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An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of
Kevin Ng1,2, Erron W Titus3, Krystien V Lieve4,5
1Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (K.N., J.W., A.S.T., A.C.S., J.M., J.D.R.).
Circulation
|July 23, 2020
Summary
Genetic variants in calsequestrin-2 (CASQ2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). This study shows heterozygous CASQ2 variants can also cause CPVT, necessitating clinical screening for these individuals.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Inherited Arrhythmia Syndromes
Background:
- Genetic variants in calsequestrin-2 (CASQ2) are linked to autosomal recessive catecholaminergic polymorphic ventricular tachycardia (CPVT).
- Isolated reports suggest arrhythmic phenotypes in heterozygotes, prompting further investigation into CASQ2-CPVT inheritance and mechanisms.
Purpose of the Study:
- To investigate inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-related CPVT.
- To clarify the clinical significance of heterozygous CASQ2 variants in CPVT.
Main Methods:
- Conducted an international multicenter study analyzing genotype-phenotype segregation in CASQ2-CPVT families.
- Evaluated arrhythmic risk using Cox regression models and assessed variant impact via in vitro oligomerization assays and structural mapping.
Main Results:
- Identified 112 individuals with CASQ2 variants; 97.1% penetrance in homozygotes/compound heterozygotes with a median onset of 7 years.
- 33.3% of heterozygous family members met CPVT criteria.
- Homozygous/compound heterozygous status significantly increased cardiac event hazard (3.2-fold), while heterozygous status showed a 38.8-fold increased hazard in genotype-positive family members.
Conclusions:
- Pathogenic heterozygous CASQ2 variants can manifest with a CPVT phenotype, requiring clinical screening.
- Certain missense variants exhibit dominant inheritance due to their critical location and function within the CASQ2 filament structure.
Keywords:
arrhythmias, cardiaccatecholaminergic polymorphic ventricular tachycardiadeath, sudden, cardiacgeneticsMore Related Videos
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