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

dc.contributor.authorTung, Matthew
dc.contributor.authorVan Petegem, Filip
dc.contributor.authorLauson, Samantha
dc.contributor.authorCollier, Ashley
dc.contributor.authorHodgkinson, Kathy
dc.contributor.authorFernandez, Bridget
dc.contributor.authorConnors, Sean
dc.contributor.authorLeather, Rick
dc.contributor.authorSantani, Shubhayan
dc.contributor.authorArbour, Laura
dc.date.accessioned2020-06-18T22:53:23Z
dc.date.available2020-06-18T22:53:23Z
dc.date.copyright2020en_US
dc.date.issued2020
dc.description.abstractBackground: 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.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipWe gratefully acknowledge the participation of this extended family in this report. We would like to thank Alexa McAdam MSc for her assistance in preparing the manuscript for publication.en_US
dc.identifier.citationTung, 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.en_US
dc.identifier.urihttps://doi.org/10.1002/mgg3.1151
dc.identifier.urihttp://hdl.handle.net/1828/11858
dc.language.isoenen_US
dc.publisherMolecular Genetics & Genomic Medicineen_US
dc.subjectcatecholaminergic polymorphic ventricular tachycardiaen_US
dc.subjectcrystallographyen_US
dc.subjectRYR2en_US
dc.subjectvariable expressionen_US
dc.titleCardiac 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 familyen_US
dc.typeArticleen_US

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