An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2 -Catecholaminergic Polymorphic Ventricular Tachycardia - Sorbonne Université
Journal Articles Circulation Year : 2020

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

Kevin Ng
  • Function : Author
Erron Titus
  • Function : Author
Krystien Lieve
  • Function : Author
Thomas Roston
  • Function : Author
Andrea Mazzanti
  • Function : Author
Frederick Deiter
  • Function : Author
Jodie Ingles
  • Function : Author
Jan Till
  • Function : Author
Tomas Robyns
  • Function : Author
Sean Connors
  • Function : Author
Christian Steinberg
Dominic Abrams
Benjamin Pang
  • Function : Author
Melvin Scheinman
  • Function : Author
J Martijn Bos
  • Function : Author
Stephen Duffett
  • Function : Author
Christian van Der Werf
  • Function : Author
Alice Maltret
Martin Green
  • Function : Author
Julie Rutberg
  • Function : Author
Seshadri Balaji
  • Function : Author
Julia Cadrin-Tourigny
  • Function : Author
Kate Orland
  • Function : Author
Linda Knight
  • Function : Author
Caitlin Brateng
  • Function : Author
Jeremy Wu
  • Function : Author
Anthony Tang
  • Function : Author
Allan Skanes
  • Function : Author
Jaimie Manlucu
  • Function : Author
Jeff Healey
  • Function : Author
Craig January
  • Function : Author
Andrew Krahn
  • Function : Author
Kathryn Collins
  • Function : Author
Kathleen Maginot
  • Function : Author
Peter Fischbach
  • Function : Author
Susan Etheridge
  • Function : Author
Lee Eckhardt
  • Function : Author
Robert Hamilton
  • Function : Author
Michael Ackerman
  • Function : Author
Ferran Rosés I. Noguer
  • Function : Author
Christopher Semsarian
  • Function : Author
Natalia Jura
  • Function : Author
Antoine Leenhardt
  • Function : Author
Michael Gollob
  • Function : Author
Silvia Priori
  • Function : Author
Shubhayan Sanatani
Arthur A.M. Wilde
  • Function : Author
Rahul Deo
  • Function : Author
Jason Roberts

Abstract

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% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P<0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. Conclusions: This international multicenter study of CASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

Dates and versions

hal-02947925 , version 1 (24-09-2020)

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Cite

Kevin Ng, Erron Titus, Krystien Lieve, Thomas Roston, Andrea Mazzanti, et al.. An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2 -Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation, 2020, 142 (10), pp.932-947. ⟨10.1161/CIRCULATIONAHA.120.045723⟩. ⟨hal-02947925⟩
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