; Kapplinger et al. 2009).

To date, no pathogenic large deletions or duplications in the SCN4B gene have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SCN4B 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).