Catecholaminergic Polymorphic Ventricular Tachycardia via the RYR2 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. GeneReviews, 2009). 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 due to RYR2 variants is inherited in an autosomal dominant manner. The large RYR2 (ryanodine receptor type 2) gene with 105 exons encodes the cardiac muscle calcium release channel. RYR2 pathogenic variants are almost entirely missense and are clustered in specific portions of the gene (eg Priori et al. Circulation 106:69-74, 2002; Medeiros-Domingo et al. J Am Coll Cardiol 54:2065-2074, 2009). In-frame deletions or insertions of one or two amino acids have also been reported. A few patients had a deletion of the entire exon 3 (in-frame loss of 35 amino acids) (Marjamaa et al. BMC Med Genet 10:12, 2009). The penetrance of RYR2 causative variants is high, but not 100% (Napolitano et al. GeneReviews, 2012). Some patients have been reported to carry de novo variants (Roux-Buisson et al. Europace 13:130-132, 2010). CPVT can also be caused by recessive variants in the CASQ2 gene (diBarletta et al. Circulation 114:1012-1019, 2006). In addition to CPVT, dominant variants in RYR2 have been reported to be a rare cause of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (McNally et al. GeneReviews, 2009).

Priori et al. (Circulation 106:69-74, 2002) reported that about 50% of CPVT patients have variants in the RYR2 gene. Tester et al. (Mayo Clin Proc 79:1380-1384, 2004) reported that 14% of sudden unexplained death cases had RYR2 variants. CASQ2 variants are reported in only 1-2% of CPVT patients (Napolitano et al. GeneReviews, 2009).

This test provides full coverage of all coding exons of the RYR2 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).