Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is an autosomal recessive arrhythmia syndrome characterized by exercise‐ or emotion‐induced bidirectional or polymorphic ventricular tachycardia, syncope, and sudden cardiac death. Biallelic pathogenic variants in CASQ2 impair sarcoplasmic reticulum Ca²⁺ buffering and predispose to adrenergically mediated arrhythmias.
The association between CASQ2 and CPVT2 is Definitive. Over 25 unrelated probands with biallelic CASQ2 variants, including 24 homozygotes or compound heterozygotes in an international cohort and one novel case, have been reported with concordant AR segregation and recurrent neurological or arrhythmic features ([PMID:32693635], [PMID:37995796]). Segregation across >20 families, consistent cosegregation of variants with disease, and robust functional and animal model data underpin this determination.
Inheritance is autosomal recessive with complete or variable penetrance. Twenty-five probands with biallelic CASQ2 variants have been described: 24 homozygous/compound heterozygous cases in a multicenter study and one novel homozygote carrying c.268_269insTA (p.Gly90ValfsTer4) ([PMID:37995796]). Segregation in families demonstrated 26 additional affected homozygotes exhibiting CPVT2 features ([PMID:32693635]). The variant spectrum includes at least 10 truncating alleles (nonsense, frameshift, splice) and >14 missense changes, with recurrent founder variants such as p.Arg33Gln and p.Asp307His in multiple populations.
CASQ2 loss‐of‐function destabilizes SR Ca²⁺ storage and RyR2 regulation, leading to delayed afterdepolarizations (DADs) and arrhythmias. In adult rat myocytes, expression of D307H reduces SR Ca²⁺ capacity, alters Ca²⁺ sparks and sparks termination, and induces DADs reversible by citrate buffering ([PMID:14715535]). Knock-in and null mouse models recapitulate stress‐induced CPVT, with mutant D307H and CASQ2-null myocytes showing reduced SR Ca²⁺ load, elevated RyR2 leak, and arrhythmias that normalize with RyR2 inhibitors ([PMID:17607358]). iPSC‐derived cardiomyocytes from CPVT2 patients with D307H exhibit defective lusitropy, arrhythmogenic Ca²⁺ transients, and isoproterenol‐induced afterdepolarizations, mirroring patient phenotypes ([PMID:26153920]).
No substantial conflicting evidence has been reported for CASQ2 in CPVT2; rare population variants have not been overrepresented in healthy controls at a frequency inconsistent with AR disease prevalence.
AR CASQ2 variants cause loss of Ca²⁺ buffering and RyR2 regulation, leading to stress‐induced arrhythmias in humans, cell models, and animals. Genetic testing for CASQ2 should be considered in patients with exercise‐triggered ventricular tachycardia, especially when RYR2 is negative. Functional assays and animal data confirm pathogenicity, supporting genotype‐driven risk stratification and targeted therapy with beta‐blockers or RyR2 inhibitors.
Key Take-home: Biallelic CASQ2 variants definitively underlie CPVT2, and molecular diagnosis guides clinical management and genetic counseling.
Gene–Disease AssociationDefinitiveBiallelic CASQ2 variants identified in >25 probands from >20 families with AR inheritance ([PMID:32693635], [PMID:37995796]); robust segregation and concordant functional and animal model data Genetic EvidenceStrong25 probands with biallelic CASQ2 variants, AR inheritance, segregation in multiple families, variant classes include truncating and missense, recurrent p.Arg33Gln founder allele ([PMID:32693635], [PMID:37995796]) Functional EvidenceStrongMultiple cellular and animal models demonstrate that CASQ2 loss-of-function variants impair SR Ca²⁺ buffering, destabilize Ca²⁺ release and cause CPVT phenotypes; rescue with Ca²⁺ buffer or RyR2 inhibitors ameliorates arrhythmias ([PMID:14715535], [PMID:17607358], [PMID:26153920]) |