Catecholaminergic Polymorphic Ventricular Tachycardia via the TRDN Gene

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited arrhythmogenic heart disorder characterized by life-threatening electrical instability induced by physical or emotion stress without any structural cardiac abnormalities (Napolitano et al. 2014). The electrical instability may degenerate into cardiac arrest and sudden death. CPVT typically onsets during childhood and often presents as syncope. Preventative drugs (beta-blockers) and other treatments are available for susceptible individuals.

CPVT is inherited in an autosomal dominant (ANK2; CALM1; KCNJ2; KCNQ1; RYR2; SCN5A) or in an autosomal recessive manner (CASQ2; TRDN). The true prevalence of CPVT is unknown, but is estimated to be about 1 in 10,000 people (Liu et al. 2008).

TRDN encodes an integral membrane protein, Triadin, which contains a single transmembrane domain. Triadin plays a role in skeletal muscle excitation-contraction coupling by interacting with the RYR2 and RYR1 proteins and contributing to sarcoplasmic reticulum calcium regulation (Györke et al. 2004). So far, causative variants reported in TRDN include one missense, one nonsense and one small deletion (Human Gene Mutation Database)

Approximately 55%-65% of CPVT cases have identifiable pathogenic variants (Ackerman et al. 2011). CPVT is primarily caused by pathogenic variants in the RYR2 and CASQ2 genes. Variants in RYR2 are responsible for 50-55% of CPVT cases (Priori et al 2002). Less commonly, variants in CASQ2 contribute another 1% ~ 2% of CPVT. Pathogenic variants in the ANK2, CALM1, KCNJ2, KCNQ1, SCN5A and TRDN genes appear to be a rare cause of CPVT (Napolitano et al. 2014). Insufficient data are available to estimate numeric sensitivities.

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