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, Island Health Program
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.