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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1161/CIRCULATIONAHA.120.045723
Journal or Publication Title: Circulation
Volume: 142
Number: 10
Page Range: pp. 932-947
Date: 2020
Divisions: Molecular Cardiology
Depositing User: General Admin
Identification Number: 10.1161/CIRCULATIONAHA.120.045723
ISSN: 0009-7322
Date Deposited: 04 Jan 2021 01:13
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.

Creators:
Creators
Email
Ng, Kevin
UNSPECIFIED
Titus, Erron W.
UNSPECIFIED
Lieve, Krystien V.
UNSPECIFIED
Roston, Thomas M.
UNSPECIFIED
Mazzanti, Andrea
UNSPECIFIED
Deiter, Frederick H.
UNSPECIFIED
Denjoy, Isabelle
UNSPECIFIED
Ingles, Jodie
UNSPECIFIED
Till, Jan
UNSPECIFIED
Robyns, Tomas
UNSPECIFIED
Connors, Sean P.
UNSPECIFIED
Steinberg, Christian
UNSPECIFIED
Abrams, Dominic J.
UNSPECIFIED
Pang, Benjamin
UNSPECIFIED
Scheinman, Melvin M.
UNSPECIFIED
Bos, J. Martijn
UNSPECIFIED
Duffett, Stephen A.
UNSPECIFIED
van der Werf, Christian
UNSPECIFIED
Maltret, Alice
UNSPECIFIED
Green, Martin S.
UNSPECIFIED
Rutberg, Julie
UNSPECIFIED
Balaji, Seshadri
UNSPECIFIED
Cadrin-Tourigny, Julia
UNSPECIFIED
Orland, Kate M.
UNSPECIFIED
Knight, Linda M.
UNSPECIFIED
Brateng, Caitlin
UNSPECIFIED
Wu, Jeremy
UNSPECIFIED
Tang, Anthony S.
UNSPECIFIED
Skanes, Allan C.
UNSPECIFIED
Manlucu, Jaimie
UNSPECIFIED
Healey, Jeff S.
UNSPECIFIED
January, Craig T.
UNSPECIFIED
Krahn, Andrew D.
UNSPECIFIED
Collins, Kathryn K.
UNSPECIFIED
Maginot, Kathleen R.
UNSPECIFIED
Fischbach, Peter
UNSPECIFIED
Etheridge, Susan P.
UNSPECIFIED
Eckhardt, Lee L.
UNSPECIFIED
Hamilton, Robert M.
UNSPECIFIED
Ackerman, Michael J.
UNSPECIFIED
Noguer, Ferran Rosés I.
UNSPECIFIED
Semsarian, Christopher
UNSPECIFIED
Jura, Natalia
UNSPECIFIED
Leenhardt, Antoine
UNSPECIFIED
Gollob, Michael H.
UNSPECIFIED
Priori, Silvia G.
UNSPECIFIED
Sanatani, Shubhayan
UNSPECIFIED
Wilde, Arthur A.M.
UNSPECIFIED
Deo, Rahul C.
UNSPECIFIED
Roberts, Jason D.
UNSPECIFIED
Last Modified: 04 Jan 2021 01:13
URI: https://eprints.centenary.org.au/id/eprint/795

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