Clinical and Mechanistic Evaluation of CASQ2-CPVT

Quick Takes

  • Homozygous or compound heterozygous mutations in CASQ2 carry a high risk of clinical catecholaminergic polymorphic ventricular tachycardia (CPVT).
  • Heterozygous CASQ2 mutations may cause clinical CPVT dependent on the mutation location with varied penetrance.
  • Patients with heterozygous mutations should also be screened for clinical CPVT.

Study Questions:

What are the inheritance patterns and arrhythmic risk of various heterozygous or homozygous mutation patterns in the calsequestrin-2 (CASQ2)-related catecholaminergic polymorphic ventricular tachycardia (CPVT)?


Identified individuals from international CPVT registries with suspected pathologic mutations in CASQ2 were clinically evaluated for presence of a CPVT phenotype. Candidate CASQ2 variants were tested in vitro to clarify the mechanism by which some mutations appear to cause only an autosomal recessive disease pattern, while others in an autosomal dominant pattern.


The study identified 112 individuals with a suspect CASQ2 mutation, of which 34 had a homozygous or compound heterozygous mutation pattern. These patients had a high risk of CPVT phenotype (97.1%) with 76% having had a potentially fatal arrhythmia. Median age of onset was 7 years. Seventy-eight heterozygote patients were identified including 12 probands. The heterozygous family members demonstrated a 33% risk of a CPVT phenotype. Risk of life-threatening event was higher in homozygous or compound heterozygous patients versus heterozygous patients. All presenting arrhythmic events were prior to beta-blocker treatment. In vitro analysis demonstrated a functional processing difference in the mutation variants causing autosomal recessive disease versus autosomal dominant disease.


CASQ2-related CPVT exists as both an autosomal recessive and an autosomal dominant disease dependent on the mutation type. Clinical screening for CPVT phenotype is advisable in patients with these mutations. Phenotypic penetration in heterozygous variants is low.


The majority of CPVT results from ryanodine receptor mutations. This study enhances knowledge of the rarer CASQ2 mutation variant of the disease and clarifies the clinical evidence for the risk of disease in heterozygous patients in addition to explaining the variation in inheritance patterns. Clinical screening for CPVT phenotype is advisable even in the case of heterozygous pathologic mutations for those patients with a class 1 or VUS (variant of unknown significance) mutation, especially when evaluating due to positive familial cascade screening.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Prevention, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism

Keywords: Arrhythmias, Cardiac, Calsequestrin, Heterozygote, Homozygote, Inheritance Patterns, Mutation, Phenotype, Risk, Ryanodine Receptor Calcium Release Channel, Secondary Prevention, Tachycardia, Ventricular

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