Related Experiment Video
Updated: Mar 21, 2026
Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
Published on: December 22, 2023
A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic
Belinda Gray1, Richard D Bagnall2, Lien Lam2
1Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia.
Background:
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. Mutations in the cardiac ryanodine receptor gene (RYR2) cause an autosomal dominant form of CPVT, while mutations in the cardiac calsequestrin 2 gene (CASQ2) cause an autosomal recessive form.
Objective:
The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant CPVT.
Methods:
Clinical evaluation of family members was performed, including detailed history, physical examination, electrocardiogram, exercise stress test, and autopsy review of decedents. We performed genome-wide linkage analysis in 12 family members and exome sequencing in 2 affected family members. In silico models of mouse and rabbit myocyte electrophysiology were used to predict potential disease mechanisms.
Results:
Severe CPVT with dominant inheritance in 6 members was diagnosed in a large family with 2 sudden deaths, 2 resuscitated cardiac arrests, and multiple appropriate implantable cardioverter-defibrillator shocks. A comprehensive analysis of cardiac arrhythmia genes did not reveal a pathogenic variant. Exome sequencing identified a novel heterozygous missense variant in CASQ2 (Lys180Arg) affecting a highly conserved residue, which cosegregated with disease and was absent in unaffected family members. Genome-wide linkage analysis confirmed a single linkage peak at the CASQ2 locus (logarithm of odds ratio score 3.01; θ = 0). Computer simulations predicted that haploinsufficiency was unlikely to cause the severe CPVT phenotype and suggested a dominant negative mechanism.
Conclusion:
We show for the first time that a variant in CASQ2 causes autosomal dominant CPVT. Genetic testing in dominant CPVT should include screening for heterozygous CASQ2 variants.
Insights
A novel variant in the CASQ2 gene causes a severe form of catecholaminergic polymorphic ventricular tachycardia (CPVT) with dominant inheritance. Genetic testing for dominant CPVT should now include screening for CASQ2 variants.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Inherited Arrhythmia Syndromes
Background:
- Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening inherited arrhythmia.
- Mutations in RYR2 cause autosomal dominant CPVT, while CASQ2 mutations cause the autosomal recessive form.
- The genetic basis for some CPVT cases remains elusive.
Purpose of the Study:
- To clinically and genetically characterize a large family with severe autosomal dominant CPVT.
- To identify the genetic cause of CPVT in a family with a history of sudden cardiac death and resuscitated cardiac arrest.
- To elucidate the disease mechanism of a novel genetic variant.
Main Methods:
- Clinical evaluation including ECG, stress testing, and autopsy review.
- Genome-wide linkage analysis and exome sequencing were performed on affected and unaffected family members.
- In silico modeling of myocyte electrophysiology was used to predict disease mechanisms.
Main Results:
- A novel heterozygous missense variant (Lys180Arg) in the CASQ2 gene was identified in affected family members and cosegregated with the disease.
- Genome-wide linkage analysis confirmed linkage to the CASQ2 locus.
- In silico simulations suggested a dominant-negative mechanism, rather than haploinsufficiency, underlies the severe CPVT phenotype.
Conclusions:
- This study demonstrates that a CASQ2 variant can cause autosomal dominant CPVT, challenging previous understanding.
- Genetic screening for dominant CPVT should now incorporate testing for heterozygous CASQ2 variants.
- Identification of this variant provides new insights into the molecular mechanisms of CPVT.
Related Concept Videos
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:25Cardiomyopathy I: Introduction and Classification
01:43Incomplete Dominance
01:28Mechanism of Cardiac Arrhythmias
01:29Dysrhythmias III: Characteristics of Dysrhythmias
01:30Cardiomyopathy II: Dilated Cardiomyopathy