AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. METHODS AND RESULTS: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. CONCLUSION: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.

BC Inherited Arrhythmia Program 211 1033 Davie St Vancouver BC V6E 1M7 Canada

Children's Heart Centre 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Vúvalu 84 15006 Prague Czech Republic

Département de Pédiatrie CHU Ste Justine 3175 chemin Côte Sainte Catherine Montréal QC H3T 1C5 Canada

Department of Arrhythmia and Cardiac Pacing Cardiocentro Pediatrico William Soler 100 y perla Boyeros 10800 Havana Cuba

Department of Cardiology Children's Memorial Health Institute Dzieci Polskich 20 04 730 Warsaw Poland

Department of Electrophysiology German Heart Center Munich Technical University Lazarettstr 3680636 Munich Germany

Department of Pediatric Cardiology Heart Center University of Leipzig Strümpellstrasse 39 Leipzig Germany

Department of Pediatrics A 1 DuPont Hospital For Children 1600 Rockland Rd Wilmington DE 19803 USA

Department of Pediatrics and the Vanderbilt Center for Arrhythmia Research and Therapeutics Vanderbilt University Medical Center and the Monroe Carell Jr Children's Hospital at Vanderbilt 2200 Children's Way Suite 5230 Nashville TN 37232 9119 USA

Department of Pediatrics Children's Hospital Los Angeles 4650 Sunset Blvd 34 Los Angeles CA 90027 USA

Department of Pediatrics Joe DiMaggio Children's Hospital 1150 North 35th Avenue Suite 575 Hollywood FL 33021 USA

Department of Pediatrics University of California at Irvine Medical Center 1140 W La Veta Ave Suite 750 Orange CA 92868 USA

Department of Pediatrics University of Colorado 13123 East 16th Avenue Aurora CO 80045 USA

Department of Pediatrics University of Louisville 601 S Floyd St 602 Louisville KY 40208 USA

Department of Pediatrics University of Michigan 1500 E Medical Center Drive 6303 Ann Arbor MI 48109 USA

Department of Pediatrics University of Rochester 601 Elmwood Ave Box 631 Rochester NY 14642 USA

Department of Pediatrics University of Toronto Hospital for Sick Children 555 University Avenue Toronto Ontario M5G 1X8 Canada

Department of Pediatrics University of Utah 81 N Mario Capecchi Drive Salt Lake City UT 84113 USA

Department of Pediatrics University of Washington 4800 Sand Point Way NE Seattle WA 98105 USA

Department of Pediatrics University of Wisconsin School of Medicine and Public Health 1675 Highland Ave Madison WI 53792 USA

Departments of Pediatrics Medicine Biochemistry and Molecular Biology University of British Columbia 4480 Oak Street Room 1F3 Vancouver BC V6H 3V4 Canada

Division of Cardiology Phoenix Children's Hospital 1919 E Thomas Road 2nd Floor Heart Center Phoenix AZ 85016 USA

Division of Cardiology UNMC CUMC Children's Hospital and Medical Center 8200 Dodge Street Omaha NE 68114 USA

Division of Pediatric Cardiology University of Alabama at Birmingham 1700 6th Ave S Birmingham AL 35233 USA

Nicklaus Children's Hospital 3100 SW 62 Ave Cardiology ACB 2nd Floor Miami FL 33155 USA

Providence Sacred Heart Children's Hospital 101 W 8th Ave Suite 4300E Spokane WA 99204 USA

Royal Children's Hospital MCRI and University of Melbourne 50 Flemington Road Parkville Melbourne 3052 Australia

Stollery Children's Hospital University of Alberta Clinical Sciences Building 8440 112 St NW Edmonton AB T6G 2B7 Canada

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