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.

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

Molecular genetics & genomic medicine 2020 Apr

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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. 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. 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. 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. © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Citation

Matthew Tung, Filip Van Petegem, Samantha Lauson, Ashley Collier, Kathy Hodgkinson, Bridget Fernandez, Sean Connors, Rick Leather, Shubhayan Sanatani, Laura Arbour. 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. 2020 Apr;8(4):e1151