An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2 -Catecholaminergic Polymorphic Ventricular Tachycardia

作者：Kevin Ng, Erron W. Titus, Krystien V.V. Lieve, Thomas M. Roston, Andrea Mazzanti, Fred Deiter, Isabelle Denjoy, Jodie Ingles, Jan Till, Tomas Robyns, Sean P. Connors, Christian Steinberg, Dominic J. Abrams, B. Pang, Melvin M. Scheinman, J. Martijn Bos, Stephen A. Duffett, Christian van der Werf, Alice Maltret, Martin S. Green, Julie Rutberg, Seshadri Balaji, Julia Cadrin‐Tourigny, Kate M. Orland, Linda M. Knight, Caitlin Brateng, Jeremy Wu, Anthony Tang, Allan C. Skanes, Jaimie Manlucu, Jeff S. Healey, Craig T. January, Andrew D. Krahn, Kathryn K. Collins, Kathleen R. Maginot, Peter Fischbach, Susan P. Etheridge, Lee L. Eckhardt, Robert M. Hamilton, Michael J. Ackerman, Ferran Rosés‐Noguer, Christopher Semsarian, Natalia Jura, Antoine Leenhardt, Michael H. Gollob, Silvia G. Priori, Shubhayan Sanatani, Arthur A.M. Wilde, Rahul C. Deo, Jason D. Roberts · 发表于：Circulation · 年份：2020 · DOI：10.1161/circulationaha.120.045723 · 被引用次数：83 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Cardiac Arrhythmias and Treatments

Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% C...