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

Figures

• 

  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