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.

Keywords: RYR2; catecholaminergic polymorphic ventricular tachycardia; crystallography; variable expression.

Figure 1

Pedigree of first‐degree relatives of the index case. Index case indicated by black triangle. Red central symbols indicate positive status for the RYR2 variant. Green upper right quadrant indicates a previous cardiac arrest. Blue lower left quadrant designates bidirectional ventricular ectopy. Black upper left quadrant represents positive status for the KCNQ1 variant. Lower left quadrant dot indicates syncope. Diamond represents additional sibling(s)

Figure 2

Post‐genetic testing exercise stress test demonstrating bidirectional premature ventricular ectopy with exercise, consistent with a CPVT phenotype in the son of the index case

Figure 3

Expanded pedigree of the family of the index case. Index case indicated by black triangle. Red central symbols indicate positive status for the RYR2 variant. Green upper right quadrant indicates a previous cardiac arrest. Blue lower left quadrant designates bidirectional ventricular ectopy. Black upper left quadrant represents positive status for the KCNQ1 variant. Lower left quadrant dot indicates syncope. Diamond represents additional sibling(s)

Figure 4

Electrocardiogram of the index case's father, carrier of the p.R176L variant, demonstrating bidirectional premature ventricular contractions. This tracing was recorded during his admission for an acute coronary syndrome 7 years prior to the index case presenting with cardiac arrest

Figure 5

Structural mapping of the R176 residue. A. Cryo‐EM structure of RyR2 (PDB ID 6JI8) showing the overall position of R176 in black. Domains in the N‐terminal disease hot spot are colored: blue, Domain A; green, Domain B; red, Domain C. Two auxiliary proteins are also shown in color; FKBP12.6 (orange) and Calmodulin (cyan). B. Close‐up of the R176 residue, showing that it is in the vicinity of two interfaces, including an interface with domain B of a neighboring subunit (green), and also with a C‐terminal area (gray helices). C. Cryo‐EM density map of the structure shown in panels A and B shows that the local resolution around R176 is low, and its precise chemical environment cannot be interpreted directly. D. Crystal structure of the N‐terminal disease hot spot of RyR2 (PDB ID 4L4H), showing the chemical environment of R176 (black). Several residues involved in packing around R176 are labeled. Black dotted lines indicate hydrogen bonds