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Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a lethal inherited arrhythmia characterized by exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardias in structurally normal hearts. Patients often present with syncope or sudden cardiac arrest during catecholaminergic stress. CPVT2, the autosomal recessive form, results from biallelic mutations in CASQ2, encoding cardiac calsequestrin, the primary high-capacity Ca²⁺ buffer within the sarcoplasmic reticulum. CASQ2 modulates ryanodine receptor 2 (RyR2) channel refractoriness via luminal Ca²⁺-dependent interactions and polymerization. Disruption of CASQ2 function reduces SR Ca²⁺ storage capacity, precipitating uncontrolled diastolic Ca²⁺ release and delayed afterdepolarizations. This cascade underlies the arrhythmogenic phenotype in CPVT2.
An international multicenter evaluation identified 36 CASQ2-related CPVT probands from 24 families, including 24 homozygous or compound heterozygous individuals and 12 heterozygotes (PMID:32693635). Clinical penetrance among recessive genotypes reached 97.1%, with 76.5% of homozygotes or compound heterozygotes experiencing potentially fatal arrhythmic events by a median age of 7 years. Segregation analysis confirmed autosomal recessive inheritance, while 33.3% of heterozygous relatives met CPVT diagnostic criteria, suggesting dominant-negative effects of certain missense alleles. A study of three additional families reported three CASQ2 truncating mutations (R33X, splice-site 532+1G>A, 62delA) in homozygous carriers presenting with early-onset syncope (PMID:12386154). Heterozygous carriers were mostly asymptomatic, underscoring a dosage-dependent risk. Genetic linkage across multiple pedigrees reinforces CASQ2 as a causal gene in CPVT2.
To date, over 30 pathogenic CASQ2 variants have been described, encompassing missense changes such as c.98G>A (p.Arg33Gln), splice-site mutations (c.532+1G>A), frameshift deletions (c.339_354del (p.Ser113fs)), and nonsense substitutions (c.97C>T (p.Arg33Ter)) (PMID:16908766). Population-specific alleles, including p.Asp307His in Bedouin families and p.Lys180Arg in autosomal dominant presentations, reflect allelic heterogeneity. Variant classes are predominantly loss-of-function, consistent with haploinsufficiency and polymerization defects. Recurrent mutations have been documented in consanguineous cohorts and Asian populations, broadening the ethnic spectrum (PMID:29178653; PMID:31482657). The allele frequency in large exome databases is negligible, supporting disease specificity. Founder and recurrent alleles facilitate targeted genetic screening in high-prevalence groups.
Functional studies in adult rat cardiomyocytes demonstrated that the R33Q variant increases excitation-contraction coupling gain and spontaneous Ca²⁺ waves, coupled with significant intra-SR Ca²⁺ depletion, due to abrogated CASQ2–RyR2 interaction at low luminal Ca²⁺ (PMID:16601229). In vitro Ca²⁺-binding assays confirmed normal binding capacity of mutant protein but failed to inhibit RyR2 activity in planar lipid bilayers. Murine models homozygous for CASQ2 D307H or null alleles recapitulate stress-induced ventricular arrhythmias, exhibiting reduced SR Ca²⁺, elevated RyR2 and calreticulin expression, and diastolic Ca²⁺ leak mitigated by RyR2 inhibitors (PMID:14715535). Human iPSC-derived cardiomyocytes carrying D307H and R420Q mutations show aberrant Ca²⁺ transients and arrhythmias under β-adrenergic stimulation, linking genetic defects to cellular phenotype. Splice-site mutations disrupt polymerization and splicing, further emphasizing loss-of-function pathways. Collectively, these data consolidate the pathogenic mechanism of CASQ2 variants in CPVT2.
Despite extensive variant cataloging, no conclusive evidence has refuted the CASQ2–CPVT association. Large-scale exome analyses in diverse populations reveal rare CASQ2 alleles at frequencies inconsistent with a fully penetrant monogenic trait in the absence of a CPVT phenotype, highlighting the critical role of phenotypic context and functional validation in variant interpretation (PMID:27538377). Disputed cases often involve heterozygous carriers with milder phenotypes, underscoring the complexity of dosage sensitivity. Guideline recommendations endorse CASQ2 testing in CPVT diagnostic panels, with subsequent cascade screening of at-risk relatives. Functional annotations and variant pathogenicity predictions integrated with clinical data minimize false positives and guide management. Emerging iPSC and animal studies refine genotype–phenotype correlations.
Integration of genetic segregation, comprehensive variant spectrum, and concordant functional studies establishes a definitive association between CASQ2 and CPVT2. Genetic testing for CASQ2 variants is recommended in patients presenting with exercise-induced syncope or bidirectional ventricular tachycardia, enabling precise arrhythmia risk stratification and preventive therapy. Early identification of pathogenic CASQ2 alleles permits implementation of β-blockade, flecainide, or device therapy while facilitating family member screening. Further research into dominant-negative missense variants may expand inheritance paradigms. Key take-home: CASQ2 variant detection provides a critical diagnostic and prognostic tool in CPVT management.
Gene–Disease AssociationDefinitive36 probands from 24 families with biallelic CASQ2 variants; extensive segregation and functional concordance ([PMID:32693635]) Genetic EvidenceStrong24 recessive probands with >97% penetrance and 33% heterozygous affected relatives across multiple pedigrees ([PMID:32693635], [PMID:12386154]) Functional EvidenceModerateMultiple cellular and animal models demonstrate CASQ2 loss-of-function causing SR Ca²⁺ dysregulation and arrhythmogenesis ([PMID:16601229], [PMID:14715535]) |