Catecholaminergic Polymorphic Ventricular Tachycardia Panel

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited arrhythmogenic heart disorder characterized by life-threatening electrical instability induced by physical or emotional 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). This panel includes 8 genes associated with CPVT: ANK2, CALM1, CASQ2, KCNJ2, KCNQ1, RYR2, SCN5A and TRDN. A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported. Large deletions/duplications and complex genomic rearrangements have also been reported in a few genes (KCNQ1, KCNJ2, RYR2 and SCN5A) (Human Gene Mutation Database).

Ankyrin-B protein, encoded by the ANK2 gene, is a member of the ankyrin family of proteins and plays essential roles in the targeting and membrane stabilization of ion channels and transporters in cardiomyocytes, such as Na/K-ATPase, Na/Ca exchanger, and InsP3 receptor (Mohler et al. 2007).

CALM1 is the archetype of the calmodulin (calcium-modulated proteins) family of which nearly 20 members have been identified. Calmodulin (CaM) is a multifunctional calcium ion sensor protein that transduces much of the calcium signaling (Kobayashi et al. 2015).

CASQ2 (calsequestrin 2) encodes for the cardiac sarcoplasmic reticulum calcium buffering protein and RYR2 (ryanodine receptor 2) encodes for the cardiac calcium release channel. Both proteins play essential roles in the release of calcium from the sarcoplasmic reticulum (Priori et al. 2011).

KCNJ2, encoding the inward rectifier potassium channel 2 protein (Kir2.1), is an important determinant of resting membrane potential and cell excitability (Plaster et al. 2001).

KCNQ1 codes for the voltage-gated potassium channel protein KvLQT1 that is highly expressed in the heart muscle and inner ear, and helps transport positively charged potassium ions out of cells. In the heart, the channels are involved in recharging the cardiac muscle after each heartbeat to maintain a regular rhythm. In the inner ear, these channels help maintain the proper ion balance needed for normal hearing.

The SCN5A gene encodes the alpha-subunit of human cardiac sodium channel, which is responsible for the generation of cardiac action potential and for rapid impulse conduction through the myocardium.

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).

Pathogenic variants in these eight genes account for 52%-60% of CPVT cases (Napolitano et al. 2014).

Clinical sensitivity for deletion and duplications is currently not known. To date, three large deletions in the RYR2 gene have been described in patients with CPVT (Bhuiyan et al. 2007; Marjamaa et al. 2009, Medeiros-Domingo et al. 2009).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 100% coverage of all coding exons of the genes 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 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).