Cardiac arrest in a mother and daughter and the identification of a novel RYR2 variant, predisposing to low penetrant catecholaminergic polymorphic ventricular tachycardia in a four-generation Canadian family

Date

2020

Authors

Tung, Matthew
Van Petegem, Filip
Lauson, Samantha
Collier, Ashley
Hodgkinson, Kathy
Fernandez, Bridget
Connors, Sean
Leather, Rick
Santani, Shubhayan
Arbour, Laura

Journal Title

Journal ISSN

Volume Title

Publisher

Molecular Genetics & Genomic Medicine

Abstract

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by adrenergically driven ventricular arrhythmia predominantly caused by pathogenic variants in the cardiac ryanodine receptor (RyR2). We describe a novel variant associated with cardiac arrest in a mother and daughter. Methods: Initial sequencing of the RYR2 gene identified a novel variant (c.527G > T, p.R176L) in the index case (the mother), and her daughter. Structural analysis demonstrated the variant was located within the N-terminal domain of RyR2, likely leading to a gain-of-function effect facilitating enhanced calcium ion release. Four generation cascade genetic and clinical screening was carried out. Results: Thirty-eight p.R176L variant carriers were identified of 94 family members with genetic testing, and 108 family members had clinical evaluations. Twelve carriers were symptomatic with previous syncope and 2 additional survivors of cardiac arrest were identified. Thirty-two had clinical features suggestive of CPVT. Of 52 noncarriers, 11 had experienced previous syncope with none exhibiting any clinical features of CPVT. A documented arrhythmic event rate of 2.89/1000 person-years across all carriers was calculated. Conclusion: The substantial variability in phenotype and the lower than previously reported penetrance is illustrative of the importance of exploring family variants beyond first-degree relatives.

Description

Keywords

catecholaminergic polymorphic ventricular tachycardia, crystallography, RYR2, variable expression

Citation

Tung, M., Van Petegem, F., Lauson, S., Collier, A., Hodgkinson, K., Fernandez, B., Connors, S., Leather, R., Santani, S., & Arbour, L. (2020). Cardiac arrest in a mother and daughter and the identification of a novel RYR2 variant, predisposing to low penetrant catecholaminergic polymorphic ventricular tachycardia in a four-generation Canadian family. Molecular Genetics & Genomic Medicine, 8(4), 1-9. https://doi.org/10.1002/mgg3.1151.