Circulation. Arrhythmia and electrophysiology · 2025
RYR2 Variants in Catecholaminergic Polymorphic Ventricular Tachycardia Patients: Insights From Protein Structure and Clinical Data.
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Chang Alexander, Beqaj Halil, Sittenfeld Leah, Miotto Marco C, Dridi Haikel, Willson Gloria, Martinez Jorge Carolyn, Altosaar Li Jaan, Reiken Steven, Liu Yang, Dai Zonglin, Tchagou Carl, Elsayed Sana, Marx Steven O, Marks Andrew R
Аннотация
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia, with pathogenic variants in the RYR2 gene responsible for 60% of clinically well-defined CPVT cases. Diagnosis of CPVT often occurs after a major cardiac event, posing a severe threat to the patient's life. A data set of patients with CPVT would improve the diagnosis and treatment of patients with CPVT.
METHODS: This review cataloged clinical data on patients with RYR2-related CPVT variants from articles published up to October 2020 from PubMed, Scopus, and Embase. Variants were mapped to the structural domains of RYR2. Differences in the age of onset based on variant location and incidence of CPVT symptoms, and differences in treatment strategies were analyzed.
RESULTS: In 221 publications analyzed, 964 patients with CPVT (351 male, 463 female) were identified with 263 RYR2 protein-coding variants and a median age of onset of CPVT of 11 years (interquartile range, 7-14 years). A web app was developed to allow users to query the database and is available at https://markslab-cpvtdb.org. The proportion of patients requiring treatments in addition to β-blockers varied between variants. The age of onset of CPVT differed significantly between RYR2 variants located in different exons, domains, and subdomains. Patients with variants in the core solenoid at the domain level, and the core solenoid (exEF-hand) and channel pore at the subdomain level, tended to have a lower age of onset compared with other regions.
CONCLUSIONS: This study compiled a comprehensive data set of CPVT-associated RYR2 variants and their clinical phenotypes. The age of onset in certain domains (core solenoid) and subdomains (core solenoid[exEF-hand], channel pore) tended to be lower compared with other regions. Variability in patient phenotypes, such as age of onset and treatment efficacy, along with structural information on variants, suggests that patients may benefit from personalized interventions based on their variant.
METHODS: This review cataloged clinical data on patients with RYR2-related CPVT variants from articles published up to October 2020 from PubMed, Scopus, and Embase. Variants were mapped to the structural domains of RYR2. Differences in the age of onset based on variant location and incidence of CPVT symptoms, and differences in treatment strategies were analyzed.
RESULTS: In 221 publications analyzed, 964 patients with CPVT (351 male, 463 female) were identified with 263 RYR2 protein-coding variants and a median age of onset of CPVT of 11 years (interquartile range, 7-14 years). A web app was developed to allow users to query the database and is available at https://markslab-cpvtdb.org. The proportion of patients requiring treatments in addition to β-blockers varied between variants. The age of onset of CPVT differed significantly between RYR2 variants located in different exons, domains, and subdomains. Patients with variants in the core solenoid at the domain level, and the core solenoid (exEF-hand) and channel pore at the subdomain level, tended to have a lower age of onset compared with other regions.
CONCLUSIONS: This study compiled a comprehensive data set of CPVT-associated RYR2 variants and their clinical phenotypes. The age of onset in certain domains (core solenoid) and subdomains (core solenoid[exEF-hand], channel pore) tended to be lower compared with other regions. Variability in patient phenotypes, such as age of onset and treatment efficacy, along with structural information on variants, suggests that patients may benefit from personalized interventions based on their variant.