Multigenic burden in RYR2 missense variant carriers: Impact on ventricular arrhythmias and survival
P A Calburean, L Pannone, D G Della Rocca, L Carmagnola, L Canovi, T Sattin, E Stroker, I Overeinder, A Almorad, G Bala, A Sarkozy, G B Chierchia, J Sieira, C De AsmundisAbstract
Introduction
RYR2 missense variants are classically associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), yet their pathogenicity and clinical penetrance remain uncertain in the era of broad next-generation sequencing panels. The impact of additional variants on the severity of clinical phenotypes of RYR2 variant carriers is poorly defined.
Purpose
The purpose of this study was to assess the clinical phenotype associated with RYR2 missense variants, and to determine the additional impact of coexisting missense variants in other genes.
Methods
All patients with a RYR2 missense variant (RYR2+ group) documented using a large gene panel for channelopathies and cardiomyopathies were included in the present study. Family members of RYR2+ patients with documented wild-type RYR2 (RYR2- group) were also included. RYR2+ group was further stratified into RYR2+Associated+ and RYR2+Associated- groups if the patients carried or not additional variants in other genes from the same panel, respectively. Similarly, RYR2- group was further stratified into RYR2-Associated+ and RYR2-Associated- groups.
Results
A total of 50 patients were included in the RYR2+ group, of which 22 (44%) were included in the RYR2+Associated+ group, presenting an additional missense variant in genes such as TTN, DSG2, MYL2 or MYBPC3. An additional 29 family members were included in the RYR2- group, of which 7 (24%) were included in the RYR2-Associated+ group, carrying other missense variants. Among RYR2+ patients, spontaneous sustained ventricular arrhythmias or sudden cardiac death were documented in 17 (34%) patients. In Kaplan–Meier analysis, the RYR2+Associated+ group had the highest arrhythmic incidence, followed by the RYR2+Associated- group, whereas RYR2- individuals experienced no arrhythmic events, regardless of associated variants (Figure 1A). In stepwise multivariable Cox regression for prediction of ventricular arrhythmias, RYR2+ status was the only significant predictor (HR=12.1 [3.05–44.1], p=0.002, Figure 1A). In stepwise multivariable Cox regression for prediction of a composite outcome consisting of ventricular arrhythmias, atrial fibrillation, heart failure or SCD, RYR2+ status (HR=6.40 [1.50–27.14], p=0.012) and the presence of an associated variant gene (HR=2.36 [1.07–5.23], p=0.033) were both significant predictors. Other variables such as number of mutated genes, zygosity or variant class had no impact on event prediction.
Conclusion
RYR2 missense variants were associated with a high burden of adverse cardiovascular events, whereas RYR2 wild-type relatives remained event-free, highlighting the arrhythmogenic relevance of RYR2+ status. The presence of additional variants further amplified risk, underscoring the need for extensive genotype-guided risk stratification in RYR2 variant carriers.Figure 1 – Kaplan-Meier survival curves.