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

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. K E Y W O R D S catecholaminergic polymorphic ventricular tachycardia, crystallography, RYR2, variable expression 2 of 9 | TUNG eT al.

The link between abnormalities of calcium handling proteins and catecholaminergic polymorphic ventricular tachycardia

“…analyzed a 108-member proband and reported three of the member's variation in the RYR2 gene (c. 527G>T, p.R176L). The RyR2 R176L increases DADs causing CPVT-associated sudden cardiac arrest [ 39 ].…”