An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of
CASQ2
-Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Ng Kevin , Titus Erron W. , Lieve Krystien V. , Roston Thomas M. , Mazzanti Andrea , Deiter Frederick H. , Denjoy Isabelle , Ingles Jodie , Till Jan , Robyns Tomas , Connors Sean P. , Steinberg Christian , Abrams Dominic J. , Pang Benjamin , Scheinman Melvin M. , Bos J. Martijn , Duffett Stephen A. , van der Werf Christian , Maltret Alice , Green Martin S. , Rutberg Julie , Balaji Seshadri , Cadrin-Tourigny Julia , Orland Kate M. , Knight Linda M. , Brateng Caitlin , Wu Jeremy , Tang Anthony S. , Skanes Allan C. , Manlucu Jaimie , Healey Jeff S. , January Craig T. , Krahn Andrew D. , Collins Kathryn K. , Maginot Kathleen R. , Fischbach Peter , Etheridge Susan P. , Eckhardt Lee L. , Hamilton Robert M. , Ackerman Michael J. , Noguer Ferran Rosés I. , Semsarian Christopher , Jura Natalia , Leenhardt Antoine , Gollob Michael H. , Priori Silvia G. , Sanatani Shubhayan , Wilde Arthur A.M. , Deo Rahul C. , Roberts Jason D. 
Published: July 2020

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.