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- W2893886409 abstract "Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the gene coding cardiac ryanodine receptor (RyR2) and is one of the most dangerous inherited arrhythmia disorders. While variable expressivity and penetrance have been described in CPVT, no genetic modifiers of disease have been identified. In other inherited disorders, the cumulative gene dosage effect, whereby ≥2 mutations influence the phenotype is a potential prognosticator. However, this phenomenon has not been described in CPVT. This is a study of patients enrolled in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants. Population allele frequencies, literature review, the American College of Medical Genetics (ACMG) criteria, and mapping mutants onto a cryo-EM structure of RyR2 were used to determine pathogenicity. The 3D model of pig RyR2 in the open-state was used to predict structural impact of variants (figure). Among 237 subjects, 194 (82%) had genetic testing. Nine patients (5%) (median age 10 (IQR 7.5-12) years had ≥2 variants. Life-threatening events (cardiac arrest and/or syncope) occurred in seven subjects (78%). Ventricular tachycardia was documented in eight patients (89%), and treatment failure in 43%. No deaths occurred during follow-up (median 29 months; IQR 11-39). Two RYR2 variants affected eight patients (89%), and one patient had a heterozygous RYR2 variant and homozygous CASQ2 variants. By ACMG criteria, eight of 12 variants (67%) were pathogenic/likely pathogenic, while all others were variants of uncertain significance (VUS). Structural evaluation led to an upgrade from VUS to likely pathogenic for one variant, and a downgrade from VUS to likely benign for one variant. More than one variant may underlie a minority of CPVT cases. This observation poses challenges with respect to diagnosis and family counselling. While multiple variant carriers in the present study were usually severely affected, further research is needed to determine the significance and generalizability of this observation. The RyR2 homology model can be a useful tool when pathogenicity is unclear after applying contemporary variant classification scores." @default.
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- W2893886409 date "2018-10-01" @default.
- W2893886409 modified "2023-10-13" @default.
- W2893886409 title "MULTIPLE GENETIC VARIANTS IN CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA: A CLINICAL AND MOLECULAR REPORT FROM THE PACES CPVT REGISTRY" @default.
- W2893886409 doi "https://doi.org/10.1016/j.cjca.2018.07.376" @default.
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