The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia

Findings from an international multicentre registry

Thomas M. Roston, Zhiguang Yuchi, Prince J. Kannankeril, Julie Hathaway, Jeffrey M. Vinocur, Susan P. Etheridge, James E. Potts, Kathleen R. Maginot, Jack C. Salerno, Mitchell I. Cohen, Robert M. Hamilton, Andreas Pflaumer, Saira Mohammed, Lynn Kimlicka, Ronald J. Kanter, Martin J. Lapage, Kathryn K. Collins, Roman A. Gebauer, Joel D. Temple, Anjan S. Batra & 16 others Christopher C Erickson, Maria Miszczak-Knecht, Peter Kubuš, Yaniv Bar-Cohen, Michal Kantoch, Vincent C. Thomas, Gabriele Hessling, Chris Anderson, Ming Lon Young, Sally H.J. Choi, Michel Cabrera Ortega, Yung R. Lau, Christopher L. Johnsrude, Anne Fournier, Filip Van Petegem, Shubhayan Sanatani

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)541-547
Number of pages7
JournalEuropace
Volume20
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Ryanodine Receptor Calcium Release Channel
Registries
Calsequestrin
Channelopathies
Phenotype
S 6
Mutation
Electrophysiology
Structural Models
Genetic Testing
Heart Arrest
Multicenter Studies
Cardiac Arrhythmias
Cohort Studies
Retrospective Studies
Polymorphic catecholergic ventricular tachycardia
Ions
Pediatrics
Genes

Keywords

  • Arrhythmia
  • Catecholaminergic polymorphic
  • Genetics
  • RyR2
  • Sudden unexpected death
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Roston, T. M., Yuchi, Z., Kannankeril, P. J., Hathaway, J., Vinocur, J. M., Etheridge, S. P., ... Sanatani, S. (2018). The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: Findings from an international multicentre registry. Europace, 20(3), 541-547. https://doi.org/10.1093/europace/euw389

The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia : Findings from an international multicentre registry. / Roston, Thomas M.; Yuchi, Zhiguang; Kannankeril, Prince J.; Hathaway, Julie; Vinocur, Jeffrey M.; Etheridge, Susan P.; Potts, James E.; Maginot, Kathleen R.; Salerno, Jack C.; Cohen, Mitchell I.; Hamilton, Robert M.; Pflaumer, Andreas; Mohammed, Saira; Kimlicka, Lynn; Kanter, Ronald J.; Lapage, Martin J.; Collins, Kathryn K.; Gebauer, Roman A.; Temple, Joel D.; Batra, Anjan S.; Erickson, Christopher C; Miszczak-Knecht, Maria; Kubuš, Peter; Bar-Cohen, Yaniv; Kantoch, Michal; Thomas, Vincent C.; Hessling, Gabriele; Anderson, Chris; Young, Ming Lon; Choi, Sally H.J.; Cabrera Ortega, Michel; Lau, Yung R.; Johnsrude, Christopher L.; Fournier, Anne; Van Petegem, Filip; Sanatani, Shubhayan.

In: Europace, Vol. 20, No. 3, 01.03.2018, p. 541-547.

Research output: Contribution to journalArticle

Roston, TM, Yuchi, Z, Kannankeril, PJ, Hathaway, J, Vinocur, JM, Etheridge, SP, Potts, JE, Maginot, KR, Salerno, JC, Cohen, MI, Hamilton, RM, Pflaumer, A, Mohammed, S, Kimlicka, L, Kanter, RJ, Lapage, MJ, Collins, KK, Gebauer, RA, Temple, JD, Batra, AS, Erickson, CC, Miszczak-Knecht, M, Kubuš, P, Bar-Cohen, Y, Kantoch, M, Thomas, VC, Hessling, G, Anderson, C, Young, ML, Choi, SHJ, Cabrera Ortega, M, Lau, YR, Johnsrude, CL, Fournier, A, Van Petegem, F & Sanatani, S 2018, 'The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: Findings from an international multicentre registry', Europace, vol. 20, no. 3, pp. 541-547. https://doi.org/10.1093/europace/euw389
Roston, Thomas M. ; Yuchi, Zhiguang ; Kannankeril, Prince J. ; Hathaway, Julie ; Vinocur, Jeffrey M. ; Etheridge, Susan P. ; Potts, James E. ; Maginot, Kathleen R. ; Salerno, Jack C. ; Cohen, Mitchell I. ; Hamilton, Robert M. ; Pflaumer, Andreas ; Mohammed, Saira ; Kimlicka, Lynn ; Kanter, Ronald J. ; Lapage, Martin J. ; Collins, Kathryn K. ; Gebauer, Roman A. ; Temple, Joel D. ; Batra, Anjan S. ; Erickson, Christopher C ; Miszczak-Knecht, Maria ; Kubuš, Peter ; Bar-Cohen, Yaniv ; Kantoch, Michal ; Thomas, Vincent C. ; Hessling, Gabriele ; Anderson, Chris ; Young, Ming Lon ; Choi, Sally H.J. ; Cabrera Ortega, Michel ; Lau, Yung R. ; Johnsrude, Christopher L. ; Fournier, Anne ; Van Petegem, Filip ; Sanatani, Shubhayan. / The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia : Findings from an international multicentre registry. In: Europace. 2018 ; Vol. 20, No. 3. pp. 541-547.
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abstract = "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.",
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T1 - The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia

T2 - Findings from an international multicentre registry

AU - Roston, Thomas M.

AU - Yuchi, Zhiguang

AU - Kannankeril, Prince J.

AU - Hathaway, Julie

AU - Vinocur, Jeffrey M.

AU - Etheridge, Susan P.

AU - Potts, James E.

AU - Maginot, Kathleen R.

AU - Salerno, Jack C.

AU - Cohen, Mitchell I.

AU - Hamilton, Robert M.

AU - Pflaumer, Andreas

AU - Mohammed, Saira

AU - Kimlicka, Lynn

AU - Kanter, Ronald J.

AU - Lapage, Martin J.

AU - Collins, Kathryn K.

AU - Gebauer, Roman A.

AU - Temple, Joel D.

AU - Batra, Anjan S.

AU - Erickson, Christopher C

AU - Miszczak-Knecht, Maria

AU - Kubuš, Peter

AU - Bar-Cohen, Yaniv

AU - Kantoch, Michal

AU - Thomas, Vincent C.

AU - Hessling, Gabriele

AU - Anderson, Chris

AU - Young, Ming Lon

AU - Choi, Sally H.J.

AU - Cabrera Ortega, Michel

AU - Lau, Yung R.

AU - Johnsrude, Christopher L.

AU - Fournier, Anne

AU - Van Petegem, Filip

AU - Sanatani, Shubhayan

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

KW - Arrhythmia

KW - Catecholaminergic polymorphic

KW - Genetics

KW - RyR2

KW - Sudden unexpected death

KW - Ventricular tachycardia

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