The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry.
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.



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.



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.
Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.
Thomas M
TM
Roston
Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.
Zhiguang
Z
Yuchi
Department of Pediatrics and the Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART) 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.
Prince J
PJ
Kannankeril
BC Inherited Arrhythmia Program, 211-1033 Davie St, Vancouver, BC V6E 1M7, Canada.
Julie
J
Hathaway
Department of Pediatrics, University of Rochester, 601 Elmwood Ave, Box 631, Rochester, NY 14642, USA.
Jeffrey M
JM
Vinocur
Department of Pediatrics, University of Utah, 81 N Mario Capecchi Drive Salt Lake City, UT 84113, USA.
Susan P
SP
Etheridge
Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.
James E
JE
Potts
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 1675 Highland Ave, Madison, WI 53792, USA.
Kathleen R
KR
Maginot
Department of Pediatrics, University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
Jack C
JC
Salerno
Division of Cardiology Phoenix Children's Hospital, 1919 E. Thomas Road, 2nd Floor, Heart Center, Phoenix, AZ 85016, USA.
Mitchell I
MI
Cohen
Department of Pediatrics, University of Toronto, Hospital for Sick Children, 555 University Avenue Toronto, Ontario M5G 1X8, Canada.
Robert M
RM
Hamilton
Royal Children's Hospital MCRI and University of Melbourne, 50 Flemington Road Parkville, Melbourne 3052, Australia.
Andreas
A
Pflaumer
Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.
Saira
S
Mohammed
Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.
Lynn
L
Kimlicka
Nicklaus Children's Hospital, 3100 SW 62 Ave, Cardiology ACB - 2nd Floor Miami, FL 33155, USA.
Ronald J
RJ
Kanter
Department of Pediatrics, University of Michigan, 1500 E Medical Center Drive, #6303, Ann Arbor, MI 48109, USA.
Martin J
MJ
LaPage
Department of Pediatrics, University of Colorado, 13123 East 16th Avenue, Aurora, CO 80045, USA.
Kathryn K
KK
Collins
Department of Pediatric Cardiology, Heart Center, University of Leipzig, Strümpellstrasse 39, Leipzig, Germany.
Roman A
RA
Gebauer
Department of Pediatrics, A. I. DuPont Hospital For Children, 1600 Rockland Rd, Wilmington, DE 19803, USA.
Joel D
JD
Temple
Department of Pediatrics, University of California at Irvine Medical Center, 1140 W. La Veta Ave., Suite 750, Orange, CA 92868, USA.
Anjan S
AS
Batra
Division of Cardiology, UNMC/CUMC/Children's Hospital and Medical Center, 8200 Dodge Street, Omaha, NE 68114, USA.
Christopher
C
Erickson
Department of Cardiology, Children's Memorial Health Institute, Dzieci Polskich 20, 04 -730 Warsaw, Poland.
Maria
M
Miszczak-Knecht
Children's Heart Centre, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Vúvalu 84, 15006, Prague, Czech Republic.
Peter
P
Kubuš
Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd #34, Los Angeles, CA 90027, USA.
Yaniv
Y
Bar-Cohen
Stollery Children's Hospital, University of Alberta, Clinical Sciences Building, 8440 112 St NW, Edmonton, AB T6G 2B7, Canada.
Michal
M
Kantoch
Division of Cardiology, UNMC/CUMC/Children's Hospital and Medical Center, 8200 Dodge Street, Omaha, NE 68114, USA.
Vincent C
VC
Thomas
Department of Electrophysiology, German Heart Center Munich, Technical University, Lazarettstr. 3680636 Munich, Germany.
Gabriele
G
Hessling
Providence Sacred Heart Children's Hospital, 101 W. 8th Ave. Suite 4300E, Spokane, WA 99204, USA.
Chris
C
Anderson
Department of Pediatrics, Joe DiMaggio Children's Hospital, 1150 North 35th Avenue Suite 575, Hollywood, FL 33021, USA.
Ming-Lon
ML
Young
Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.
Sally H J
SHJ
Choi
Department of Arrhythmia and Cardiac Pacing, Cardiocentro Pediatrico William Soler, 100 y perla, Boyeros. 10800, Havana, Cuba.
Michel
M
Cabrera Ortega
Division of Pediatric Cardiology, University of Alabama at Birmingham, 1700 6th Ave S, Birmingham, AL 35233, USA.
Yung R
YR
Lau
Department of Pediatrics, University of Louisville, 601 S Floyd St #602, Louisville, KY 40208, USA.
Christopher L
CL
Johnsrude
Département de Pédiatrie, CHU Ste Justine, 3175, chemin Côte Sainte-Catherine, Montréal, QC H3T 1C5 Canada.
Anne
A
Fournier
Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.
Filip
F
Van Petegem
Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.
Shubhayan
S
Sanatani
D000293:Adolescent; D002155:Calsequestrin / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D011487:Protein Conformation; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
C443109:CASQ2 protein, human; D002155:Calsequestrin; D005819:Genetic Markers; C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel