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

Tung, MatthewVan Petegem, FilipLauson, SamanthaCollier, AshleyHodgkinson, KathyFernandez, BridgetConnors, SeanLeather, RickSantani, ShubhayanArbour, Laura2020-06-182020-06-1820202020Tung, 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.https://doi.org/10.1002/mgg3.1151http://hdl.handle.net/1828/11858Background: 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.encatecholaminergic polymorphic ventricular tachycardiacrystallographyRYR2variable expressionIsland Health ProgramCardiac 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 familyArticleDivision of Medical SciencesSchool of Medical Sciences