Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a rare, but potentially fatal channelopathy. Genetic testing may be used to confirm a diagnosis in unclear cases and therefore, is increasingly being performed in a heterogeneous patient population.
Another aim was to collect further information of the distribution of the disease causing variants in RYR2 as 1/113 individuals in gnomAD reference population carries a unique RYR2 missense variant (not present in anybody else in this cohort) indicating that vast majority unique RYR2 missense variants are not disease causing.
Total of 134 patients with clinical suspicion of CPVT send for targeted panel testing either using Blueprint Genetics CPVT panel or Arrhythmia Panel over a 5-year period were analyzed.
Diagnostic genetic defect was identified in 35 patients (29%). These include all pathogenic (P), and likely pathogenic (LP) variants and those variants of uncertain significance (VUS) in RYR2, that were absent from gnomAD, fully conserved in evolution and located within four previously described variants clusters.
Five VUS favoring pathogenic RYR2 variants were identified in this study. Twenty eight patients (80% of diagnoses) had a diagnostic finding in a CPVT-associated gene.
NGS-based panel testing offers good diagnostic yield for patients with clinical suspicion of CPVT (26% in this series). 29% (10/35) of patients with a diagnostic test result had a clinically significant variant in a gene other than RYR2.
Keywords: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), NGS panel testing, RYR2, diagnostic yield
Authors: Seppälä EH, Saarinen I, Tallila J, Hathaway J, Tuupanen S, Turpeinen H, Kangas-Kontio T, Schleit J, Tommiska J, Salminen E, Salmenperä P, Sistonen J, Gentile M, Myllykangas S, Paananen J, Alastalo TP, Koskenvuo J