CASQ2 CPVT

Genetic MONDO:0012762 Pathograph 59 Show in embeddings browser Cardiac Arrhythmia Channelopathy

CASQ2-related catecholaminergic polymorphic ventricular tachycardia (CPVT2) is a cardiac calcium-handling disorder, usually caused by biallelic pathogenic CASQ2 variants. Reduced calsequestrin abundance or altered protein assembly disrupts sarcoplasmic-reticulum calcium buffering and regulation of RyR2-mediated release. Adrenergic stress promotes spontaneous diastolic calcium release, delayed afterdepolarizations and triggered ventricular arrhythmias, which can cause syncope, cardiac arrest or sudden death despite a usually structurally normal heart. The recessive gene–disease association is definitive. A variant-dependent heterozygous association has moderate ClinGen validity; a dominant-negative mechanism remains a hypothesis for selected missense alleles rather than an established property of every heterozygous CASQ2 variant.

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Classifications

Harrison's Part

Channelopathy

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Inheritance

Autosomal Recessive HP:0000007

The definitive, predominant association is autosomal recessive. Pathogenic variants may be homozygous or compound heterozygous. In the selected 2020 family cohort, 33/34 biallelic carriers were phenotype positive; the remaining four-year-old had Holter monitoring but no exercise test. This age- and ascertainment-dependent observation is not a population penetrance estimate.

Autosomal recessive inheritance

Show evidence (4 references)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"CASQ2-related CPVT is typically inherited in an autosomal recessive manner"

GeneReviews states that CASQ2-related CPVT is typically autosomal recessive.

PMID:11704930 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"we describe a missense mutation in a highly conserved region of the calsequestrin 2 gene (CASQ2) as the potential cause of the autosomal recessive form"

The original CASQ2 mapping study established the recessive mode of inheritance for CPVT2.

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1%"

Clinical positivity was 33/34 in the selected cohort, with incomplete provocative testing in the young negative child.

+ 1 more reference

Autosomal Dominant HP:0000006

A heterozygous, variant-dependent association is supported at Moderate ClinGen validity. In the 2020 cohort, 17/51 evaluated heterozygous relatives met study CPVT criteria, but only four had polymorphic or bidirectional ventricular tachycardia. These selected families cannot estimate population penetrance. Candidate variants include missense and truncating/splice alleles; biochemical filamentation defects do not by themselves prove dominant interference. Clinical screening is warranted, while a heterozygous genotype alone should not automatically establish CPVT or mandate treatment in a phenotype-negative relative.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT."

The 17/51 result is from clinically ascertained families and is not general penetrance of CASQ2 heterozygosity.

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure."

The authors propose allele-dependent dominance; functional evidence does not directly demonstrate mixed wild-type/mutant dominant interference.

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"because a subset of individuals (still unquantified but rare) with heterozygous CASQ2 pathogenic variants show a mild CPVT phenotype, autosomal dominant inheritance may not be ruled out for CASQ2-related CPVT"

GeneReviews explicitly leaves autosomal dominant inheritance open for CASQ2-related CPVT.

+ 1 more reference

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Subtypes

Biallelic (recessive) CASQ2-CPVT

CASQ2 hgnc:1513

Biallelic pathogenic CASQ2 variants produce the established recessive form, with substantial childhood arrhythmic risk. The 2020 cohort recorded a composite first arrhythmic event in 26/34 carriers at median age seven; this is neither a mean age of ventricular-tachycardia onset nor a population risk.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years"

Characterises the arrhythmic burden and early onset of the biallelic subtype.

Putative heterozygous CASQ2-associated CPVT

CASQ2 hgnc:1513

CPVT has been reported with selected heterozygous CASQ2 variants. The association is less secure than the recessive form and is not invariably mild: heterozygous probands can have severe events. Risk in screened relatives was lower than in biallelic relatives, but variant-specific penetrance and mechanisms remain unresolved.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals"

Supports clinical evaluation of heterozygous relatives, without upgrading every allele to a dominant cause.

Discussions and Knowledge Gaps

How do allele-specific buffering, release-channel regulation and SR compensation combine to determine spontaneous release?

KNOWLEDGE GAP OPEN gap_intra_sr_calcium_kinetics_casq2

Attached to

pathophysiology#Reduced Sarcoplasmic Reticulum Calcium Buffering

Free luminal calcium has been measured in a heterozygous null model and was unchanged despite increased leak. Complete-null hearts also compensate by increasing SR volume. These observations support a regulatory contribution alongside buffering and leave variant-specific dynamic release thresholds unresolved.

Proposed experiments

Direct luminal calcium kinetics in calsequestrin-deficient cardiomyocytes

luminal sarcoplasmic reticulum calcium imaging experiment

exp_casq2_luminal_calcium_kinetics

Measure free intra-SR calcium kinetics with a targeted luminal calcium sensor in calsequestrin-deficient versus wild-type cardiomyocytes during beta-adrenergic stimulation, testing whether free luminal calcium near RyR2 rises faster and reaches the spontaneous-release threshold sooner.

Truncating versus filament-defective CASQ2 allele comparison

allele-series calcium handling comparison

exp_casq2_truncating_vs_missense_kinetics

Compare intra-SR calcium kinetics between truncating CASQ2 alleles (complete protein loss) and missense alleles that retain protein but impair filament assembly, to separate the pure buffering deficit from the RyR2-regulatory deficit.

Show evidence (1 reference)

PMID:17656677 SUPPORT DIRECT PRIMARY RESULT In Vitro

"SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction."

A measured negative result contradicts a blanket claim that all relevant luminal-calcium measurements are absent.

How do cardiac conduction-system and working-myocardial contributions to arrhythmia differ between Casq2 mice and human CASQ2 disease?

HUMAN MODEL MISMATCH OPEN mismatch_purkinje_casq2_tissue_origin

Attached to

pathophysiology#Triggered Cardiomyocyte Action Potentials pathophysiology#Sinoatrial Node Dysfunction

The 2018 conditional study found that concurrent loss in the conduction system and working myocardium was needed for CPVT, while conduction-system rescue prevented it. The targeted system includes sinoatrial tissue and is not equivalent to the Purkinje network alone. These mouse results do not establish the tissue origin in genotype-confirmed human CASQ2 disease, and general CPVT mapping studies should not be assumed to be CASQ2-specific.

Proposed experiments

High-density endocardial mapping in genotyped CASQ2-CPVT patients

high-density endocardial electroanatomic mapping study

exp_casq2_human_endocardial_mapping

Where electrophysiological mapping is clinically indicated, compare trigger localization in genotype-confirmed CASQ2 cases, separating conduction-system from working-myocardial origins without extrapolating from mixed-genotype CPVT series.

CASQ2-mutant iPSC cardiomyocyte lineage comparison

iPSC-derived cardiomyocyte lineage comparison experiment

exp_casq2_ipsc_conduction_vs_working

Compare triggered-activity thresholds in patient-derived CASQ2-mutant iPSC cardiomyocytes differentiated toward conduction-system versus working-myocardial identity, in a human cellular background.

Show evidence (1 reference)

PMID:29452352 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Our study shows that the CPVT phenotype is dependent upon concurrent loss of Casq2 function in both the CCS and in working cardiomyocytes. Accordingly, restoration of Casq2 in only the CCS prevents CPVT."

The study already performed conduction-system rescue; proposed work must address the remaining human or lineage-specific uncertainty.

How common are dominant-acting CASQ2 variants, and by what mechanism does a single defective allele impair calsequestrin filament function enough to cause CPVT?

KNOWLEDGE GAP OPEN gap_dominant_casq2_prevalence_mechanism

Attached to

pathophysiology#Impaired CASQ2 Filament Assembly genetic#CASQ2 heterozygous variants

The selected 2020 families and the K180R pedigree support a heterozygous association but do not measure population penetrance. Biochemical filamentation defects do not directly test wild-type/mutant interference, and a corrected K180R iPSC resource is available without reported functional rescue in that resource paper. Variant-specific segregation, isogenic physiology and population ascertainment remain important.

Proposed experiments

Population-scale penetrance estimation for candidate dominant CASQ2 alleles

population-scale genotype-first penetrance study

exp_casq2_dominant_allele_penetrance

Ascertain CASQ2 missense carriers at population scale and phenotype them by exercise stress testing, to estimate the penetrance of candidate dominant-acting alleles independently of clinically ascertained families.

Heterozygous filament-interface CASQ2 knock-in models

heterozygous knock-in disease model

exp_casq2_heterozygous_knockin_model

Use isogenic mutant/corrected human cardiomyocytes, including the available K180R control resource, and selected heterozygous knock-in models to distinguish dominant interference from dosage effects under matched maturation and adrenergic protocols.

Show evidence (1 reference)

PMID:32115705 SUPPORT DIRECT REVIEW SYNTHESIS Other

"More work is needed to understand the physiological role of calsequestrin in the EC coupling cycle, to determine the prevalence of autosomal-dominant calsequestrin mutations, and to understand how they cause CPVT."

The review names the prevalence and mechanism of dominant CASQ2 variants as explicit open questions.

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Pathophysiology

CASQ2 Coding Missense Variation

Mechanism confidence: Established

Germline CASQ2 missense variants constitute one initiating alteration class. Biallelic pathogenic combinations underlie the definitive recessive association; heterozygous effects require allele-specific interpretation.

CASQ2 hgnc:1513

Genetic context CASQ2 hgnc:1513 Variant type: single nucleotide variant Genomic context: coding sequence variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Physical variant class is distinct from its allele-dependent protein consequence.

Downstream

Reduced CASQ2 Protein Abundance Protein truncation or destabilization can reduce cardiac calsequestrin abundance; the extent depends on the allele.

Impaired CASQ2 Filament Assembly Selected missense substitutions impair dimer formation or higher-order filament assembly.

Endoplasmic Reticulum Stress R33Q mouse hearts show a proteostasis response whose intermediates and human generality remain unresolved.

Calpain-Dependent Triadin Degradation R33Q mice show calpain-dependent loss of triadin before calsequestrin destabilization; the link from the sequence change to protease activity remains unresolved.

Show evidence (1 reference)

PMID:11704930 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The mutation, which is in full segregation in seven Bedouin families affected by the disorder"

D307H identifies a segregating coding missense allele; its biochemical consequence was predicted in the founding study.

CASQ2 Coding Stop-Gain Variation

Mechanism confidence: Established

Germline CASQ2 stop gain variants constitute one initiating alteration class. Biallelic pathogenic combinations underlie the definitive recessive association; heterozygous effects require allele-specific interpretation.

CASQ2 hgnc:1513

Genetic context CASQ2 hgnc:1513 Variant type: single nucleotide variant Genomic context: coding sequence variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Physical variant class is distinct from its allele-dependent protein consequence.

Downstream

Reduced CASQ2 Protein Abundance Protein truncation or destabilization can reduce cardiac calsequestrin abundance; the extent depends on the allele.

Show evidence (1 reference)

PMID:12386154 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons."

The R33X coding substitution introduces a premature stop; protein absence was predicted.

CASQ2 Splice-Site Variation

Mechanism confidence: Established

Germline CASQ2 splice-site variants constitute one initiating alteration class. Biallelic pathogenic combinations underlie the definitive recessive association; heterozygous effects require allele-specific interpretation.

CASQ2 hgnc:1513

Genetic context CASQ2 hgnc:1513 Variant type: single nucleotide variant Genomic context: intron variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Physical variant class is distinct from its allele-dependent protein consequence.

Downstream

Reduced CASQ2 Protein Abundance Protein truncation or destabilization can reduce cardiac calsequestrin abundance; the extent depends on the allele.

Show evidence (1 reference)

PMID:12386154 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons."

The reported 532+1 G>A variant affects a splice donor; it is physically distinct from a coding stop substitution.

CASQ2 Small Coding Deletion

Mechanism confidence: Established

Germline CASQ2 frameshift variants constitute one initiating alteration class. Biallelic pathogenic combinations underlie the definitive recessive association; heterozygous effects require allele-specific interpretation.

CASQ2 hgnc:1513

Genetic context CASQ2 hgnc:1513 Variant type: deletion Genomic context: coding sequence variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Physical variant class is distinct from its allele-dependent protein consequence.

Downstream

Reduced CASQ2 Protein Abundance Protein truncation or destabilization can reduce cardiac calsequestrin abundance; the extent depends on the allele.

Show evidence (1 reference)

PMID:12386154 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons."

The one-base deletion is a small coding frameshift, distinct from a stop-gain SNV.

Reduced CASQ2 Protein Abundance

Mechanism confidence: Established

Reduced functional calsequestrin abundance removes both a luminal calcium buffer and a regulator of the junctional release complex. Some missense alleles destabilize protein despite preserved transcript; truncating variants need not share the same degradation pathway. The decreased calcium-binding annotation refers to the smaller protein pool, not an intrinsic binding defect in every remaining mutant molecule.

CASQ2 hgnc:1513

calcium ion binding GO:0005509 ↓ DECREASED

Animal models

D307H Knock-In and Exon-9 Null Mice Mouse partially recapitulates Protein depletion with retained D307H transcript supports post-transcriptional instability.

Adult and Neonatal AAV-CASQ2 Rescue Models Mouse rescues Wild-type gene delivery restores release-complex protein expression.

Eight-Week D307H Knock-In Proteostasis Model Mouse partially recapitulates The age-specific D307H heart measurements demonstrate severe protein depletion.

Downstream

Reduced Sarcoplasmic Reticulum Calcium Buffering Reduced calsequestrin abundance decreases the capacity of its luminal calcium-binding pool.

Destabilized RyR2 Closed State Loss of calsequestrin-mediated regulation promotes abnormal RyR2 release.

Sinoatrial Node Dysfunction Calsequestrin deficiency disrupts pacemaker calcium cycling in null mice.

Sarcoplasmic Reticulum Volume Expansion Null mouse hearts show compensatory SR enlargement, with model-dependent changes in other release-complex proteins.

Increased Mitochondrial Reactive Oxygen Species Null-mouse ventricular cells show excess mitochondrial ROS; the intervening calcium-metabolic pathway is incompletely resolved.

Reduced Sarcolemmal SK Current Null-mouse myocytes show reduced functional SK current under adrenergic stimulation; the path from CASQ2 loss to channel dysfunction is unresolved.

Show evidence (2 references)

PMID:42770222 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Inhibition of the proteasome or autophagy in neonatal cardiomyocytes and adult mice partially restored CASQ2 but not TRDN levels, suggesting distinct degradation mechanisms."

R33Q protein loss is partly reversible through different proteolytic pathways; this finding is model and allele specific.

PMID:32902830 SUPPORT DIRECT PRIMARY RESULT Model Organism

"we confirmed the drastic reduction of expression of D307H CASQ2, as compared to control (14.4 ± 1.5%, p < 0.005)"

Direct protein depletion in the young D307H knock-in heart, independent of the R33Q degradation experiment.

Impaired CASQ2 Filament Assembly

Mechanism confidence: Established

Some pathogenic or candidate missense proteins show abnormal dimerization or higher-order filamentation. In 2020 assays five of six candidate dominant proteins were abnormal at pH 7.4, whereas R251H required pH 5.6. Five retained near-wild-type dimerization; Y55C showed a partly reversible disulfide-related abnormality. Dominant interference in mixed wild-type/mutant complexes is inferred rather than directly demonstrated.

Experimental models

Recombinant Candidate Dominant CASQ2 Proteins OTHER Candidate missense proteins show assay-dependent filamentation defects.

Downstream

Destabilized RyR2 Closed State Altered calsequestrin assembly may disrupt its regulation of the release complex.

Reduced Sarcoplasmic Reticulum Calcium Buffering Abnormal assembly can impair effective store capacity, although calcium binding is not reduced by every missense allele.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize."

Assay-specific assembly defects support a biochemical phenotype, with the pH and protein-mixing limitations described above.

Reduced Sarcoplasmic Reticulum Calcium Buffering

Mechanism confidence: Established

Loss of the calsequestrin calcium-binding pool reduces luminal buffering, but total SR content is partially preserved by structural compensation. In rat myocytes both G112+5X and L167H reduce store capacity, although L167H retains normal calcium binding. Buffering loss is therefore not the only route to abnormal release. Free luminal calcium, release threshold and total store content are distinct measurements.

cardiomyocyte CL:0000746

sarcoplasmic reticulum calcium ion transport GO:0070296 ↕ DYSREGULATED

myocardium UBERON:0002349

Experimental models

G112+5X and L167H Expression in Rat Myocytes PRIMARY CELL CULTURE Both variants reduce calcium-storing capacity despite differing calcium-binding effects.

Computational models

Stochastic CASQ2-Deficient Guinea-Pig Myocyte Simulation PHYSIOLOGICAL The model varies luminal-buffer and release parameters to explore instability.

Downstream

Diastolic Sarcoplasmic Reticulum Calcium Leak Altered luminal buffering can shorten the refractory interval before spontaneous release; direct RyR2 regulation also contributes.

Show evidence (4 references)

PMID:16908766 SUPPORT DIRECT PRIMARY RESULT In Vitro

"When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca2+-storing capacity"

Direct in-vitro demonstration that CPVT2-causing CASQ2 mutants reduce SR calcium-storing capacity.

PMID:16932808 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin"

The Casq2-null mouse shows the structural and complex-composition remodelling that accompanies loss of the luminal buffer.

PMID:32115705 SUPPORT DIRECT REVIEW SYNTHESIS Other

"there is extensive evidence that absence of calsequestrin in mice leads to hyperactive RyR2 channels, impaired calcium-release termination, a shortened calcium release refractory period, and enhanced spontaneous release of calcium"

Review summary of the mechanistic consequences of calsequestrin loss, framed as the accepted model for CPVT2.

+ 1 more reference

Destabilized RyR2 Closed State

Mechanism confidence: Established

Calsequestrin loss renders RyR2 hyperactive and impairs termination of calcium release, so the channel spends more time open during diastole than it should. This is mechanistically distinct from CPVT1, in which the RyR2 channel itself carries the gain-of-function lesion, but the two converge on the same release-channel behaviour.

cardiomyocyte CL:0000746

ryanodine-sensitive calcium-release channel activity GO:0005219 ↑ INCREASED

Animal models

Heterozygous Casq2 Null Mouse Mouse partially recapitulates Leak increases without a detectable change in free luminal calcium.

Downstream

Diastolic Sarcoplasmic Reticulum Calcium Leak Hyperactive, poorly terminating RyR2 channels release calcium into the cytosol during diastole.

Show evidence (2 references)

PMID:32115705 SUPPORT DIRECT REVIEW SYNTHESIS Other

"missense mutations (e.g. R33Q) may alter calsequestrin interaction with RyR2 in addition to reducing calcium buffering"

Supports a direct RyR2-regulatory arm of CASQ2 pathogenesis beyond the buffering deficit.

PMID:17656677 SUPPORT DIRECT PRIMARY RESULT In Vitro

"SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction."

Heterozygous null myocytes had greater leak despite unchanged free luminal calcium, supporting a regulatory contribution beyond bulk buffering.

Beta-Adrenergic Stimulation

Mechanism confidence: Established

Adrenergic receptor stimulation during exertion or emotion increases calcium cycling and SR loading, amplifying instability of the CASQ2-deficient release apparatus. It promotes arrhythmias but is not an absolute requirement for every abnormal cellular release event. Beta-blockers attenuate receptor signaling; they do not prevent the catecholamine surge itself.

cardiomyocyte CL:0000746

adenylate cyclase-activating adrenergic receptor signaling pathway GO:0071880 ↑ INCREASED

heart UBERON:0000948

Downstream

Diastolic Sarcoplasmic Reticulum Calcium Leak The catecholamine surge raises SR calcium loading and release-channel phosphorylation, unmasking the latent calcium leak.

Show evidence (1 reference)

PMID:16908766 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2(G112+5X)"

Beta-adrenergic agonist exposure is what unmasks afterdepolarizations in CASQ2-mutant myocytes.

Diastolic Sarcoplasmic Reticulum Calcium Leak

Mechanism confidence: Established

Premature RyR2-mediated calcium release during diastole can propagate as spontaneous intracellular calcium waves. These local events can trigger electrical activity without requiring a sustained increase in bulk diastolic calcium in every cell.

cardiomyocyte CL:0000746

release of sequestered calcium ion into cytosol by sarcoplasmic reticulum GO:0014808 ↑ INCREASED

myocardium UBERON:0002349

Experimental models

Casq2 Null Myocytes for Flecainide Mechanism Dissection PRIMARY CELL CULTURE Flecainide inhibits spontaneous release even without functional sarcolemmal sodium channels.

Computational models

Multiscale RyR2 Open- and Closed-Block Model KINETIC Different blocking kinetics produce different steady-state spark and SR-load behavior.

Downstream

Diastolic Cytosolic Calcium Elevation Spontaneous SR release transiently raises local cytosolic calcium before the next paced beat.

Show evidence (2 references)

PMID:16932808 SUPPORT DIRECT PRIMARY RESULT Model Organism

"lack of Casq2 also causes increased diastolic SR Ca2+ leak, rendering Casq2-null mice susceptible to catecholaminergic ventricular arrhythmias"

Establishes increased diastolic SR calcium leak as the direct consequence of calsequestrin loss in vivo.

PMID:19835880 SUPPORT DIRECT PRIMARY RESULT In Vitro

"field-stimulated Casq2-/- myocytes exhibit spontaneous Ca2+ release resulting in Ca2+ waves that occur prior to the next pacing stimulus"

Directly demonstrates premature diastolic calcium waves in calsequestrin-null cardiomyocytes.

Diastolic Cytosolic Calcium Elevation

Mechanism confidence: Established

Spontaneous SR calcium release causes transient local cytosolic elevations. Sustained whole-cell calcium overload is variable rather than obligatory: D307H patient-derived cells showed heterogeneous arrhythmic, nonresponsive and raised-diastolic-calcium responses to isoproterenol.

cardiomyocyte CL:0000746

Experimental models

D307H Patient-Derived Cardiomyocytes IPSC DERIVED MODEL Mutant cells can develop diastolic calcium elevation or arrhythmia under adrenergic stimulation.

Downstream

Depolarizing Sodium-Calcium Exchange Current Forward-mode calcium extrusion couples local calcium elevation to a net inward current.

Show evidence (1 reference)

PMID:19835880 SUPPORT DIRECT PRIMARY RESULT In Vitro

"field-stimulated Casq2-/- myocytes exhibit spontaneous Ca2+ release resulting in Ca2+ waves that occur prior to the next pacing stimulus"

Directly observed spontaneous waves in null myocytes.

Depolarizing Sodium-Calcium Exchange Current

Mechanism confidence: Established

Forward sodium-calcium exchange extrudes cytosolic calcium while bringing net positive charge inward. Recruitment of this normal electrogenic process by spontaneous release can depolarize the membrane; increased exchanger expression or intrinsic exchanger activity is not required.

cardiomyocyte CL:0000746

calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential GO:0086038

Downstream

Delayed Afterdepolarizations The net inward exchanger current produces a depolarization after repolarization is complete.

Show evidence (1 reference)

PMID:40438932 SUPPORT DIRECT BACKGROUND Other

"Untimely RyR2-mediated SR Ca2+ release depolarizes sarcolemma by stimulating electrogenic NCX and inducing DADs that underlie arrhythmogenic triggered activity at the organ level."

Background electrophysiological mechanism connecting calcium release to electrical depolarization, not a new exchanger-expression measurement.

Delayed Afterdepolarizations

Mechanism confidence: Established

Membrane depolarizations after repolarization occur in CASQ2-mutant cardiomyocytes under adrenergic stimulation. They may remain subthreshold; threshold crossing generates a separate triggered action potential.

cardiomyocyte CL:0000746

cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL

Experimental models

G112+5X Patient-Derived Cardiomyocytes and AAV Rescue IPSC DERIVED MODEL Homozygous patient-derived cells exhibit adrenergic DADs.

G112+5X Patient-Derived Cardiomyocytes and AAV Rescue IPSC DERIVED MODEL AAV9-CASQ2 reduced DAD/triggered-activity-positive cells from 17/22 to 2/9.

Downstream

Triggered Cardiomyocyte Action Potentials An afterdepolarization generates an ectopic action potential if it reaches the excitation threshold.

Show evidence (1 reference)

PMID:16908766 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2(G112+5X)"

Direct evidence that a CPVT2 CASQ2 mutant produces delayed afterdepolarizations under adrenergic stimulation.

Triggered Cardiomyocyte Action Potentials

Mechanism confidence: Established

Calcium-dependent depolarizations that reach threshold generate premature action potentials. Translation from isolated-cell activity to sustained tissue arrhythmia depends on propagation, source–sink relationships and the conducting system.

cardiomyocyte CL:0000746

Experimental models

Directed-Maturation CASQ2 Knockout Cardiac Organoids ORGANOID Engineered CASQ2-deficient cardiac organoids exhibit pro-arrhythmic contraction patterns.

Downstream

Bidirectional and Polymorphic Ventricular Tachycardia Ectopic impulses can initiate organized or polymorphic ventricular rhythms when they propagate through susceptible tissue.

Palpitations Ectopic or rapid beats may be perceived as palpitations.

Premature Ventricular Contractions Propagation of a premature ventricular action potential produces an ectopic ventricular contraction.

Show evidence (1 reference)

PMID:16932808 SUPPORT DIRECT PRIMARY RESULT In Vitro

"resulting in premature spontaneous SR Ca2+ releases and triggered beats"

Isolated null myocytes demonstrate triggered beats.

Sinoatrial Node Dysfunction

Mechanism confidence: Provisional

Casq2-null mice show abnormal pacemaker calcium cycling, sinus-node conduction defects and atrial-pacemaker-complex fibrosis. Conditional studies implicate the broader cardiac conduction system, including the sinoatrial node, rather than proving rescue restricted to the sinoatrial node alone. Low basal rate increases the opportunity for spontaneous release between beats. Human sinus bradycardia is documented, but the mouse fibrosis has not been established as its human substrate.

cardiac pacemaker cell of sinoatrial node CL:1000477

cardiac conduction GO:0061337 ↓ DECREASED

Animal models

Conditional Conduction-System Deletion and Rescue Mouse perturbs Resting-rate effects depend on conduction-system expression and developmental timing.

Downstream

Bradycardia Impaired sinus automaticity and conduction can reduce resting heart rate.

Diastolic Sarcoplasmic Reticulum Calcium Leak Longer diastolic intervals can permit spontaneous release before the next driven beat.

Atrial Triggered Activity Pacemaker dysfunction and ectopic atrial activity coexist in null mice; calcium-cycling and structural intermediates are model dependent.

Show evidence (2 references)

PMID:24216388 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Casq2(-/-) mice exhibited bradycardia, SAN conduction abnormalities, and beat-to-beat heart rate variability due to enhanced atrial ectopic activity both at baseline and with autonomic stimulation."

Mouse pacemaker dysfunction; this does not establish fibrosis in patients.

PMID:29452352 SUPPORT DIRECT PRIMARY RESULT Model Organism

"resting heart rate depends upon Casq2 gene activity only in the CCS and upon developmental history."

Conditional genetics localizes basal-rate dependence to the cardiac conduction system with a developmental component.

Atrial Triggered Activity

Mechanism confidence: Provisional

Casq2-null mouse atrial preparations show enhanced latent pacemaker activity and atrial ectopy. Fibrosis and conduction defects also promote macro- and micro-reentry, so atrial fibrillation in this model is not explained by triggered activity alone. This experimental branch does not establish a CASQ2-specific human atrial-fibrillation frequency.

cardiomyocyte CL:0000746

Show evidence (1 reference)

PMID:24216388 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Loss of CASQ2 increased fibrosis within the pacemaker complex, depressed primary SAN activity, and conduction, but enhanced atrial ectopic activity and atrial fibrillation (AF) associated with macro- and micro-reentry during autonomic stimulation."

Mouse atrial phenotype involves both abnormal pacemaking and reentry.

Bidirectional and Polymorphic Ventricular Tachycardia

Mechanism confidence: Established

Stress-related ventricular tachyarrhythmia can have bidirectional or polymorphic morphology; neither pattern must invariably precede the other. Cellular triggers require tissue-level propagation before they produce these clinical rhythms.

cardiac conduction GO:0061337 ⚠ ABNORMAL

heart UBERON:0000948

Animal models

Casq2 Promoter/Exon-1 Null Mouse Mouse partially recapitulates Stress-provoked ventricular rhythms reproduce a central human manifestation.

D307H Knock-In and Exon-9 Null Mice Mouse partially recapitulates Stress-provoked arrhythmia occurred before late structural remodeling.

Conditional Conduction-System Deletion and Rescue Mouse rescues Conduction-system restoration prevents CPVT in the conditional experiment.

R33Q Proteostasis and Calpain Model Mouse rescues Calpain inhibition reduces ventricular tachycardia episodes.

Downstream

Effort-Induced Polymorphic Ventricular Tachycardia Adrenergic stress can elicit a polymorphic ventricular rhythm.

Bidirectional Ventricular Tachycardia Alternating ventricular activation produces the bidirectional clinical pattern.

Ventricular Fibrillation An unstable ventricular rhythm may degenerate into fibrillation.

Reduced Effective Cardiac Output Sustained rapid ventricular activation can impair effective cardiac output.

Show evidence (2 references)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic)."

GeneReviews identifies bidirectional or polymorphic VT as the arrhythmia underlying CPVT episodes.

PMID:16908766 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a child with stress-induced ventricular tachycardia and cardiac arrest"

Human CASQ2-mutant case presenting with stress-induced ventricular tachycardia and cardiac arrest.

Reduced Effective Cardiac Output

Mechanism confidence: Established

Hemodynamically significant ventricular tachyarrhythmia can reduce forward blood flow. Transient cerebral hypoperfusion produces syncope, sometimes with convulsive movements; prolonged circulatory failure can cause cardiac arrest and death.

Downstream

Syncope Transient cerebral hypoperfusion causes loss of consciousness.

Cardiac Arrest Persistent ineffective ventricular pumping causes circulatory arrest.

Sudden Cardiac Death Unreversed circulatory arrest can be fatal.

Show evidence (2 references)

PMID:11704930 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress"

Describes the clinical endpoints of catecholamine-induced polymorphic VT in the families in which CASQ2 was identified.

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years"

Quantifies the arrhythmic-event burden and early age of onset in biallelic CASQ2-CPVT.

Sarcoplasmic Reticulum Volume Expansion

Mechanism confidence: Provisional

Complete Casq2 deletion causes marked SR enlargement in mice, partly compensating for loss of the luminal buffering pool. Other release-complex proteins differ between mouse lines and assays; triadin/junctin depletion and calreticulin/RyR2 increases are not universal consequences in every model or in patients.

Animal models

Casq2 Promoter/Exon-1 Null Mouse Mouse partially recapitulates Structural SR enlargement in the complete-null heart.

Show evidence (1 reference)

PMID:16932808 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin"

Structural compensation in the promoter/exon-1 null model.

Endoplasmic Reticulum Stress

Mechanism confidence: Provisional

R33Q mouse hearts activate endoplasmic-reticulum stress and the unfolded-protein response. The finding is allele and model dependent; it is not established as a universal human CPVT feature.

Show evidence (1 reference)

PMID:42770222 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Casq2R33Q/R33Q hearts showed activation of endoplasmic reticulum stress, the unfolded protein response, and alterations in major proteolytic pathways."

R33Q mouse heart proteostasis phenotype.

Calpain-Dependent Triadin Degradation

Mechanism confidence: Provisional

In the R33Q model triadin is a direct calpain substrate, and its degradation precedes loss of calsequestrin. This places triadin destabilization upstream of part of the CASQ2 protein-loss phenotype; the process has not been established for all CASQ2 alleles.

Animal models

R33Q Proteostasis and Calpain Model Mouse partially recapitulates Triadin loss precedes CASQ2 loss, and calpain inhibition restores both proteins.

Downstream

Reduced CASQ2 Protein Abundance Triadin overexpression restores calsequestrin abundance in mutant cells and mice, supporting an upstream stabilizing role.

Show evidence (2 references)

PMID:42770222 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Biochemical assays showed that TRDN is a direct calpain substrate."

Biochemical substrate evidence for triadin proteolysis.

PMID:42770222 SUPPORT DIRECT PRIMARY RESULT Model Organism

"TRDN degradation preceded CASQ2 loss"

Temporal order in the R33Q model, not a human natural-history observation.

Increased Mitochondrial Reactive Oxygen Species

Mechanism confidence: Provisional

Casq2-null ventricular myocytes show increased mitochondrial ROS. The 2025 study also found widened cristae, reduced respiratory-chain supercomplex assembly and impaired ATP production under adrenergic stimulation. NS309 reversed several of these abnormalities, but a specific mitochondrial SK-channel mechanism is inferred from pharmacology rather than isolated genetically.

Experimental models

Casq2 Null Myocytes for SK and Mitochondrial Studies PRIMARY CELL CULTURE NS309 reduces excess mitochondrial ROS.

Animal models

Casq2 Null Mouse with Conditional Mcu Deletion Mouse perturbs Additional Mcu loss aggravates oxidative stress and calcium-handling abnormalities.

Downstream

Increased RyR2 Oxidation Mitochondrial oxidative stress is a proposed contributor to the RyR2 oxidation reversed by NS309; the specific mediator was not isolated.

Show evidence (1 reference)

PMID:40438932 SUPPORT DIRECT PRIMARY RESULT In Vitro

"SK channel enhancement reversed the increased rate of reactive oxygen species production by mitochondria in CPVT VMs."

Null-mouse ventricular myocytes show excess mitochondrial ROS, reduced by NS309.

Increased RyR2 Oxidation

Mechanism confidence: Provisional

Stress-challenged Casq2-null hearts have increased RyR2 oxidation, reduced by SK-channel enhancement. This is a model-specific amplifier, not an established biochemical measurement in human CASQ2 hearts.

Downstream

Destabilized RyR2 Closed State Oxidative modification can amplify abnormal release-channel activity; its quantitative contribution to human disease is unresolved.

Show evidence (1 reference)

PMID:40438932 SUPPORT DIRECT PRIMARY RESULT Model Organism

"It also reversed increased cardiac RyR2 (ryanodine receptor 2) oxidation measured in samples from CPVT hearts of the animals after the stress challenge."

Treatment-sensitive RyR2 oxidation in stressed null mouse hearts.

Reduced Sarcolemmal SK Current

Mechanism confidence: Provisional

Small-conductance calcium-activated potassium current is reduced in adrenergically stimulated Casq2-null ventricular myocytes despite increased surface SK3 protein. NS309 increases this current. This functional-expression mismatch cautions against equating protein abundance with channel activity.

Experimental models

Casq2 Null Myocytes for SK and Mitochondrial Studies PRIMARY CELL CULTURE Reduced current was measured directly by voltage clamp.

Downstream

Triggered Cardiomyocyte Action Potentials Reduced repolarizing potassium current may facilitate triggered excitation; NS309 effects also involve intracellular calcium and mitochondria.

Show evidence (1 reference)

PMID:40438932 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Voltage-clamp experiments in isolated VMs treated with β-adrenergic agonist isoproterenol showed a reduction of sarcolemmal SK channel current (ISK) density in CPVT VMs."

Reduced functional SK current despite increased surface SK3 protein in the detailed study.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Effort-Induced Polymorphic Ventricular Tachycardia Cardiovascular HP:0004758

Show evidence (3 references)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years"

CASQ2-specific source for the childhood onset category and the age-of-onset value on this phenotype.

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The diagnosis of CPVT is established in the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia"

GeneReviews defines exercise- or emotion-induced polymorphic VT as the diagnostic phenotype of CPVT, including its CASQ2 form.

PMID:16908766 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a child with stress-induced ventricular tachycardia and cardiac arrest"

Documents stress-induced ventricular tachycardia in a child carrying a homozygous CASQ2 truncating variant.

Bidirectional Ventricular Tachycardia Cardiovascular HP:0034040

Show evidence (1 reference)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic)."

GeneReviews identifies bidirectional VT as the arrhythmia underlying CPVT episodes.

Syncope Cardiovascular HP:0001279

Show evidence (4 references)

PMID:12386154 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Two patients who experienced syncopes before the age of 7 years were homozygous carriers, suggesting a complete absence of calsequestrin 2."

Direct CASQ2-specific evidence for early-childhood syncope in biallelic carriers.

PMID:12386154 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"One patient was heterozygous for the stop codon and experienced syncopes from the age of 11 years."

Documents later-onset syncope in a heterozygous CASQ2 carrier.

PMID:11704930 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress"

Seizure-like episodes are part of the presenting spectrum described in the CASQ2 mapping study.

+ 1 more reference

Context-specific annotations (1)

Biallelic carriers in the clinically ascertained 2020 multicenter family cohort Biallelic CPVT2 FREQUENT

26/34 (76.5%) across 24 biallelic probands and 10 biallelic relatives in the selected 2020 family cohort.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Cardiac Syncope | 21 (87.5) | 5 (50) | 2 (3.8) | 6 (50) | 2 (14.3) |"

Table 1 reports separate proband and relative columns; the contextual count combines the first two columns only.

Cardiac Arrest Cardiovascular HP:0001695

Show evidence (2 references)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death"

Aborted cardiac arrest is an explicit component of the arrhythmic endpoint studied in the CASQ2-CPVT cohort.

PMID:16908766 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a child with stress-induced ventricular tachycardia and cardiac arrest"

Cardiac arrest in a child with a homozygous CASQ2 truncating variant.

Context-specific annotations (1)

Biallelic carriers in the clinically ascertained 2020 multicenter family cohort Biallelic CPVT2 OCCASIONAL

5/34 (14.7%) across 24 biallelic probands and 10 biallelic relatives; this is not population risk.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Aborted Cardiac Arrest | 5 (20.8) | 0 (0) | 0 (0) | 3 (25) | 1 (7.1) |"

Table 1 reports separate proband and relative columns; the contextual count combines the first two columns only.

Sudden Cardiac Death Cardiovascular HP:0001645

Show evidence (3 references)

PMID:11704930 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress"

Sudden death is part of the presenting spectrum in the families in which CASQ2 was identified.

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death"

Sudden cardiac death is an explicit endpoint in the CASQ2-CPVT risk analysis.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Sudden death may be the first manifestation of the disorder in previously asymptomatic individuals"

Clinical synthesis for CPVT generally, not a CASQ2-specific frequency.

Context-specific annotations (1)

Biallelic carriers in the clinically ascertained 2020 multicenter family cohort Biallelic CPVT2 VERY_RARE

1/34 (2.9%) across 24 biallelic probands and 10 biallelic relatives; ascertainment and survival bias limit interpretation. The frequency band describes this observed cohort count only and must not be used as an untreated lifetime risk.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Sudden Cardiac Death | 0 (0) | 1 (10) | 0 (0) | 0 (0) | 0 (0) |"

Table 1 reports separate proband and relative columns; the contextual count combines the first two columns only.

Ventricular Fibrillation Cardiovascular HP:0001663

Show evidence (1 reference)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available"

GeneReviews describes degeneration to ventricular fibrillation as the mechanism of sudden death in CPVT.

Bradycardia Cardiovascular HP:0001662

Bradycardia may reflect intrinsic sinus dysfunction, medication effects or both; the mouse conduction-system experiments do not determine their relative contribution in a patient.

Show evidence (2 references)

PMID:32115705 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Sinus node dysfunction and bradycardia are well-documented phenotypes of CPVT in humans and in mouse models of CPVT"

Review evidence for bradycardia as a documented CPVT phenotype in humans and in the calsequestrin-null mouse model.

PMID:42692439 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Electrocardiography revealed sinus bradycardia (57 bpm) and normal QTc"

Observed before the reported treatment sequence in the Korean case; apparent CASQ2 homozygosity had unresolved parental segregation.

Palpitations Cardiovascular HP:0001962

As for Bradycardia, the cited review statement describes CPVT as a whole rather than CASQ2-CPVT specifically; no CASQ2-restricted symptom-frequency series reports palpitations separately, so no frequency band is asserted.

Show evidence (1 reference)

PMID:32115705 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Symptoms range from palpitations to cardiac arrest"

Review evidence placing palpitations at the mild end of the CPVT symptom spectrum.

Premature Ventricular Contractions Cardiovascular HP:0006682

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Adrenergic-Induced PVCs | 24 (100) | 8/9 (88.9) | 8/37 (21.6) | 12 (100) | 9 (64.3) |"

Adrenergic PVCs occurred in 32/33 evaluated biallelic carriers, combining the first two table columns.

Context-specific annotations (1)

Biallelic carriers with adrenergic testing in the 2020 multicenter cohort Biallelic CPVT2 VERY_FREQUENT

32/33 (97.0%) tested carriers; one biallelic relative lacked the required testing.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Adrenergic-Induced PVCs | 24 (100) | 8/9 (88.9) | 8/37 (21.6) | 12 (100) | 9 (64.3) |"

Adrenergic PVCs occurred in 32/33 evaluated biallelic carriers, combining the first two table columns.

🧬

Genetic Associations

CASQ2 biallelic loss-of-function variants

Gene: CASQ2 hgnc:1513 relationship_type: CAUSATIVE

Show evidence (5 references)

PMID:11704930 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The mutation, which is in full segregation in seven Bedouin families affected by the disorder"

Establishes full segregation of the founder CASQ2 missense allele with recessive CPVT.

PMID:12386154 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons."

Documents the protein-truncating allelic class in CASQ2-CPVT.

PMID:16908766 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the first CPVT patient carrier of compound heterozygous CASQ2 mutations"

Documents compound heterozygosity as a route to biallelic CASQ2 loss of function.

+ 2 more references

CASQ2 heterozygous variants

Gene: CASQ2 hgnc:1513 relationship_type: UNKNOWN

Show evidence (3 references)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT."

The 17/51 result is from clinically ascertained families and is not general penetrance of CASQ2 heterozygosity.

PMID:27157848 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"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."

Segregation in the K180R pedigree supports an allele-specific association; the abstract death count includes an ungenotyped motor-vehicle-accident death and is not used as a confirmed CASQ2 death count.

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the collective prevalence of presumed pathogenic CASQ2 variants in gnomAD is at least 398-fold greater than the expected prevalence of CASQ2-CPVT"

Population-variant versus estimated disease-frequency discordance supports caution about generalizing selected pedigrees. These are presumed culprit variants, and the comparison is not an allele-specific penetrance measurement.

💊

Medical Actions

Nonselective Beta-Blocker Therapy (Nadolol)

Action: Pharmacotherapy NCIT:C15986

Agent: nadolol CHEBI:7444

Platform: Small molecule

Nonselective beta-blockade, commonly nadolol or propranolol, is first-line therapy for clinically affected CPVT and for established disease genotypes assessed by a specialist. It attenuates cardiac adrenergic receptor signaling rather than the catecholamine surge. Dose, adherence, bradycardia and exercise-test response require monitoring. The 2020 CASQ2 family study does not mandate treatment of every phenotype-negative heterozygous carrier.

Mechanism Target:

INHIBITS Beta-Adrenergic Stimulation — Nonselective beta-blockade attenuates the beta-adrenergic drive that unmasks the latent calsequestrin-deficient calcium instability.

Show evidence (2 references)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"nadolol is the most effective beta blocker in CPVT"

GeneReviews identifies nadolol as the most effective beta blocker in CPVT.

PMID:26432584 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The incidence and severity of ventricular arrhythmias decreased during treatment with nadolol compared with during treatment with β1-selective β-blockers"

Human comparative data supporting nonselective over beta1-selective blockade in CPVT.

Flecainide

Action: Pharmacotherapy NCIT:C15986

Agent: flecainide CHEBI:75984

Platform: Small molecule

Flecainide added to beta-blockade suppresses exercise-induced ventricular arrhythmias in CASQ2-associated CPVT, but residual clinical events can occur despite a normal exercise test. It blocks cardiac sodium channels and, in CASQ2-model experiments, inhibits RyR2-mediated release. The relative contribution of these mechanisms in patients is not established by isolated-cell or mouse experiments.

Mechanism Target:

INHIBITS Diastolic Sarcoplasmic Reticulum Calcium Leak — Flecainide reduces the propagation of spontaneous calcium waves in null myocytes; spark mass falls while spark frequency can rise, so net SR leak and SR content need not decrease.

INHIBITS Triggered Cardiomyocyte Action Potentials — Sodium-channel block reduces excitation; CASQ2-model experiments support an additional contribution from RyR2 block.

Show evidence (9 references)

PMID:19835880 SUPPORT DIRECT PRIMARY RESULT In Vitro

"flecainide significantly reduced the amplitude, duration and spatial width of Ca2+ sparks in Casq2-/- myocytes"

Demonstrates the spark-mass mechanism of flecainide specifically in calsequestrin-null myocytes.

PMID:19835880 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Flecainide induced a sustained decrease in the frequency of spontaneous Ca2+ waves, whereas tetracaine was ineffective"

Establishes flecainide efficacy against arrhythmogenic calcium waves in Casq2-null myocytes, and distinguishes it from tetracaine.

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Flecainide can be added for primary prevention of a cardiac arrest when beta blockers alone cannot control the onset of arrhythmias during an exercise stress test."

GeneReviews management guidance for adding flecainide to beta-blockade in CPVT.

+ 6 more references

Left Cardiac Sympathetic Denervation

Action: left cardiac sympathetic denervation Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Adjunctive reduction of left-sided cardiac sympathetic input may be considered for persistent arrhythmias or drug intolerance. It does not provide complete protection and does not replace medication or continued surveillance.

Mechanism Target:

INHIBITS Beta-Adrenergic Stimulation — Interrupting left-sided sympathetic input reduces the catecholaminergic drive that precipitates the calcium leak and triggered activity.

Show evidence (2 references)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"a significant burden of life-threatening arrhythmias persists after left cardiac sympathetic denervation"

GeneReviews recognises LCSD as a CPVT intervention while documenting the residual arrhythmic burden.

PMID:42692439 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Post-LCSD, the premature ventricular contraction (PVC) heart rate (HR) threshold increased from 108 to 120 bpm."

A case showed improved provocation threshold but later recurrent arrhythmias; the genotype segregation remained unresolved.

Implantable Cardioverter-Defibrillator Placement

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

An ICD is considered for selected high-risk patients, including survivors of cardiac arrest or persistent serious arrhythmias despite optimal treatment. Medications should remain optimized because shocks and adrenergic stress can provoke further arrhythmia. Device choice and pacing needs require individualized assessment, particularly when bradycardia limits medication.

Show evidence (2 references)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"an implantable cardioverter defibrillator is effective for those individuals in whom arrhythmias are not adequately controlled by drug therapy"

GeneReviews management guidance for ICD implantation in CPVT.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"pharmacologic therapy should be maintained/optimized even in persons w/an ICD"

The device complements pharmacological control rather than replacing it.

Individualized Exercise and Adrenergic Trigger Management

Action: exercise restriction and trigger avoidance Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Exertional risk requires specialist assessment, optimized treatment and serial exercise testing. The 2025 AHA/ACC statement allows consideration of competitive sport in selected adequately controlled patients through shared decision-making; couplets or nonsustained ventricular tachycardia require continued treatment intensification and exclusion during optimization. This is broader CPVT guidance, not a CASQ2-specific safety trial.

Mechanism Target:

INHIBITS Beta-Adrenergic Stimulation — Avoiding the precipitating exertional and emotional triggers reduces the catecholamine surges that unmask the calcium instability.

Show evidence (2 references)

PMID:39976316 SUPPORT DIRECT REVIEW SYNTHESIS Other

"With adequate suppression, competitive sports participation can be considered with SDM."

Expert statement supports conditional individualized participation, not unrestricted exercise.

PMID:39976316 SUPPORT DIRECT REVIEW SYNTHESIS Other

"couplets or nonsustained ventricular tachycardia require continued treatment intensification and ongoing exclusion from competitive sports participation during treatment optimization."

Explicit safety boundary of the same guidance.

Genetic Counseling and Cascade Family Screening

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

When both parents are confirmed heterozygous for the familial recessive pathogenic variant(s), each pregnancy has a 25% probability of biallelic inheritance, 50% of heterozygosity and 25% of neither variant. These conditional probabilities do not establish that both parents must always be carriers. Heterozygous relatives require clinical assessment, with counseling reflecting variant uncertainty and the Moderate dominant association. Prenatal or preimplantation testing depends on identifying the familial pathogenic variants.

Show evidence (3 references)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected"

The 25% biallelic recurrence risk applies when both parents are known carriers; apparent homozygosity alone does not establish that condition.

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"clinical screening is indicated accordingly in individuals who are heterozygous for a CASQ2 pathogenic variant"

GeneReviews requires clinical screening of CASQ2 heterozygotes, a CASQ2-specific counselling point.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"If both parents are known to be heterozygous for a ... pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants"

Conditional recessive recurrence risk; gene names are omitted across markup without changing the condition.

Avoidance of Digitalis

Action: Avoidance of digitalis Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Digitalis can promote delayed afterdepolarizations and triggered activity and is listed as an agent to avoid in CPVT. This calcium-loading risk is distinct from adrenergic receptor stimulation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Digitalis favors the onset of cardiac arrhythmias as a result of delayed afterdepolarization and triggered activity; therefore, digitalis should be avoided in all individuals with CPVT."

General CPVT avoidance guidance.

Pregnancy Arrhythmia Management

Action: Pharmacotherapy NCIT:C15986

Agent: nadolol CHEBI:7444 propranolol CHEBI:8499

Platform: Small molecule

GeneReviews recommends continuing beta-blockade, preferentially nadolol or propranolol, throughout pregnancy in affected women, with specialist monitoring of maternal arrhythmia control and medication effects.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"Beta blockers (preferentially nadolol or propranolol) should be administered throughout pregnancy in affected women."

Expert pregnancy-management guidance for CPVT.

Experimental CASQ2 Gene Replacement

Action: AAV-mediated CASQ2 gene replacement Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

AAV-mediated wild-type CASQ2 delivery improves protein expression and arrhythmia readouts in R33Q, D307H and null mice and in G112+5X patient-derived cardiomyocytes. Neonatal R33Q treatment was followed for one year; adult rescue was assessed over shorter intervals. This is preclinical evidence, not established treatment of CASQ2-CPVT patients.

Mechanism Target:

RESTORES Reduced CASQ2 Protein Abundance — AAV-mediated wild-type CASQ2 delivery improves protein expression and arrhythmia readouts in R33Q, D307H and null mice and in G112+5X patient-derived cardiomyocytes. Neonatal R33Q treatment was followed for one year; adult rescue was assessed over shorter intervals. This is preclinical evidence, not established treatment of CASQ2-CPVT patients.

Show evidence (3 references)

PMID:24888331 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin"

Mouse neonatal prevention and adult rescue experiments.

PMID:28336343 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Lower levels of expression prevented sustained VT in AAVCASQ2-treated mice (0 of 26; P < .001 vs controls)."

Lower transgene expression prevented sustained VT but did not necessarily suppress all premature beats or nonsustained VT.

PMID:27711080 SUPPORT DIRECT PRIMARY RESULT In Vitro

"from 78%, 17/22 in HO cells to 22%, 2/9 in HO-CASQ2"

DAD/triggered-activity incidence was reduced, not abolished, in patient-derived cells.

Experimental Calpain Inhibition

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Calpain inhibition in the R33Q model restores triadin and CASQ2 abundance and reduces isolated-cell triggered activity and mouse ventricular tachycardia. The September 2026 abstract does not establish a human drug, dose or clinical benefit.

Mechanism Target:

INHIBITS Calpain-Dependent Triadin Degradation — Calpain inhibition in the R33Q model restores triadin and CASQ2 abundance and reduces isolated-cell triggered activity and mouse ventricular tachycardia. The September 2026 abstract does not establish a human drug, dose or clinical benefit.

Show evidence (1 reference)

PMID:42770222 SUPPORT DIRECT PRIMARY RESULT Model Organism

"calpain inhibition restored CASQ2 and TRDN protein levels, decreased triggered activity in isolated cardiomyocytes, and reduced ventricular tachycardia episodes in vivo in Casq2R33Q/R33Q mice."

Combined preclinical intervention result; clinical efficacy is untested.

Experimental ent-Verticilide B1

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

The RyR2 inhibitor ent-B1 reduces spontaneous release in null myocytes and catecholamine-induced arrhythmia burden in mice. Its mouse half-life was about 45 minutes; the significant antiarrhythmic response at the highest tested dose did not abolish all ectopy. No human efficacy is established.

Mechanism Target:

INHIBITS Destabilized RyR2 Closed State — The RyR2 inhibitor ent-B1 reduces spontaneous release in null myocytes and catecholamine-induced arrhythmia burden in mice. Its mouse half-life was about 45 minutes; the significant antiarrhythmic response at the highest tested dose did not abolish all ectopy. No human efficacy is established.

Show evidence (1 reference)

PMID:38253398 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In vivo, ent-B1 significantly reduced catecholamine-induced ventricular arrhythmias in Casq2 -/- mice in a dose-dependent manner."

Mouse arrhythmia reduction, not complete clinical protection.

Experimental SK-Channel Enhancement with NS309

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

NS309 partially reduces arrhythmia burden in Casq2-null mice and improves repolarizing current, calcium handling and mitochondrial readouts. Protection was transient and absent by 18 hours; pharmacology suggests both sarcolemmal and mitochondrial contributions without establishing their separate clinical effects.

Mechanism Target:

RESTORES Reduced Sarcolemmal SK Current — NS309 partially reduces arrhythmia burden in Casq2-null mice and improves repolarizing current, calcium handling and mitochondrial readouts. Protection was transient and absent by 18 hours; pharmacology suggests both sarcolemmal and mitochondrial contributions without establishing their separate clinical effects.

Show evidence (1 reference)

PMID:40438932 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Bidirectional and polymorphic ventricular tachycardias in CASQ2 KO mice induced by stress challenge (epinephrine+caffeine cocktail) were attenuated by injection of NS309, a specific SK channel enhancer."

Whole-animal stress-provocation result.

🔬

Diagnosis

Exercise stress testing

Supervised exercise testing is the principal provocative test, assessing progressively complex ventricular ectopy and bidirectional or polymorphic tachycardia. Results also guide treatment and activity advice. A normal resting ECG or brief Holter does not exclude disease, and a young child unable to exercise may not have been adequately challenged.

exercise cardiac stress test NCIT:C168192

Results: Exercise-related complex ventricular ectopy in an otherwise compatible cardiac assessment supports CPVT. A negative test does not establish zero future risk or complete protection on treatment.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader SUPPORT DIRECT REVIEW SYNTHESIS Other

"The exercise stress test is the single most important diagnostic test."

Expert guidance supports provocative exercise testing rather than relying on a normal resting ECG or Holter.

PMID:12386154 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"2 of them had ventricular arrhythmias at ECG on exercise tests"

CASQ2-specific demonstration that exercise testing unmasks arrhythmia in otherwise asymptomatic heterozygous carriers.

Molecular genetic testing of CASQ2

Biallelic pathogenic CASQ2 variants support the established recessive diagnosis. A single heterozygous finding requires phenotype, segregation and variant-level assessment because the dominant association has Moderate validity. Apparent homozygosity should be checked against parental results; discordance may require investigation for an undetected deletion, uniparental disomy or technical allele dropout.

genetic testing NCIT:C15709

Results: Distinguish pathogenic/likely pathogenic variants from VUS, verify phase or apparent homozygosity where possible, and clinically evaluate heterozygous relatives without equating carrier status with a confirmed dominant diagnosis.

Show evidence (2 references)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"a heterozygous pathogenic variant in RYR2, CALM1, CALM2, CALM3, CASQ2, or KCNJ2 or biallelic pathogenic variants in CASQ2, TECRL, or TRDN"

GeneReviews lists biallelic CASQ2 variants and selected heterozygous variants; the latter require interpretation in light of weaker gene-validity evidence.

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals"

Sets the screening obligation for heterozygous carriers identified by cascade genetic testing.

Resting ECG and structural cardiac assessment

A usually normal resting ECG and structurally normal heart are compatible with CPVT; resting sinus bradycardia may be present. ECG and imaging help exclude alternative diagnoses, but normal baseline studies do not exclude exercise-induced disease.

resting electrocardiography NCIT:C38053

Results: Structurally normal heart with a normal resting ECG.

The NCIT electrocardiography term covers the resting 12-lead ECG component of this assessment; the accompanying echocardiographic exclusion of structural heart disease is described in the name and description rather than separately coded.

Show evidence (1 reference)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The diagnosis of CPVT is established in the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia"

A structurally normal heart and normal resting ECG are explicit components of the diagnostic criteria.

Longitudinal cardiology surveillance

Ongoing follow-up rather than a one-off diagnostic act. Review by a cardiologist every six to twelve months, with the interval set by disease severity, is important throughout growth because rapid weight gain in childhood and adolescence means beta-blocker dosing must be adjusted continually to stay protective. Serial exercise stress testing is the instrument that both monitors control and individualises permitted exercise intensity.

exercise cardiac stress test NCIT:C168192

Results: Recurrence or worsening of exercise-induced ectopy on serial testing indicates loss of arrhythmia control and prompts dose escalation or escalation of therapy.

Show evidence (2 references)

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Follow-up visits with a cardiologist every six to 12 months (depending on disease severity) are very important, especially until puberty, since body weight increases rapidly and drug dosages must be continually adjusted."

GeneReviews surveillance recommendation, including the growth-related rationale for continual dose adjustment.

PMID:20301466 SUPPORT DIRECT REVIEW SYNTHESIS Other

"allowed exercise intensity should be individualized based on exercise stress test results"

Serial exercise stress testing is the basis for individualising activity restriction during surveillance.

📊

Prevalence

Clinically ascertained international CASQ2 families in the 2020 multicenter study

Cases In Literature

The study assembled 112 genotype-positive people from 36 families: 24 biallelic and 12 heterozygous probands plus 76 relatives. Not all relatives were phenotype positive, and inclusion permitted variants of uncertain significance. This is a cohort size, not a count of 112 confirmed affected patients or a population-prevalence estimate.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified."

Reports the composition of an ascertained family cohort; no population prevalence can be calculated from it.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from CASQ2 CPVT:

📊

Related Datasets

Mouse sequence data bioproject:PRJNA916203

The WT and Casq2-null RNA-seq subset used in the mitochondrial-uptake study. The project also contains CypD and double-knockout samples not included in this contrast.

Mus musculus BULK RNA SEQ

PMID:39691471

NCBI BioProject and ENA run metadata were verified on October 1, 2026. The 13 runs associated with each project are not all samples from this specific comparison; no aggregate sample count is assigned.

Show evidence (1 reference)

PMID:39691471 SUPPORT DIRECT PRIMARY RESULT Model Organism

"All the sequencing data were deposited in the NCBI sequence Read Archive (SRA) database under the Bioproject acession number PRJNA916203 (WT and CASQ2-/- samples) and PRJNA623119 (MCUCKO and CASQ2-/--MCUCKO samples)"

The paper identifies genotype-specific subsets from two BioProjects.

Gene regulation in CPVT model bioproject:PRJNA623119

The conditional Mcu-knockout and Casq2/Mcu double-knockout RNA-seq subset. The broader project also includes earlier SERCA2a-related experiments.

Mus musculus BULK RNA SEQ

PMID:39691471

Show evidence (1 reference)

PMID:39691471 SUPPORT DIRECT PRIMARY RESULT Model Organism

The paper identifies genotype-specific subsets from two BioProjects.

🔬

Clinical Trials

NCT01117454 NOT_APPLICABLE COMPLETED

Completed randomized placebo-controlled crossover trial of flecainide added to standard beta-blocker therapy. One of 13 treated participants had CASQ2-associated disease; 12 had paired outcome tests. Exercise ectopy improved in the mixed cohort, but the trial did not establish a CASQ2-specific effect or reduction in sudden death.

Show evidence (2 references)

clinicaltrials:NCT01117454 SUPPORT DIRECT PRIMARY RESULT Other

"The purpose of this study is to test whether the addition of oral flecainide to standard therapy will reduce ventricular ectopy on exercise test compared to placebo plus standard therapy in patients with Catecholaminergic Polymorphic Ventricular Tachycardia."

Registry describes the add-on trial question.

PMID:28492868 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Putative pathogenic mutations were present in RYR2 in 10 patients and CASQ2 in 1; 2 patients had negative genetic findings."

The randomized trial included one CASQ2 participant; the pooled response cannot be interpreted as a CASQ2-specific effect estimate.

🧫

Experimental Models

G112+5X Patient-Derived Cardiomyocytes and AAV Rescue IPSC_DERIVED_MODEL

Two clones per donor from a homozygous child, a healthy heterozygous father and an unrelated control. Adrenergic DADs and triggered activity were reduced after wild-type CASQ2 gene delivery.

Cell source

Patient and family iPSC-derived cardiomyocytes

Publication

PMID:27711080

Pathograph links

Delayed Afterdepolarizations partially recapitulates fidelity: moderate observes: cellular Homozygous patient-derived cells exhibit adrenergic DADs.

Limitations: Immature cells, donor differences and few clones limit transfer to adult myocardium.

Show evidence (1 reference)

PMID:27711080 SUPPORT DIRECT PRIMARY RESULT In Vitro

"HO-CMs displayed delayed afterdepolarizations (DADs) and, less frequently, triggered activity (TA)"

Patient-specific cellular arrhythmia readout.

Delayed Afterdepolarizations rescues fidelity: moderate observes: cellular AAV9-CASQ2 reduced DAD/triggered-activity-positive cells from 17/22 to 2/9.

Limitations: Small cell counts and incomplete rescue; no clinical gene-transfer outcome was studied.

Show evidence (1 reference)

PMID:27711080 SUPPORT DIRECT PRIMARY RESULT In Vitro

"from 78%, 17/22 in HO cells to 22%, 2/9 in HO-CASQ2"

Rescue was substantial but not absolute; empty vector did not reproduce it.

D307H Patient-Derived Cardiomyocytes IPSC_DERIVED_MODEL

Cardiomyocytes from four patients, two overlapping an earlier report, were compared with non-isogenic controls. Isoproterenol produced heterogeneous responses: arrhythmia, no response or raised diastolic calcium.

Cell source

D307H patient iPSC-derived cardiomyocytes

Publication

PMID:26153920

Pathograph links

Diastolic Cytosolic Calcium Elevation partially recapitulates fidelity: moderate observes: cellular Mutant cells can develop diastolic calcium elevation or arrhythmia under adrenergic stimulation.

Limitations: Immature non-isogenic cells. Augmented caffeine responses do not by themselves establish increased total SR calcium; mean peripheral SR width was not significantly different.

Show evidence (1 reference)

PMID:26153920 SUPPORT DIRECT PRIMARY RESULT In Vitro

"in the mutated cardiomyocytes isoproterenol was either ineffective, caused arrhythmias, or markedly increased diastolic"

Heterogeneous responses; sustained bulk calcium overload is not required in every arrhythmic recording.

Directed-Maturation CASQ2 Knockout Cardiac Organoids ORGANOID

Three engineered knockout clones in an isogenic pluripotent-cell background were matured with AMPK/ERR activation. Organoids showed reduced spontaneous rate, preserved force and more ectopic activity after rest under If blockade.

Cell source

Isogenic PB006.6 pluripotent cells with engineered CASQ2 knockout

Publication

PMID:40562874

Pathograph links

Triggered Cardiomyocyte Action Potentials partially recapitulates fidelity: moderate observes: tissue Engineered CASQ2-deficient cardiac organoids exhibit pro-arrhythmic contraction patterns.

Limitations: Engineered knockout rather than a patient allele; neural and immune compartments are absent. BET-inhibitor rescue in this paper concerns DSP cardiomyopathy, not CASQ2.

Show evidence (2 references)

PMID:40562874 SUPPORT DIRECT PRIMARY RESULT In Vitro

"when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype."

The paper includes a distinct CASQ2-knockout organoid arm.

+ 1 more reference

K180R Isogenic Corrected iPSC Resource IPSC_DERIVED_MODEL

A CRISPR-corrected control line, CIAUi003-A-1, complements the parental heterozygous K180R line. The resource paper reports genetic correction, not rescue of a cardiac electrophysiological phenotype.

Cell source

CIAUi003-A patient line and CRISPR-corrected isogenic control

Publication

PMID:39826349

No RESCUES mechanism link is assigned because functional rescue was not reported.

Show evidence (1 reference)

PMID:39826349 SUPPORT DIRECT PRIMARY RESULT In Vitro

"creating a CRISPR-corrected isogenic control line (CIAUi003-A-1)"

Documents availability of the isogenic resource without claiming functional rescue.

Recombinant Candidate Dominant CASQ2 Proteins OTHER

Purified proteins were examined by turbidity, size-exclusion and structural mapping. Assays identify assembly defects but do not directly model mixed mutant/wild-type filaments in human cardiomyocytes.

Cell source

Recombinant CASQ2 proteins

Publication

PMID:32693635

Pathograph links

Impaired CASQ2 Filament Assembly partially recapitulates fidelity: moderate observes: molecular Candidate missense proteins show assay-dependent filamentation defects.

Limitations: R251H required acidic pH, Y55C showed disulfide-related behavior and W361R could not be expressed. Dominant interference was not directly tested by protein mixing.

Show evidence (1 reference)

PMID:32693635 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize."

Purified-protein assembly result.

G112+5X and L167H Expression in Rat Myocytes PRIMARY_CELL_CULTURE

Expression of two mutant proteins distinguishes calcium binding from effective store capacity.

Cell source

Rat cardiomyocytes expressing mutant CASQ2

Publication

PMID:16908766

Pathograph links

Reduced Sarcoplasmic Reticulum Calcium Buffering perturbs fidelity: moderate observes: cellular Both variants reduce calcium-storing capacity despite differing calcium-binding effects.

Limitations: Heterologous expression and dosage may differ from patient cardiomyocytes; normal binding by L167H excludes universal binding loss as an explanation.

Show evidence (1 reference)

PMID:16908766 SUPPORT DIRECT PRIMARY RESULT In Vitro

"When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca2+-storing capacity"

Mutant expression perturbs SR storage.

Casq2 Null Myocytes for Flecainide Mechanism Dissection PRIMARY_CELL_CULTURE

Permeabilized cells, sodium-channel blockade and flecainide analogues separate sodium-channel from RyR2 contributions.

Cell source

Isolated Casq2-null mouse ventricular myocytes

Publication

PMID:33297863

Pathograph links

Diastolic Sarcoplasmic Reticulum Calcium Leak perturbs fidelity: moderate observes: cellular Flecainide inhibits spontaneous release even without functional sarcolemmal sodium channels.

Limitations: Demonstrates an independent RyR2 contribution in this assay, not an exclusive mechanism in treated patients.

Show evidence (1 reference)

PMID:33297863 SUPPORT DIRECT PRIMARY RESULT In Vitro

"In membrane-permeabilized Casq2-/- cardiomyocytes-lacking intact sarcolemma and devoid of sodium channel contribution-flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations."

Direct intracellular mechanism experiment.

Casq2 Null Myocytes for SK and Mitochondrial Studies PRIMARY_CELL_CULTURE

Voltage clamp, calcium imaging and mitochondrial assays assess NS309 responses in null ventricular myocytes.

Cell source

Isolated Casq2-null mouse ventricular myocytes

Publication

PMID:40438932

Pathograph links

Reduced Sarcolemmal SK Current partially recapitulates fidelity: moderate observes: cellular Reduced current was measured directly by voltage clamp.

Limitations: Increased surface SK3 protein does not imply increased current; mitochondrial effects complicate drug specificity.

Show evidence (1 reference)

PMID:40438932 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Voltage-clamp experiments in isolated VMs treated with β-adrenergic agonist isoproterenol showed a reduction of sarcolemmal SK channel current (ISK) density in CPVT VMs."

Reduced functional SK current despite increased surface SK3 protein in the detailed study.

Increased Mitochondrial Reactive Oxygen Species rescues fidelity: moderate observes: cellular NS309 reduces excess mitochondrial ROS.

Limitations: Incomplete antagonism by membrane-impermeable apamin suggests a mitochondrial component, but does not genetically isolate it.

Show evidence (1 reference)

PMID:40438932 SUPPORT DIRECT PRIMARY RESULT In Vitro

"SK channel enhancement reversed the increased rate of reactive oxygen species production by mitochondria in CPVT VMs."

Null-mouse ventricular myocytes show excess mitochondrial ROS, reduced by NS309.

🐁

Animal Models

Casq2 Promoter/Exon-1 Null Mouse

The complete-null model retains basal contractile function despite loss of the principal SR calcium buffer. SR enlargement partly preserves content, while adrenergic stimulation promotes spontaneous release and ventricular tachyarrhythmia.

Species

Mouse

Genotype

Homozygous targeted deletion abolishing Casq2

Publication

PMID:16932808

Pathograph links

Sarcoplasmic Reticulum Volume Expansion partially recapitulates fidelity: moderate observes: cellular Structural SR enlargement in the complete-null heart.

Limitations: Triadin/junctin and calreticulin changes differ across lines and assays; these are not established universal human adaptations.

Show evidence (1 reference)

PMID:16932808 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin"

Mouse ultrastructural and protein-complex response.

Bidirectional and Polymorphic Ventricular Tachycardia partially recapitulates fidelity: moderate observes: organism Stress-provoked ventricular rhythms reproduce a central human manifestation.

Limitations: The study did not reproduce spontaneous sudden death or ventricular fibrillation; basal contractility was largely preserved.

Show evidence (1 reference)

PMID:16932808 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In vivo, Casq2-null mice phenocopied the human arrhythmias"

Whole-animal arrhythmic phenotype.

D307H Knock-In and Exon-9 Null Mice

The 2007 study compared D307H and exon-9-null models. Both had severe protein depletion, calreticulin/RyR2 increases and stress-related arrhythmia. Older animals developed hypertrophy and impaired function, unlike the usually structurally normal human presentation.

Species

Mouse

Genotype

Homozygous D307H or exon-9 deletion

Publication

PMID:17607358

Pathograph links

Reduced CASQ2 Protein Abundance partially recapitulates fidelity: moderate observes: molecular Protein depletion with retained D307H transcript supports post-transcriptional instability.

Limitations: Calreticulin elevation was not reproduced at eight weeks in a later D307H study; age, line and assay context matter.

Show evidence (1 reference)

PMID:17607358 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Mutant myocytes had reduced CASQ2 and increased calreticulin and RyR2"

Reports protein changes in these particular lines.

Bidirectional and Polymorphic Ventricular Tachycardia partially recapitulates fidelity: moderate observes: organism Stress-provoked arrhythmia occurred before late structural remodeling.

Limitations: Late mouse hypertrophy does not establish CASQ2-related human hypertrophic cardiomyopathy.

Show evidence (1 reference)

PMID:17607358 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Young mutant mice had structurally normal hearts but stress-induced ventricular arrhythmias"

Mouse age-dependent phenotype.

Heterozygous Casq2 Null Mouse

A modest dosage reduction increases stress-induced ventricular ectopy despite unchanged SR volume, other measured SR proteins and free luminal calcium.

Species

Mouse

Genotype

Casq2+/−, approximately 25% protein reduction

Publication

PMID:17656677

Pathograph links

Destabilized RyR2 Closed State partially recapitulates fidelity: moderate observes: cellular Leak increases without a detectable change in free luminal calcium.

Limitations: A dosage model does not directly test dominant-negative effects of a human missense allele.

Show evidence (1 reference)

PMID:17656677 SUPPORT DIRECT PRIMARY RESULT In Vitro

"SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction."

Isolated cells demonstrate the negative luminal-calcium result.

Conditional Conduction-System Deletion and Rescue

Genetic timing and tissue targeting separate developmental effects on resting rate from the requirements for stress arrhythmia.

Species

Mouse

Genotype

Conditional Casq2 deletion/rescue in cardiac conduction system and working myocardium

Publication

PMID:29452352

Pathograph links

Bidirectional and Polymorphic Ventricular Tachycardia rescues fidelity: moderate observes: organism Conduction-system restoration prevents CPVT in the conditional experiment.

Limitations: The targeted conduction system includes sinoatrial tissue and is not a Purkinje-only intervention; human tissue origin remains uncertain.

Show evidence (1 reference)

PMID:29452352 SUPPORT DIRECT PRIMARY RESULT Model Organism

"restoration of Casq2 in only the CCS prevents CPVT."

Tissue-targeted rescue has already been demonstrated.

Sinoatrial Node Dysfunction perturbs fidelity: moderate observes: organism Resting-rate effects depend on conduction-system expression and developmental timing.

Limitations: Whole-conduction-system targeting does not isolate the sinoatrial cell lineage.

Show evidence (1 reference)

PMID:29452352 SUPPORT DIRECT PRIMARY RESULT Model Organism

"resting heart rate depends upon Casq2 gene activity only in the CCS and upon developmental history."

Conditional genetics distinguishes basal rate from CPVT timing.

R33Q Proteostasis and Calpain Model

The September 2026 study examines couplon-protein degradation and its reversibility in mutant hearts, neonatal cells and isolated adult cardiomyocytes.

Species

Mouse

Genotype

Casq2R33Q/R33Q

Publication

PMID:42770222

Pathograph links

Calpain-Dependent Triadin Degradation partially recapitulates fidelity: moderate observes: molecular Triadin loss precedes CASQ2 loss, and calpain inhibition restores both proteins.

Limitations: Available cached source is the abstract; pharmacological specificity and full experimental details cannot be assessed from it alone.

Show evidence (1 reference)

PMID:42770222 SUPPORT DIRECT PRIMARY RESULT Model Organism

"TRDN degradation preceded CASQ2 loss"

Temporal order supports an upstream triadin destabilization process.

Bidirectional and Polymorphic Ventricular Tachycardia rescues fidelity: moderate observes: organism Calpain inhibition reduces ventricular tachycardia episodes.

Limitations: Reduction in events is not a demonstrated cure or human treatment effect.

Show evidence (1 reference)

PMID:42770222 SUPPORT DIRECT PRIMARY RESULT Model Organism

"reduced ventricular tachycardia episodes in vivo in Casq2R33Q/R33Q mice"

Whole-mouse intervention endpoint.

Adult and Neonatal AAV-CASQ2 Rescue Models

Neonatal treatment prevented severe manifestations during follow-up to one year; adult administration was assessed after two months.

Species

Mouse

Genotype

R33Q/R33Q treated with AAV9 wild-type CASQ2

Publication

PMID:24888331

Pathograph links

Reduced CASQ2 Protein Abundance rescues fidelity: moderate observes: molecular Wild-type gene delivery restores release-complex protein expression.

Limitations: Durability differs by treatment age and follow-up window; this does not establish lifelong protection or human dosing.

Show evidence (1 reference)

PMID:24888331 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin"

Mouse prevention and adult rescue protocols.

Casq2 Null Mouse with Conditional Mcu Deletion

A mitochondrial-calcium-uptake perturbation tests compensatory adaptation rather than reproducing the usual human genotype. Surviving animals show heterogeneous remodeling and greater oxidative stress.

Species

Mouse

Genotype

Casq2−/− with inducible cardiac Mcu knockout

Publication

PMID:39691471

Pathograph links

Increased Mitochondrial Reactive Oxygen Species perturbs fidelity: moderate observes: cellular Additional Mcu loss aggravates oxidative stress and calcium-handling abnormalities.

Limitations: Severe early mortality creates survivor selection. Remodeling occurred in 6/12 examined double mutants and mean fractional shortening was not significantly different; neither Mcu loss nor this structural phenotype is established as typical human CASQ2 disease.

Show evidence (1 reference)

PMID:39691471 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Live-cell imaging identified altered Ca2+ handling and increased oxidative stress in CASQ2-/--MCUCKO myocytes."

Cellular readout from double-mutant animals.

CaMKII/calcineurin activation and the usual fetal-gene program were not increased. Greater spontaneous waves were pacing-dependent (2 Hz rather than 0.5 Hz).

Eight-Week D307H Knock-In Proteostasis Model

Male eight-week D307H hearts, four per group, retained approximately 14.4% of control CASQ2 protein. Calreticulin, GRP78 and GRP94 were not significantly increased, unlike some other Casq2 models. Protein-marker measurements do not by themselves demonstrate increased degradation or autophagic flux.

Species

Mouse

Genotype

Homozygous D307H knock-in

Publication

PMID:32902830

Pathograph links

Reduced CASQ2 Protein Abundance partially recapitulates fidelity: moderate observes: molecular The age-specific D307H heart measurements demonstrate severe protein depletion.

Limitations: Small male-only group and a specific age; findings should not be combined uncritically with older D307H or R33Q hearts.

Show evidence (1 reference)

PMID:32902830 SUPPORT DIRECT PRIMARY RESULT Model Organism

"we confirmed the drastic reduction of expression of D307H CASQ2, as compared to control (14.4 ± 1.5%, p < 0.005)"

Protein measurement in young D307H knock-in hearts.

Show evidence (1 reference)

PMID:32902830 SUPPORT DIRECT PRIMARY RESULT Model Organism

"The conspicuous decrease of D307H CASQ2 protein was not accompanied by up-regulation of ER stress markers"

Negative marker finding limits generalization of an ER-stress response across alleles and ages; it does not refute the R33Q-specific node.

🧮

Computational Models

Stochastic CASQ2-Deficient Guinea-Pig Myocyte Simulation PHYSIOLOGICAL

A stochastic local-control ventricular-myocyte model approximates G112+5X-associated changes in CASQ2 buffering and calcium-release-unit parameters. Rapid pacing with adrenergic stimulation produces alternans; a rapid-to-slow transition produces EADs, not a direct experimental demonstration of DADs.

PMID:36672764

Pathograph links

Reduced Sarcoplasmic Reticulum Calcium Buffering perturbs fidelity: moderate observes: cellular The model varies luminal-buffer and release parameters to explore instability.

Limitations: Species and parameter assumptions, no modeled calcium-wave propagation, and protocol-dependent EADs limit transfer to human DAD-mediated disease.

Show evidence (1 reference)

PMID:36672764 SUPPORT DIRECT PRIMARY RESULT Computational

"In the simulation studies under rapid pacing (6 Hz), electromechanically concordant cellular alternans appeared under β-adrenergic stimulation in the CPVT mutant but not in the wild-type nor in the non-β-stimulated mutant."

Computational alternans under a defined pacing protocol.

Multiscale RyR2 Open- and Closed-Block Model KINETIC

The 2026 dynamic model couples experimentally determined RyR2 gating with SERCA uptake to explain why flecainide and tetracaine can differ despite both inhibiting channels.

PMID:42363594

Pathograph links

Diastolic Sarcoplasmic Reticulum Calcium Leak perturbs fidelity: moderate observes: cellular Different blocking kinetics produce different steady-state spark and SR-load behavior.

Limitations: Permeabilized-cell calcium-release model, not a whole-heart arrhythmia or clinical drug-efficacy trial.

Show evidence (1 reference)

PMID:42363594 SUPPORT DIRECT PRIMARY RESULT Computational

"Acute closed block also decreased spark frequency due to reduced frequency of RyR2 opening. This resulted in a much stronger inhibition of overall spark Ca2+ leak and a larger increase in SR load to achieve a new steady state."

A model prediction explaining compensation to closed-channel block.

{ }

Source YAML

click to show

name: CASQ2 CPVT
creation_date: '2026-07-31T00:00:00Z'
description: >-
  CASQ2-related catecholaminergic polymorphic ventricular tachycardia (CPVT2) is a cardiac calcium-handling disorder, usually caused by biallelic pathogenic CASQ2 variants. Reduced calsequestrin abundance or altered protein assembly disrupts sarcoplasmic-reticulum calcium buffering and regulation of RyR2-mediated release. Adrenergic stress promotes spontaneous diastolic calcium release, delayed afterdepolarizations and triggered ventricular arrhythmias, which can cause syncope, cardiac arrest or sudden death despite a usually structurally normal heart. The recessive gene–disease association is definitive. A variant-dependent heterozygous association has moderate ClinGen validity; a dominant-negative mechanism remains a hypothesis for selected missense alleles rather than an established property of every heterozygous CASQ2 variant.
synonyms:
- CPVT2
- catecholaminergic polymorphic ventricular tachycardia 2
- CASQ2 catecholaminergic polymorphic ventricular tachycardia
- catecholaminergic polymorphic ventricular tachycardia caused by mutation in CASQ2
- ventricular tachycardia, catecholaminergic polymorphic, 2
category: Genetic
disease_term:
  preferred_term: catecholaminergic polymorphic ventricular tachycardia 2
  term:
    id: MONDO:0012762
    label: catecholaminergic polymorphic ventricular tachycardia 2
parents:
- Cardiac Arrhythmia
- Channelopathy
classifications:
  channelopathy_category:
    classification_value: cardiac channelopathy
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
references:
- reference: PMID:32693635
  title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
- reference: PMID:20301466
  title: Catecholaminergic Polymorphic Ventricular Tachycardia.
  tags:
  - GeneReviews
- reference: PMID:11704930
  title: A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_991ee32e-280d-4bea-a638-aa1b6fa6f781-2021-01-20T170000.000Z
  title: curation results for Gene-Disease Validity
- reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c778b145-fcfc-4252-8dd8-33f982b288e8-2021-01-20T170000.000Z
  title: curation results for Gene-Disease Validity
- reference: PMID:12386154
  title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:42770222
  title: Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
- reference: PMID:32902830
  title: 'Molecular adaptation to calsequestrin 2 (CASQ2) point mutations leading to catecholaminergic polymorphic ventricular tachycardia (CPVT): comparative analysis of R33Q and D307H mutants.'
- reference: PMID:16908766
  title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:16932808
  title: Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:32115705
  title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:17656677
  title: Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice.
- reference: PMID:19835880
  title: Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass.
- reference: PMID:40438932
  title: Pharmacological Enhancement of Small Conductance Ca(2+)-Activated K(+) Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.
- reference: PMID:24216388
  title: Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1.
- reference: PMID:29452352
  title: Conditional ablation and conditional rescue models for Casq2 elucidate the role of development and of cell-type specific expression of Casq2 in the CPVT2 phenotype.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader
  title: Catecholaminergic Polymorphic Ventricular Tachycardia - GeneReviews&reg; - NCBI Bookshelf
- reference: PMID:42692439
  title: First biallelic CASQ2 variant in a Korean child with catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:42435031
  title: 'Catecholaminergic Polymorphic Ventricular Tachycardia Type 2 Presenting as Seizure in a Child: Diagnostic Pitfalls.'
- reference: PMID:27157848
  title: A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:26432584
  title: Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:23954267
  title: Flecainide therapy suppresses exercise-induced ventricular arrhythmias in patients with CASQ2-associated catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:28492868
  title: 'Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial.'
- reference: PMID:33297863
  title: RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT.
- reference: PMID:19330009
  title: Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.
- reference: PMID:39976316
  title: 'Clinical Considerations for Competitive Sports Participation for Athletes With Cardiovascular Abnormalities: A Scientific Statement From the American Heart Association and American College of Cardiology.'
- reference: PMID:24888331
  title: Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age.
- reference: PMID:28336343
  title: Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models.
- reference: PMID:27711080
  title: Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:38253398
  title: ent-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Casq2 (-/-) Mice.
- reference: clinicaltrials:NCT01117454
  title: A Prospective Randomized Crossover Trial of Oral Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia
- reference: PMID:17607358
  title: Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia.
- reference: PMID:39691471
  title: Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT.
- reference: PMID:26153920
  title: Functional abnormalities in iPSC-derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations.
- reference: PMID:40562874
  title: Maturation of human cardiac organoids enables complex disease modeling and drug discovery.
- reference: PMID:39826349
  title: Generation of an isogenic CRISPR/Cas9-corrected control induced pluripotent stem cell line from a patient with autosomal dominant catecholaminergic polymorphic ventricular tachycardia with a heterozygous variant in cardiac calsequestrin-2.
- reference: PMID:36672764
  title: Pacing Dynamics Determines the Arrhythmogenic Mechanism of the CPVT2-Causing CASQ2(G112+5X) Mutation in a Guinea Pig Ventricular Myocyte Computational Model.
- reference: PMID:42363594
  title: Different actions of RyR2 open and closed channel block explained by a multiscale Ca(2+) release model.
prevalence:
- population: Clinically ascertained international CASQ2 families in the 2020 multicenter study
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The study assembled 112 genotype-positive people from 36 families: 24 biallelic and 12 heterozygous probands plus 76 relatives. Not all relatives were phenotype positive, and inclusion permitted variants of uncertain significance. This is a cohort size, not a count of 112 confirmed affected patients or a population-prevalence estimate.
  evidence:
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified."
    explanation: Reports the composition of an ascertained family cohort; no population prevalence can be calculated from it.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
inheritance:
- name: Autosomal Recessive
  description: >-
    The definitive, predominant association is autosomal recessive. Pathogenic variants may be homozygous or compound heterozygous. In the selected 2020 family cohort, 33/34 biallelic carriers were phenotype positive; the remaining four-year-old had Holter monitoring but no exercise test. This age- and ascertainment-dependent observation is not a population penetrance estimate.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CASQ2-related CPVT is typically inherited in an autosomal recessive manner"
    explanation: GeneReviews states that CASQ2-related CPVT is typically autosomal recessive.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:11704930
    reference_title: A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe a missense mutation in a highly conserved region of the calsequestrin 2 gene (CASQ2) as the potential cause of the autosomal recessive form"
    explanation: The original CASQ2 mapping study established the recessive mode of inheritance for CPVT2.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1%"
    explanation: Clinical positivity was 33/34 in the selected cohort, with incomplete provocative testing in the young negative child.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - &id003
    reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_991ee32e-280d-4bea-a638-aa1b6fa6f781-2021-01-20T170000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In summary, CASQ2 variants are definitively associated with autosomal recessive CPVT.
    explanation: 'ClinGen CASQ2–autosomal recessive CPVT assertion, approved January 2021: Definitive.'
- name: Autosomal Dominant
  description: >-
    A heterozygous, variant-dependent association is supported at Moderate ClinGen validity. In the 2020 cohort, 17/51 evaluated heterozygous relatives met study CPVT criteria, but only four had polymorphic or bidirectional ventricular tachycardia. These selected families cannot estimate population penetrance. Candidate variants include missense and truncating/splice alleles; biochemical filamentation defects do not by themselves prove dominant interference. Clinical screening is warranted, while a heterozygous genotype alone should not automatically establish CPVT or mandate treatment in a phenotype-negative relative.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT."
    explanation: The 17/51 result is from clinically ascertained families and is not general penetrance of CASQ2 heterozygosity.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure."
    explanation: The authors propose allele-dependent dominance; functional evidence does not directly demonstrate mixed wild-type/mutant dominant interference.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "because a subset of individuals (still unquantified but rare) with heterozygous CASQ2 pathogenic variants show a mild CPVT phenotype, autosomal dominant inheritance may not be ruled out for CASQ2-related CPVT"
    explanation: GeneReviews explicitly leaves autosomal dominant inheritance open for CASQ2-related CPVT.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - &id004
    reference: url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c778b145-fcfc-4252-8dd8-33f982b288e8-2021-01-20T170000.000Z
    reference_title: curation results for Gene-Disease Validity
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In summary, there is moderate evidence to support this gene-disease relationship.
    explanation: 'ClinGen CASQ2–autosomal dominant CPVT assertion, approved January 2021: Moderate; additional evidence is needed for a definitive association.'
has_subtypes:
- name: Biallelic CPVT2
  display_name: Biallelic (recessive) CASQ2-CPVT
  description: >-
    Biallelic pathogenic CASQ2 variants produce the established recessive form, with substantial childhood arrhythmic risk. The 2020 cohort recorded a composite first arrhythmic event in 26/34 carriers at median age seven; this is neither a mean age of ventricular-tachycardia onset nor a population risk.
  genes:
  - preferred_term: CASQ2
    term:
      id: hgnc:1513
      label: CASQ2
  evidence:
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years"
    explanation: Characterises the arrhythmic burden and early onset of the biallelic subtype.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Heterozygous CPVT2
  display_name: Putative heterozygous CASQ2-associated CPVT
  description: >-
    CPVT has been reported with selected heterozygous CASQ2 variants. The association is less secure than the recessive form and is not invariably mild: heterozygous probands can have severe events. Risk in screened relatives was lower than in biallelic relatives, but variant-specific penetrance and mechanisms remain unresolved.
  genes:
  - preferred_term: CASQ2
    term:
      id: hgnc:1513
      label: CASQ2
  evidence:
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals"
    explanation: Supports clinical evaluation of heterozygous relatives, without upgrading every allele to a dominant cause.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
pathophysiology:
- name: CASQ2 Coding Missense Variation
  description: Germline CASQ2 missense variants constitute one initiating alteration class. Biallelic pathogenic combinations underlie the definitive recessive association; heterozygous effects require allele-specific interpretation.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:11704930
    reference_title: A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The mutation, which is in full segregation in seven Bedouin families affected by the disorder
    explanation: D307H identifies a segregating coding missense allele; its biochemical consequence was predicted in the founding study.
  role: trigger
  genes:
  - &id001
    preferred_term: CASQ2
    term:
      id: hgnc:1513
      label: CASQ2
  genetic_context:
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: Physical variant class is distinct from its allele-dependent protein consequence.
  downstream:
  - target: Reduced CASQ2 Protein Abundance
    description: Protein truncation or destabilization can reduce cardiac calsequestrin abundance; the extent depends on the allele.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired CASQ2 Filament Assembly
    description: Selected missense substitutions impair dimer formation or higher-order filament assembly.
    causal_link_type: DIRECT
  - target: Endoplasmic Reticulum Stress
    description: R33Q mouse hearts show a proteostasis response whose intermediates and human generality remain unresolved.
    causal_link_type: UNKNOWN
  - target: Calpain-Dependent Triadin Degradation
    description: R33Q mice show calpain-dependent loss of triadin before calsequestrin destabilization; the link from the sequence change to protease activity remains unresolved.
    causal_link_type: UNKNOWN
- name: CASQ2 Coding Stop-Gain Variation
  description: Germline CASQ2 stop gain variants constitute one initiating alteration class. Biallelic pathogenic combinations underlie the definitive recessive association; heterozygous effects require allele-specific interpretation.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons.
    explanation: The R33X coding substitution introduces a premature stop; protein absence was predicted.
  role: trigger
  genes:
  - *id001
  genetic_context:
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: Physical variant class is distinct from its allele-dependent protein consequence.
  downstream:
  - target: Reduced CASQ2 Protein Abundance
    description: Protein truncation or destabilization can reduce cardiac calsequestrin abundance; the extent depends on the allele.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: CASQ2 Splice-Site Variation
  description: Germline CASQ2 splice-site variants constitute one initiating alteration class. Biallelic pathogenic combinations underlie the definitive recessive association; heterozygous effects require allele-specific interpretation.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons.
    explanation: The reported 532+1 G>A variant affects a splice donor; it is physically distinct from a coding stop substitution.
  role: trigger
  genes:
  - *id001
  genetic_context:
    gene: *id001
    variant_type: single nucleotide variant
    genomic_contexts:
    - intron
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: Physical variant class is distinct from its allele-dependent protein consequence.
  downstream:
  - target: Reduced CASQ2 Protein Abundance
    description: Protein truncation or destabilization can reduce cardiac calsequestrin abundance; the extent depends on the allele.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: CASQ2 Small Coding Deletion
  description: Germline CASQ2 frameshift variants constitute one initiating alteration class. Biallelic pathogenic combinations underlie the definitive recessive association; heterozygous effects require allele-specific interpretation.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons.
    explanation: The one-base deletion is a small coding frameshift, distinct from a stop-gain SNV.
  role: trigger
  genes:
  - *id001
  genetic_context:
    gene: *id001
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: Physical variant class is distinct from its allele-dependent protein consequence.
  downstream:
  - target: Reduced CASQ2 Protein Abundance
    description: Protein truncation or destabilization can reduce cardiac calsequestrin abundance; the extent depends on the allele.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced CASQ2 Protein Abundance
  description: Reduced functional calsequestrin abundance removes both a luminal calcium buffer and a regulator of the junctional release complex. Some missense alleles destabilize protein despite preserved transcript; truncating variants need not share the same degradation pathway. The decreased calcium-binding annotation refers to the smaller protein pool, not an intrinsic binding defect in every remaining mutant molecule.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:42770222
    reference_title: Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Inhibition of the proteasome or autophagy in neonatal cardiomyocytes and adult mice partially restored CASQ2 but not TRDN levels, suggesting distinct degradation mechanisms.
    explanation: R33Q protein loss is partly reversible through different proteolytic pathways; this finding is model and allele specific.
  - reference: PMID:32902830
    reference_title: 'Molecular adaptation to calsequestrin 2 (CASQ2) point mutations leading to catecholaminergic polymorphic ventricular tachycardia (CPVT): comparative analysis of R33Q and D307H mutants.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: we confirmed the drastic reduction of expression of D307H CASQ2, as compared to control (14.4 ± 1.5%, p < 0.005)
    explanation: Direct protein depletion in the young D307H knock-in heart, independent of the R33Q degradation experiment.
  genes:
  - *id001
  downstream:
  - target: Reduced Sarcoplasmic Reticulum Calcium Buffering
    description: Reduced calsequestrin abundance decreases the capacity of its luminal calcium-binding pool.
    causal_link_type: DIRECT
  - target: Destabilized RyR2 Closed State
    description: Loss of calsequestrin-mediated regulation promotes abnormal RyR2 release.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sinoatrial Node Dysfunction
    description: Calsequestrin deficiency disrupts pacemaker calcium cycling in null mice.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sarcoplasmic Reticulum Volume Expansion
    description: Null mouse hearts show compensatory SR enlargement, with model-dependent changes in other release-complex proteins.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased Mitochondrial Reactive Oxygen Species
    description: Null-mouse ventricular cells show excess mitochondrial ROS; the intervening calcium-metabolic pathway is incompletely resolved.
    causal_link_type: UNKNOWN
  - target: Reduced Sarcolemmal SK Current
    description: Null-mouse myocytes show reduced functional SK current under adrenergic stimulation; the path from CASQ2 loss to channel dysfunction is unresolved.
    causal_link_type: UNKNOWN
  molecular_functions:
  - preferred_term: calcium ion binding
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: DECREASED
- name: Impaired CASQ2 Filament Assembly
  description: Some pathogenic or candidate missense proteins show abnormal dimerization or higher-order filamentation. In 2020 assays five of six candidate dominant proteins were abnormal at pH 7.4, whereas R251H required pH 5.6. Five retained near-wild-type dimerization; Y55C showed a partly reversible disulfide-related abnormality. Dominant interference in mixed wild-type/mutant complexes is inferred rather than directly demonstrated.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:32693635
    reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize.
    explanation: Assay-specific assembly defects support a biochemical phenotype, with the pH and protein-mixing limitations described above.
  downstream:
  - target: Destabilized RyR2 Closed State
    description: Altered calsequestrin assembly may disrupt its regulation of the release complex.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Sarcoplasmic Reticulum Calcium Buffering
    description: Abnormal assembly can impair effective store capacity, although calcium binding is not reduced by every missense allele.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Sarcoplasmic Reticulum Calcium Buffering
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    Loss of the calsequestrin calcium-binding pool reduces luminal buffering, but total SR content is partially preserved by structural compensation. In rat myocytes both G112+5X and L167H reduce store capacity, although L167H retains normal calcium binding. Buffering loss is therefore not the only route to abnormal release. Free luminal calcium, release threshold and total store content are distinct measurements.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: sarcoplasmic reticulum calcium ion transport
    term:
      id: GO:0070296
      label: sarcoplasmic reticulum calcium ion transport
    modifier: DYSREGULATED
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:16908766
    reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca2+-storing capacity"
    explanation: Direct in-vitro demonstration that CPVT2-causing CASQ2 mutants reduce SR calcium-storing capacity.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16932808
    reference_title: "Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin"
    explanation: The Casq2-null mouse shows the structural and complex-composition remodelling that accompanies loss of the luminal buffer.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "there is extensive evidence that absence of calsequestrin in mice leads to hyperactive RyR2 channels, impaired calcium-release termination, a shortened calcium release refractory period, and enhanced spontaneous release of calcium"
    explanation: Review summary of the mechanistic consequences of calsequestrin loss, framed as the accepted model for CPVT2.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:16908766
    reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: CASQ2(G112+5X) did not bind Ca2+, whereas CASQ2(L167H) had normal calcium-binding properties.
    explanation: Reduced store capacity does not imply loss of calcium binding by every mutant protein.
  downstream:
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    description: Altered luminal buffering can shorten the refractory interval before spontaneous release; direct RyR2 regulation also contributes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  mechanism_confidence: ESTABLISHED
- name: Destabilized RyR2 Closed State
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    Calsequestrin loss renders RyR2 hyperactive and impairs termination of
    calcium release, so the channel spends more time open during diastole than
    it should. This is mechanistically distinct from CPVT1, in which the RyR2
    channel itself carries the gain-of-function lesion, but the two converge on
    the same release-channel behaviour.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: ryanodine-sensitive calcium-release channel activity
    term:
      id: GO:0005219
      label: ryanodine-sensitive calcium-release channel activity
    modifier: INCREASED
  evidence:
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "missense mutations (e.g. R33Q) may alter calsequestrin interaction with RyR2 in addition to reducing calcium buffering"
    explanation: Supports a direct RyR2-regulatory arm of CASQ2 pathogenesis beyond the buffering deficit.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:17656677
    reference_title: Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction.
    explanation: Heterozygous null myocytes had greater leak despite unchanged free luminal calcium, supporting a regulatory contribution beyond bulk buffering.
  downstream:
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    description: >-
      Hyperactive, poorly terminating RyR2 channels release calcium into the
      cytosol during diastole.
    causal_link_type: DIRECT
  mechanism_confidence: ESTABLISHED
- name: Beta-Adrenergic Stimulation
  role: trigger
  conforms_to: "cardiac_camp_pka_calcium_handling#Cardiomyocyte cAMP-Raising Stimulus"
  biological_scale: ORGANISM
  description: >-
    Adrenergic receptor stimulation during exertion or emotion increases calcium cycling and SR loading, amplifying instability of the CASQ2-deficient release apparatus. It promotes arrhythmias but is not an absolute requirement for every abnormal cellular release event. Beta-blockers attenuate receptor signaling; they do not prevent the catecholamine surge itself.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: adenylate cyclase-activating adrenergic receptor signaling pathway
    term:
      id: GO:0071880
      label: adenylate cyclase-activating adrenergic receptor signaling pathway
    modifier: INCREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:16908766
    reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2(G112+5X)"
    explanation: Beta-adrenergic agonist exposure is what unmasks afterdepolarizations in CASQ2-mutant myocytes.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    description: >-
      The catecholamine surge raises SR calcium loading and release-channel
      phosphorylation, unmasking the latent calcium leak.
    causal_link_type: DIRECT
  mechanism_confidence: ESTABLISHED
- name: Diastolic Sarcoplasmic Reticulum Calcium Leak
  conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    Premature RyR2-mediated calcium release during diastole can propagate as spontaneous intracellular calcium waves. These local events can trigger electrical activity without requiring a sustained increase in bulk diastolic calcium in every cell.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: INCREASED
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:16932808
    reference_title: "Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "lack of Casq2 also causes increased diastolic SR Ca2+ leak, rendering Casq2-null mice susceptible to catecholaminergic ventricular arrhythmias"
    explanation: Establishes increased diastolic SR calcium leak as the direct consequence of calsequestrin loss in vivo.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:19835880
    reference_title: Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "field-stimulated Casq2-/- myocytes exhibit spontaneous Ca2+ release resulting in Ca2+ waves that occur prior to the next pacing stimulus"
    explanation: Directly demonstrates premature diastolic calcium waves in calsequestrin-null cardiomyocytes.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Diastolic Cytosolic Calcium Elevation
    description: Spontaneous SR release transiently raises local cytosolic calcium before the next paced beat.
    causal_link_type: DIRECT
  mechanism_confidence: ESTABLISHED
- name: Diastolic Cytosolic Calcium Elevation
  description: 'Spontaneous SR calcium release causes transient local cytosolic elevations. Sustained whole-cell calcium overload is variable rather than obligatory: D307H patient-derived cells showed heterogeneous arrhythmic, nonresponsive and raised-diastolic-calcium responses to isoproterenol.'
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:19835880
    reference_title: Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: field-stimulated Casq2-/- myocytes exhibit spontaneous Ca2+ release resulting in Ca2+ waves that occur prior to the next pacing stimulus
    explanation: Directly observed spontaneous waves in null myocytes.
  cell_types:
  - &id002
    preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Depolarizing Sodium-Calcium Exchange Current
    description: Forward-mode calcium extrusion couples local calcium elevation to a net inward current.
    causal_link_type: DIRECT
- name: Depolarizing Sodium-Calcium Exchange Current
  description: Forward sodium-calcium exchange extrudes cytosolic calcium while bringing net positive charge inward. Recruitment of this normal electrogenic process by spontaneous release can depolarize the membrane; increased exchanger expression or intrinsic exchanger activity is not required.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:40438932
    reference_title: Pharmacological Enhancement of Small Conductance Ca(2+)-Activated K(+) Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Untimely RyR2-mediated SR Ca2+ release depolarizes sarcolemma by stimulating electrogenic NCX and inducing DADs that underlie arrhythmogenic triggered activity at the organ level.
    explanation: Background electrophysiological mechanism connecting calcium release to electrical depolarization, not a new exchanger-expression measurement.
  cell_types:
  - *id002
  molecular_functions:
  - preferred_term: calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential
    term:
      id: GO:0086038
      label: calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential
  downstream:
  - target: Delayed Afterdepolarizations
    description: The net inward exchanger current produces a depolarization after repolarization is complete.
    causal_link_type: DIRECT
- name: Delayed Afterdepolarizations
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    Membrane depolarizations after repolarization occur in CASQ2-mutant cardiomyocytes under adrenergic stimulation. They may remain subthreshold; threshold crossing generates a separate triggered action potential.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16908766
    reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2(G112+5X)"
    explanation: Direct evidence that a CPVT2 CASQ2 mutant produces delayed afterdepolarizations under adrenergic stimulation.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Triggered Cardiomyocyte Action Potentials
    description: An afterdepolarization generates an ectopic action potential if it reaches the excitation threshold.
    causal_link_type: DIRECT
  mechanism_confidence: ESTABLISHED
- name: Triggered Cardiomyocyte Action Potentials
  description: Calcium-dependent depolarizations that reach threshold generate premature action potentials. Translation from isolated-cell activity to sustained tissue arrhythmia depends on propagation, source–sink relationships and the conducting system.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:16932808
    reference_title: Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: resulting in premature spontaneous SR Ca2+ releases and triggered beats
    explanation: Isolated null myocytes demonstrate triggered beats.
  cell_types:
  - *id002
  downstream:
  - target: Bidirectional and Polymorphic Ventricular Tachycardia
    description: Ectopic impulses can initiate organized or polymorphic ventricular rhythms when they propagate through susceptible tissue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Palpitations
    description: Ectopic or rapid beats may be perceived as palpitations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Premature Ventricular Contractions
    description: Propagation of a premature ventricular action potential produces an ectopic ventricular contraction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Sinoatrial Node Dysfunction
  role: amplifier
  biological_scale: TISSUE
  description: >-
    Casq2-null mice show abnormal pacemaker calcium cycling, sinus-node conduction defects and atrial-pacemaker-complex fibrosis. Conditional studies implicate the broader cardiac conduction system, including the sinoatrial node, rather than proving rescue restricted to the sinoatrial node alone. Low basal rate increases the opportunity for spontaneous release between beats. Human sinus bradycardia is documented, but the mouse fibrosis has not been established as its human substrate.
  cell_types:
  - preferred_term: cardiac pacemaker cell of sinoatrial node
    term:
      id: CL:1000477
      label: cardiac pacemaker cell of sinoatrial node
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DECREASED
  evidence:
  - reference: PMID:24216388
    reference_title: Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Casq2(-/-) mice exhibited bradycardia, SAN conduction abnormalities, and beat-to-beat heart rate variability due to enhanced atrial ectopic activity both at baseline and with autonomic stimulation.
    explanation: Mouse pacemaker dysfunction; this does not establish fibrosis in patients.
  - reference: PMID:29452352
    reference_title: Conditional ablation and conditional rescue models for Casq2 elucidate the role of development and of cell-type specific expression of Casq2 in the CPVT2 phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: resting heart rate depends upon Casq2 gene activity only in the CCS and upon developmental history.
    explanation: Conditional genetics localizes basal-rate dependence to the cardiac conduction system with a developmental component.
  notes: >-
    Deliberately NOT declared as conforming to
    `cardiac_ion_channel_repolarization#Sinoatrial Node Pacemaker Dysfunction`.
    That module node models loss-of-function pacemaker-current channelopathy
    (HCN4, SCN5A), which is a different mechanism from the
    calsequestrin-dependent sinoatrial depression modelled here.
  downstream:
  - target: Bradycardia
    description: Impaired sinus automaticity and conduction can reduce resting heart rate.
    causal_link_type: DIRECT
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    description: Longer diastolic intervals can permit spontaneous release before the next driven beat.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Atrial Triggered Activity
    description: Pacemaker dysfunction and ectopic atrial activity coexist in null mice; calcium-cycling and structural intermediates are model dependent.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  mechanism_confidence: PROVISIONAL
- name: Atrial Triggered Activity
  role: effector
  biological_scale: TISSUE
  description: >-
    Casq2-null mouse atrial preparations show enhanced latent pacemaker activity and atrial ectopy. Fibrosis and conduction defects also promote macro- and micro-reentry, so atrial fibrillation in this model is not explained by triggered activity alone. This experimental branch does not establish a CASQ2-specific human atrial-fibrillation frequency.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:24216388
    reference_title: Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Loss of CASQ2 increased fibrosis within the pacemaker complex, depressed primary SAN activity, and conduction, but enhanced atrial ectopic activity and atrial fibrillation (AF) associated with macro- and micro-reentry during autonomic stimulation.
    explanation: Mouse atrial phenotype involves both abnormal pacemaking and reentry.
  mechanism_confidence: PROVISIONAL
- name: Bidirectional and Polymorphic Ventricular Tachycardia
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  role: effector
  biological_scale: ORGANISM
  description: >-
    Stress-related ventricular tachyarrhythmia can have bidirectional or polymorphic morphology; neither pattern must invariably precede the other. Cellular triggers require tissue-level propagation before they produce these clinical rhythms.
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic)."
    explanation: GeneReviews identifies bidirectional or polymorphic VT as the arrhythmia underlying CPVT episodes.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:16908766
    reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a child with stress-induced ventricular tachycardia and cardiac arrest"
    explanation: Human CASQ2-mutant case presenting with stress-induced ventricular tachycardia and cardiac arrest.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Effort-Induced Polymorphic Ventricular Tachycardia
    description: Adrenergic stress can elicit a polymorphic ventricular rhythm.
    causal_link_type: DIRECT
  - target: Bidirectional Ventricular Tachycardia
    description: Alternating ventricular activation produces the bidirectional clinical pattern.
    causal_link_type: DIRECT
  - target: Ventricular Fibrillation
    description: An unstable ventricular rhythm may degenerate into fibrillation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Effective Cardiac Output
    description: Sustained rapid ventricular activation can impair effective cardiac output.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  mechanism_confidence: ESTABLISHED
- name: Reduced Effective Cardiac Output
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  role: outcome
  biological_scale: ORGANISM
  description: >-
    Hemodynamically significant ventricular tachyarrhythmia can reduce forward blood flow. Transient cerebral hypoperfusion produces syncope, sometimes with convulsive movements; prolonged circulatory failure can cause cardiac arrest and death.
  evidence:
  - reference: PMID:11704930
    reference_title: A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress"
    explanation: Describes the clinical endpoints of catecholamine-induced polymorphic VT in the families in which CASQ2 was identified.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years"
    explanation: Quantifies the arrhythmic-event burden and early age of onset in biallelic CASQ2-CPVT.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Syncope
    description: Transient cerebral hypoperfusion causes loss of consciousness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cardiac Arrest
    description: Persistent ineffective ventricular pumping causes circulatory arrest.
    causal_link_type: DIRECT
  - target: Sudden Cardiac Death
    description: Unreversed circulatory arrest can be fatal.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  mechanism_confidence: ESTABLISHED
- name: Sarcoplasmic Reticulum Volume Expansion
  description: Complete Casq2 deletion causes marked SR enlargement in mice, partly compensating for loss of the luminal buffering pool. Other release-complex proteins differ between mouse lines and assays; triadin/junctin depletion and calreticulin/RyR2 increases are not universal consequences in every model or in patients.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:16932808
    reference_title: Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin
    explanation: Structural compensation in the promoter/exon-1 null model.
- name: Endoplasmic Reticulum Stress
  description: R33Q mouse hearts activate endoplasmic-reticulum stress and the unfolded-protein response. The finding is allele and model dependent; it is not established as a universal human CPVT feature.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:42770222
    reference_title: Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Casq2R33Q/R33Q hearts showed activation of endoplasmic reticulum stress, the unfolded protein response, and alterations in major proteolytic pathways.
    explanation: R33Q mouse heart proteostasis phenotype.
- name: Calpain-Dependent Triadin Degradation
  description: In the R33Q model triadin is a direct calpain substrate, and its degradation precedes loss of calsequestrin. This places triadin destabilization upstream of part of the CASQ2 protein-loss phenotype; the process has not been established for all CASQ2 alleles.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:42770222
    reference_title: Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Biochemical assays showed that TRDN is a direct calpain substrate.
    explanation: Biochemical substrate evidence for triadin proteolysis.
  - reference: PMID:42770222
    reference_title: Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: TRDN degradation preceded CASQ2 loss
    explanation: Temporal order in the R33Q model, not a human natural-history observation.
  downstream:
  - target: Reduced CASQ2 Protein Abundance
    description: Triadin overexpression restores calsequestrin abundance in mutant cells and mice, supporting an upstream stabilizing role.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased Mitochondrial Reactive Oxygen Species
  description: Casq2-null ventricular myocytes show increased mitochondrial ROS. The 2025 study also found widened cristae, reduced respiratory-chain supercomplex assembly and impaired ATP production under adrenergic stimulation. NS309 reversed several of these abnormalities, but a specific mitochondrial SK-channel mechanism is inferred from pharmacology rather than isolated genetically.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:40438932
    reference_title: Pharmacological Enhancement of Small Conductance Ca(2+)-Activated K(+) Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: SK channel enhancement reversed the increased rate of reactive oxygen species production by mitochondria in CPVT VMs.
    explanation: Null-mouse ventricular myocytes show excess mitochondrial ROS, reduced by NS309.
  downstream:
  - target: Increased RyR2 Oxidation
    description: Mitochondrial oxidative stress is a proposed contributor to the RyR2 oxidation reversed by NS309; the specific mediator was not isolated.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Increased RyR2 Oxidation
  description: Stress-challenged Casq2-null hearts have increased RyR2 oxidation, reduced by SK-channel enhancement. This is a model-specific amplifier, not an established biochemical measurement in human CASQ2 hearts.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:40438932
    reference_title: Pharmacological Enhancement of Small Conductance Ca(2+)-Activated K(+) Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: It also reversed increased cardiac RyR2 (ryanodine receptor 2) oxidation measured in samples from CPVT hearts of the animals after the stress challenge.
    explanation: Treatment-sensitive RyR2 oxidation in stressed null mouse hearts.
  downstream:
  - target: Destabilized RyR2 Closed State
    description: Oxidative modification can amplify abnormal release-channel activity; its quantitative contribution to human disease is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced Sarcolemmal SK Current
  description: Small-conductance calcium-activated potassium current is reduced in adrenergically stimulated Casq2-null ventricular myocytes despite increased surface SK3 protein. NS309 increases this current. This functional-expression mismatch cautions against equating protein abundance with channel activity.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:40438932
    reference_title: Pharmacological Enhancement of Small Conductance Ca(2+)-Activated K(+) Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Voltage-clamp experiments in isolated VMs treated with β-adrenergic agonist isoproterenol showed a reduction of sarcolemmal SK channel current (ISK) density in CPVT VMs.
    explanation: Reduced functional SK current despite increased surface SK3 protein in the detailed study.
  downstream:
  - target: Triggered Cardiomyocyte Action Potentials
    description: Reduced repolarizing potassium current may facilitate triggered excitation; NS309 effects also involve intracellular calcium and mitochondria.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Cardiovascular
  name: Effort-Induced Polymorphic Ventricular Tachycardia
  description: >-
    Exercise or emotional stress can elicit polymorphic ventricular tachycardia. Onset is often in childhood, but the median age seven reported in 2020 concerns the first composite arrhythmic event, not mean onset of this particular rhythm.
  phenotype_term:
    preferred_term: Effort-induced polymorphic ventricular tachycardia
    term:
      id: HP:0004758
      label: Effort-induced polymorphic ventricular tachycardia
  evidence:
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years"
    explanation: CASQ2-specific source for the childhood onset category and the age-of-onset value on this phenotype.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of CPVT is established in the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia"
    explanation: GeneReviews defines exercise- or emotion-induced polymorphic VT as the diagnostic phenotype of CPVT, including its CASQ2 form.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:16908766
    reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a child with stress-induced ventricular tachycardia and cardiac arrest"
    explanation: Documents stress-induced ventricular tachycardia in a child carrying a homozygous CASQ2 truncating variant.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Cardiovascular
  name: Bidirectional Ventricular Tachycardia
  description: >-
    Ventricular tachycardia with beat-to-beat alternation of the QRS axis, the
    pattern most characteristic of catecholaminergic calcium-handling
    arrhythmia.
  phenotype_term:
    preferred_term: Bidirectional ventricular tachycardia
    term:
      id: HP:0034040
      label: Bidirectional ventricular tachycardia
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic)."
    explanation: GeneReviews identifies bidirectional VT as the arrhythmia underlying CPVT episodes.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- category: Cardiovascular
  name: Syncope
  description: >-
    Transient loss of consciousness during exertion or emotion is a common presentation. The 2020 biallelic group had syncope in 26/34 individuals (76.5%); this is a clinically ascertained cohort, not a population penetrance estimate. Convulsive movements can accompany arrhythmic cerebral hypoperfusion and lead to an epilepsy misdiagnosis; the convulsive presentation is included here because it is not evidence of primary epilepsy.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients who experienced syncopes before the age of 7 years were homozygous carriers, suggesting a complete absence of calsequestrin 2."
    explanation: Direct CASQ2-specific evidence for early-childhood syncope in biallelic carriers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient was heterozygous for the stop codon and experienced syncopes from the age of 11 years."
    explanation: Documents later-onset syncope in a heterozygous CASQ2 carrier.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:11704930
    reference_title: A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress"
    explanation: Seizure-like episodes are part of the presenting spectrum described in the CASQ2 mapping study.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:42435031
    reference_title: 'Catecholaminergic Polymorphic Ventricular Tachycardia Type 2 Presenting as Seizure in a Child: Diagnostic Pitfalls.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A 6-year-old boy presented with exercise-induced seizure-like episodes despite normal neuroimaging.
    explanation: The case directly documents exertional convulsive syncope. The reported nucleotide/protein variant notation is internally inconsistent and is not reproduced as a curated variant.
  phenotype_contexts:
  - subtype: Biallelic CPVT2
    population: Biallelic carriers in the clinically ascertained 2020 multicenter family cohort
    frequency: FREQUENT
    notes: 26/34 (76.5%) across 24 biallelic probands and 10 biallelic relatives in the selected 2020 family cohort.
    evidence:
    - reference: PMID:32693635
      reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: '| Cardiac Syncope | 21 (87.5) | 5 (50) | 2 (3.8) | 6 (50) | 2 (14.3) |'
      explanation: Table 1 reports separate proband and relative columns; the contextual count combines the first two columns only.
- category: Cardiovascular
  name: Cardiac Arrest
  description: >-
    Aborted cardiac arrest occurred in 5/34 biallelic individuals in the selected 2020 cohort; the larger 26/34 composite includes syncope and must not be interpreted as the arrest rate.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death"
    explanation: Aborted cardiac arrest is an explicit component of the arrhythmic endpoint studied in the CASQ2-CPVT cohort.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16908766
    reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a child with stress-induced ventricular tachycardia and cardiac arrest"
    explanation: Cardiac arrest in a child with a homozygous CASQ2 truncating variant.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  phenotype_contexts:
  - subtype: Biallelic CPVT2
    population: Biallelic carriers in the clinically ascertained 2020 multicenter family cohort
    frequency: OCCASIONAL
    notes: 5/34 (14.7%) across 24 biallelic probands and 10 biallelic relatives; this is not population risk.
    evidence:
    - reference: PMID:32693635
      reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: '| Aborted Cardiac Arrest | 5 (20.8) | 0 (0) | 0 (0) | 3 (25) | 1 (7.1) |'
      explanation: Table 1 reports separate proband and relative columns; the contextual count combines the first two columns only.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden arrhythmic death can be the first manifestation. One of 34 biallelic individuals in the selected 2020 cohort had sudden cardiac death; ascertainment and survival bias limit interpretation.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:11704930
    reference_title: A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress"
    explanation: Sudden death is part of the presenting spectrum in the families in which CASQ2 was identified.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death"
    explanation: Sudden cardiac death is an explicit endpoint in the CASQ2-CPVT risk analysis.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader
    reference_title: Catecholaminergic Polymorphic Ventricular Tachycardia - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Sudden death may be the first manifestation of the disorder in previously asymptomatic individuals
    explanation: Clinical synthesis for CPVT generally, not a CASQ2-specific frequency.
  phenotype_contexts:
  - subtype: Biallelic CPVT2
    population: Biallelic carriers in the clinically ascertained 2020 multicenter family cohort
    frequency: VERY_RARE
    notes: 1/34 (2.9%) across 24 biallelic probands and 10 biallelic relatives; ascertainment and survival bias limit interpretation. The frequency band describes this observed cohort count only and must not be used as an untreated lifetime risk.
    evidence:
    - reference: PMID:32693635
      reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: '| Sudden Cardiac Death | 0 (0) | 1 (10) | 0 (0) | 0 (0) | 0 (0) |'
      explanation: Table 1 reports separate proband and relative columns; the contextual count combines the first two columns only.
- category: Cardiovascular
  name: Ventricular Fibrillation
  description: >-
    Degeneration of polymorphic ventricular tachycardia into disorganised
    fibrillation, the terminal rhythm of a fatal CPVT episode.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available"
    explanation: GeneReviews describes degeneration to ventricular fibrillation as the mechanism of sudden death in CPVT.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- category: Cardiovascular
  name: Bradycardia
  description: >-
    Low resting sinus rate is reported in CASQ2-associated disease and can complicate beta-blocker dosing. The detailed pacemaker-fibrosis mechanism remains based on mice.
  phenotype_term:
    preferred_term: Bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
  evidence:
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Sinus node dysfunction and bradycardia are well-documented phenotypes of CPVT in humans and in mouse models of CPVT"
    explanation: Review evidence for bradycardia as a documented CPVT phenotype in humans and in the calsequestrin-null mouse model.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:42692439
    reference_title: First biallelic CASQ2 variant in a Korean child with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Electrocardiography revealed sinus bradycardia (57 bpm) and normal QTc
    explanation: Observed before the reported treatment sequence in the Korean case; apparent CASQ2 homozygosity had unresolved parental segregation.
  notes: >-
    Bradycardia may reflect intrinsic sinus dysfunction, medication effects or both; the mouse conduction-system experiments do not determine their relative contribution in a patient.
- category: Cardiovascular
  name: Palpitations
  description: >-
    Awareness of rapid or irregular heart action, the mildest symptomatic
    expression of triggered ectopy and often the symptom that precedes more
    severe arrhythmic events.
  phenotype_term:
    preferred_term: Palpitations
    term:
      id: HP:0001962
      label: Palpitations
  evidence:
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Symptoms range from palpitations to cardiac arrest"
    explanation: Review evidence placing palpitations at the mild end of the CPVT symptom spectrum.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  notes: >-
    As for Bradycardia, the cited review statement describes CPVT as a whole
    rather than CASQ2-CPVT specifically; no CASQ2-restricted symptom-frequency
    series reports palpitations separately, so no frequency band is asserted.
- name: Premature Ventricular Contractions
  category: Cardiovascular
  description: Adrenergically induced ventricular ectopy is often the earliest exercise-test abnormality and can precede more complex rhythms.
  phenotype_term:
    preferred_term: Premature ventricular contraction
    term:
      id: HP:0006682
      label: Premature ventricular contraction
  evidence:
  - reference: PMID:32693635
    reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: '| Adrenergic-Induced PVCs | 24 (100) | 8/9 (88.9) | 8/37 (21.6) | 12 (100) | 9 (64.3) |'
    explanation: Adrenergic PVCs occurred in 32/33 evaluated biallelic carriers, combining the first two table columns.
  phenotype_contexts:
  - subtype: Biallelic CPVT2
    population: Biallelic carriers with adrenergic testing in the 2020 multicenter cohort
    frequency: VERY_FREQUENT
    notes: 32/33 (97.0%) tested carriers; one biallelic relative lacked the required testing.
    evidence:
    - reference: PMID:32693635
      reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: '| Adrenergic-Induced PVCs | 24 (100) | 8/9 (88.9) | 8/37 (21.6) | 12 (100) | 9 (64.3) |'
      explanation: Adrenergic PVCs occurred in 32/33 evaluated biallelic carriers, combining the first two table columns.
genetic:
- name: CASQ2 biallelic loss-of-function variants
  subtype: Biallelic CPVT2
  features: >-
    Biallelic pathogenic missense, stop-gain, splice-site and small frameshift-deletion variants cause recessive CPVT. The D307H founder segregated in seven related Bedouin families, not seven independent alleles. Protein loss and abnormal function vary by allele; early reports predicted absence from truncation rather than measuring protein in every patient. The combined 2020 cohort/literature catalogue included 55 presumed culprit variants: 22 missense, 32 truncating (10 nonsense, 13 splice site/region and nine frameshift), and one large deletion. The large deletion expands the reported physical variant spectrum beyond the point mutations and small coding deletion modeled explicitly.
  gene_term:
    preferred_term: CASQ2
    term:
      id: hgnc:1513
      label: CASQ2
  evidence:
  - reference: PMID:11704930
    reference_title: A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation, which is in full segregation in seven Bedouin families affected by the disorder"
    explanation: Establishes full segregation of the founder CASQ2 missense allele with recessive CPVT.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three mutations, a nonsense R33X, a splicing 532+1 G>A, and a 1-bp deletion, 62delA, are thought to induce premature stop codons."
    explanation: Documents the protein-truncating allelic class in CASQ2-CPVT.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16908766
    reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the first CPVT patient carrier of compound heterozygous CASQ2 mutations"
    explanation: Documents compound heterozygosity as a route to biallelic CASQ2 loss of function.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these additional three CASQ2 CPVT families suggest that CASQ2 mutations are more common than previously thought and produce a severe form of CPVT"
    explanation: Supports both the allelic spectrum and the severity of biallelic CASQ2-CPVT.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32693635
    reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 55 presumed culprit CASQ2 variants were identified, including 22 missense, 32 truncating (10 nonsense, 13 splice site/region, and 9 frameshift), and 1 large deletion
    explanation: Combined clinical/literature variant catalogue; includes a large deletion without implying all catalogued variants have identical pathogenic certainty.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_991ee32e-280d-4bea-a638-aa1b6fa6f781-2021-01-20T170000.000Z
    subtype: Biallelic CPVT2
    evidence:
    - *id003
  relationship_type: CAUSATIVE
- name: CASQ2 heterozygous variants
  subtype: Heterozygous CPVT2
  features: >-
    Selected heterozygous missense and truncating/splice variants occur in CPVT families. K180R segregated with a phenotype in a small ascertained pedigree, while the 2020 multicenter cohort also included uncertain variants. Dominant-negative filament interference is proposed for some missense variants but has not been established for all reported alleles. The 2020 study found a collective gnomAD allele frequency of 0.0997% for presumed culprit variants and 0.049% for truncating variants. Its estimated carrier prevalence was at least 398-fold greater than expected CASQ2-CPVT prevalence, supporting incomplete penetrance and/or uncertain variant attribution rather than a penetrance estimate for any particular allele.
  gene_term:
    preferred_term: CASQ2
    term:
      id: hgnc:1513
      label: CASQ2
  evidence:
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT."
    explanation: The 17/51 result is from clinically ascertained families and is not general penetrance of CASQ2 heterozygosity.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:27157848
    reference_title: A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: 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.
    explanation: Segregation in the K180R pedigree supports an allele-specific association; the abstract death count includes an ungenotyped motor-vehicle-accident death and is not used as a confirmed CASQ2 death count.
  - reference: PMID:32693635
    reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the collective prevalence of presumed pathogenic CASQ2 variants in gnomAD is at least 398-fold greater than the expected prevalence of CASQ2-CPVT
    explanation: Population-variant versus estimated disease-frequency discordance supports caution about generalizing selected pedigrees. These are presumed culprit variants, and the comparison is not an allele-specific penetrance measurement.
  gene_disease_validity:
  - validity_classification: MODERATE
    classified_by: CLINGEN
    external_id: CGGV:assertion_c778b145-fcfc-4252-8dd8-33f982b288e8-2021-01-20T170000.000Z
    subtype: Heterozygous CPVT2
    evidence:
    - *id004
  relationship_type: UNKNOWN
diagnosis:
- name: Exercise stress testing
  description: >-
    Supervised exercise testing is the principal provocative test, assessing progressively complex ventricular ectopy and bidirectional or polymorphic tachycardia. Results also guide treatment and activity advice. A normal resting ECG or brief Holter does not exclude disease, and a young child unable to exercise may not have been adequately challenged.
  results: >-
    Exercise-related complex ventricular ectopy in an otherwise compatible cardiac assessment supports CPVT. A negative test does not establish zero future risk or complete protection on treatment.
  diagnosis_term:
    preferred_term: exercise cardiac stress test
    term:
      id: NCIT:C168192
      label: Exercise Cardiac Stress Test
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader
    reference_title: Catecholaminergic Polymorphic Ventricular Tachycardia - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The exercise stress test is the single most important diagnostic test.
    explanation: Expert guidance supports provocative exercise testing rather than relying on a normal resting ECG or Holter.
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 of them had ventricular arrhythmias at ECG on exercise tests"
    explanation: CASQ2-specific demonstration that exercise testing unmasks arrhythmia in otherwise asymptomatic heterozygous carriers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Molecular genetic testing of CASQ2
  description: >-
    Biallelic pathogenic CASQ2 variants support the established recessive diagnosis. A single heterozygous finding requires phenotype, segregation and variant-level assessment because the dominant association has Moderate validity. Apparent homozygosity should be checked against parental results; discordance may require investigation for an undetected deletion, uniparental disomy or technical allele dropout.
  results: >-
    Distinguish pathogenic/likely pathogenic variants from VUS, verify phase or apparent homozygosity where possible, and clinically evaluate heterozygous relatives without equating carrier status with a confirmed dominant diagnosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a heterozygous pathogenic variant in RYR2, CALM1, CALM2, CALM3, CASQ2, or KCNJ2 or biallelic pathogenic variants in CASQ2, TECRL, or TRDN"
    explanation: GeneReviews lists biallelic CASQ2 variants and selected heterozygous variants; the latter require interpretation in light of weaker gene-validity evidence.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:32693635
    reference_title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals"
    explanation: Sets the screening obligation for heterozygous carriers identified by cascade genetic testing.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Resting ECG and structural cardiac assessment
  description: >-
    A usually normal resting ECG and structurally normal heart are compatible with CPVT; resting sinus bradycardia may be present. ECG and imaging help exclude alternative diagnoses, but normal baseline studies do not exclude exercise-induced disease.
  results: >-
    Structurally normal heart with a normal resting ECG.
  diagnosis_term:
    preferred_term: resting electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  notes: >-
    The NCIT electrocardiography term covers the resting 12-lead ECG component
    of this assessment; the accompanying echocardiographic exclusion of
    structural heart disease is described in the name and description rather
    than separately coded.
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of CPVT is established in the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia"
    explanation: A structurally normal heart and normal resting ECG are explicit components of the diagnostic criteria.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: Longitudinal cardiology surveillance
  description: >-
    Ongoing follow-up rather than a one-off diagnostic act. Review by a
    cardiologist every six to twelve months, with the interval set by disease
    severity, is important throughout growth because rapid weight gain in
    childhood and adolescence means beta-blocker dosing must be adjusted
    continually to stay protective. Serial exercise stress testing is the
    instrument that both monitors control and individualises permitted
    exercise intensity.
  results: >-
    Recurrence or worsening of exercise-induced ectopy on serial testing
    indicates loss of arrhythmia control and prompts dose escalation or
    escalation of therapy.
  diagnosis_term:
    preferred_term: exercise cardiac stress test
    term:
      id: NCIT:C168192
      label: Exercise Cardiac Stress Test
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Follow-up visits with a cardiologist every six to 12 months (depending on disease severity) are very important, especially until puberty, since body weight increases rapidly and drug dosages must be continually adjusted."
    explanation: GeneReviews surveillance recommendation, including the growth-related rationale for continual dose adjustment.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "allowed exercise intensity should be individualized based on exercise stress test results"
    explanation: Serial exercise stress testing is the basis for individualising activity restriction during surveillance.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
treatments:
- name: Nonselective Beta-Blocker Therapy (Nadolol)
  description: >-
    Nonselective beta-blockade, commonly nadolol or propranolol, is first-line therapy for clinically affected CPVT and for established disease genotypes assessed by a specialist. It attenuates cardiac adrenergic receptor signaling rather than the catecholamine surge. Dose, adherence, bradycardia and exercise-test response require monitoring. The 2020 CASQ2 family study does not mandate treatment of every phenotype-negative heterozygous carrier.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nadolol
      term:
        id: CHEBI:7444
        label: nadolol
  target_mechanisms:
  - target: Beta-Adrenergic Stimulation
    treatment_effect: INHIBITS
    description: >-
      Nonselective beta-blockade attenuates the beta-adrenergic drive that
      unmasks the latent calsequestrin-deficient calcium instability.
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "nadolol is the most effective beta blocker in CPVT"
    explanation: GeneReviews identifies nadolol as the most effective beta blocker in CPVT.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:26432584
    reference_title: Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with beta1-selective beta-blockers in patients with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence and severity of ventricular arrhythmias decreased during treatment with nadolol compared with during treatment with β1-selective β-blockers"
    explanation: Human comparative data supporting nonselective over beta1-selective blockade in CPVT.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    The comparative nadolol study had 34 participants, 30 with RYR2 variants; it does not provide a CASQ2-specific randomized comparison. General genotype-positive guidance should not automatically classify every heterozygous CASQ2 VUS as disease.
- name: Flecainide
  description: >-
    Flecainide added to beta-blockade suppresses exercise-induced ventricular arrhythmias in CASQ2-associated CPVT, but residual clinical events can occur despite a normal exercise test. It blocks cardiac sodium channels and, in CASQ2-model experiments, inhibits RyR2-mediated release. The relative contribution of these mechanisms in patients is not established by isolated-cell or mouse experiments.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: flecainide
      term:
        id: CHEBI:75984
        label: flecainide
  target_mechanisms:
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    treatment_effect: INHIBITS
    description: >-
      Flecainide reduces the propagation of spontaneous calcium waves in null myocytes; spark mass falls while spark frequency can rise, so net SR leak and SR content need not decrease.
  - target: Triggered Cardiomyocyte Action Potentials
    treatment_effect: INHIBITS
    description: Sodium-channel block reduces excitation; CASQ2-model experiments support an additional contribution from RyR2 block.
  evidence:
  - reference: PMID:19835880
    reference_title: Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "flecainide significantly reduced the amplitude, duration and spatial width of Ca2+ sparks in Casq2-/- myocytes"
    explanation: Demonstrates the spark-mass mechanism of flecainide specifically in calsequestrin-null myocytes.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:19835880
    reference_title: Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Flecainide induced a sustained decrease in the frequency of spontaneous Ca2+ waves, whereas tetracaine was ineffective"
    explanation: Establishes flecainide efficacy against arrhythmogenic calcium waves in Casq2-null myocytes, and distinguishes it from tetracaine.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Flecainide can be added for primary prevention of a cardiac arrest when beta blockers alone cannot control the onset of arrhythmias during an exercise stress test."
    explanation: GeneReviews management guidance for adding flecainide to beta-blockade in CPVT.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:23954267
    reference_title: Flecainide therapy suppresses exercise-induced ventricular arrhythmias in patients with CASQ2-associated catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: After combination therapy with flecainide and beta-blockers, EIVA were suppressed completely in all patients.
    explanation: All ten high-risk CPVT2 patients showed exercise-test suppression after combination therapy; this was an uncontrolled series.
  - reference: PMID:23954267
    reference_title: Flecainide therapy suppresses exercise-induced ventricular arrhythmias in patients with CASQ2-associated catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two patients had 1 VT storm episode with recurrent ICD shocks despite repeated normal stress test.
    explanation: Residual clinical events demonstrate that normalized exercise testing did not guarantee complete arrhythmia protection.
  - reference: PMID:28492868
    reference_title: 'Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Putative pathogenic mutations were present in RYR2 in 10 patients and CASQ2 in 1; 2 patients had negative genetic findings.
    explanation: The randomized trial included one CASQ2 participant; the pooled response cannot be interpreted as a CASQ2-specific effect estimate.
  - reference: PMID:33297863
    reference_title: RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas N-methyl flecainide had no significant effect on arrhythmia burden, despite comparable sodium channel block.
    explanation: Matched sodium-channel block with differing RyR2 inhibition supports an independent RyR2 contribution in this mouse protocol.
  - reference: PMID:19330009
    reference_title: Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Repeat exercise tests at 7 weeks and 12 weeks after the start of flecainide treatment showed complete suppression of ventricular tachycardia and marked reduction in the number of ventricular extrasystoles
    explanation: The first treated case was a 12-year-old homozygous CASQ2 patient continuing beta-blockade after verapamil was withdrawn; the other patient in that report had RYR2-associated disease.
  - reference: PMID:19835880
    reference_title: Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: As a result, flecainide had no significant effect on spark-mediated SR Ca(2+) leak or SR Ca(2+) content.
    explanation: In this assay, smaller sparks and increased spark frequency balance total leak despite fewer propagating waves. This is not evidence against antiarrhythmic efficacy.
  notes: The 2017 crossover trial randomized 14 people; 13 received flecainide and 12 had paired tests. The endpoint changed from ICD therapies to exercise ectopy because of poor recruitment. Complete ectopy suppression in 11/13 (85%) is a mixed-genotype surrogate outcome, not demonstrated prevention of sudden death or a CASQ2 subgroup estimate. All participants remained on beta-blockers.
- name: Left Cardiac Sympathetic Denervation
  description: >-
    Adjunctive reduction of left-sided cardiac sympathetic input may be considered for persistent arrhythmias or drug intolerance. It does not provide complete protection and does not replace medication or continued surveillance.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: left cardiac sympathetic denervation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Beta-Adrenergic Stimulation
    treatment_effect: INHIBITS
    description: >-
      Interrupting left-sided sympathetic input reduces the catecholaminergic
      drive that precipitates the calcium leak and triggered activity.
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a significant burden of life-threatening arrhythmias persists after left cardiac sympathetic denervation"
    explanation: GeneReviews recognises LCSD as a CPVT intervention while documenting the residual arrhythmic burden.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:42692439
    reference_title: First biallelic CASQ2 variant in a Korean child with catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Post-LCSD, the premature ventricular contraction (PVC) heart rate (HR) threshold increased from 108 to 120 bpm.
    explanation: A case showed improved provocation threshold but later recurrent arrhythmias; the genotype segregation remained unresolved.
- name: Implantable Cardioverter-Defibrillator Placement
  description: >-
    An ICD is considered for selected high-risk patients, including survivors of cardiac arrest or persistent serious arrhythmias despite optimal treatment. Medications should remain optimized because shocks and adrenergic stress can provoke further arrhythmia. Device choice and pacing needs require individualized assessment, particularly when bradycardia limits medication.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "an implantable cardioverter defibrillator is effective for those individuals in whom arrhythmias are not adequately controlled by drug therapy"
    explanation: GeneReviews management guidance for ICD implantation in CPVT.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader
    reference_title: Catecholaminergic Polymorphic Ventricular Tachycardia - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: pharmacologic therapy should be maintained/optimized even in persons w/an ICD
    explanation: The device complements pharmacological control rather than replacing it.
- name: Individualized Exercise and Adrenergic Trigger Management
  description: >-
    Exertional risk requires specialist assessment, optimized treatment and serial exercise testing. The 2025 AHA/ACC statement allows consideration of competitive sport in selected adequately controlled patients through shared decision-making; couplets or nonsustained ventricular tachycardia require continued treatment intensification and exclusion during optimization. This is broader CPVT guidance, not a CASQ2-specific safety trial.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: exercise restriction and trigger avoidance
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Beta-Adrenergic Stimulation
    treatment_effect: INHIBITS
    description: >-
      Avoiding the precipitating exertional and emotional triggers reduces the
      catecholamine surges that unmask the calcium instability.
  evidence:
  - reference: PMID:39976316
    reference_title: 'Clinical Considerations for Competitive Sports Participation for Athletes With Cardiovascular Abnormalities: A Scientific Statement From the American Heart Association and American College of Cardiology.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: With adequate suppression, competitive sports participation can be considered with SDM.
    explanation: Expert statement supports conditional individualized participation, not unrestricted exercise.
  - reference: PMID:39976316
    reference_title: 'Clinical Considerations for Competitive Sports Participation for Athletes With Cardiovascular Abnormalities: A Scientific Statement From the American Heart Association and American College of Cardiology.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: couplets or nonsustained ventricular tachycardia require continued treatment intensification and ongoing exclusion from competitive sports participation during treatment optimization.
    explanation: Explicit safety boundary of the same guidance.
- name: Genetic Counseling and Cascade Family Screening
  description: >-
    When both parents are confirmed heterozygous for the familial recessive pathogenic variant(s), each pregnancy has a 25% probability of biallelic inheritance, 50% of heterozygosity and 25% of neither variant. These conditional probabilities do not establish that both parents must always be carriers. Heterozygous relatives require clinical assessment, with counseling reflecting variant uncertainty and the Moderate dominant association. Prenatal or preimplantation testing depends on identifying the familial pathogenic variants.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected"
    explanation: The 25% biallelic recurrence risk applies when both parents are known carriers; apparent homozygosity alone does not establish that condition.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "clinical screening is indicated accordingly in individuals who are heterozygous for a CASQ2 pathogenic variant"
    explanation: GeneReviews requires clinical screening of CASQ2 heterozygotes, a CASQ2-specific counselling point.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader
    reference_title: Catecholaminergic Polymorphic Ventricular Tachycardia - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: If both parents are known to be heterozygous for a ... pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants
    explanation: Conditional recessive recurrence risk; gene names are omitted across markup without changing the condition.
- name: Avoidance of Digitalis
  description: Digitalis can promote delayed afterdepolarizations and triggered activity and is listed as an agent to avoid in CPVT. This calcium-loading risk is distinct from adrenergic receptor stimulation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Avoidance of digitalis
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader
    reference_title: Catecholaminergic Polymorphic Ventricular Tachycardia - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Digitalis favors the onset of cardiac arrhythmias as a result of delayed afterdepolarization and triggered activity; therefore, digitalis should be avoided in all individuals with CPVT.
    explanation: General CPVT avoidance guidance.
- name: Pregnancy Arrhythmia Management
  description: GeneReviews recommends continuing beta-blockade, preferentially nadolol or propranolol, throughout pregnancy in affected women, with specialist monitoring of maternal arrhythmia control and medication effects.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nadolol
      term:
        id: CHEBI:7444
        label: nadolol
    - preferred_term: propranolol
      term:
        id: CHEBI:8499
        label: propranolol
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1289/?report=reader
    reference_title: Catecholaminergic Polymorphic Ventricular Tachycardia - GeneReviews&reg; - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Beta blockers (preferentially nadolol or propranolol) should be administered throughout pregnancy in affected women.
    explanation: Expert pregnancy-management guidance for CPVT.
- name: Experimental CASQ2 Gene Replacement
  description: AAV-mediated wild-type CASQ2 delivery improves protein expression and arrhythmia readouts in R33Q, D307H and null mice and in G112+5X patient-derived cardiomyocytes. Neonatal R33Q treatment was followed for one year; adult rescue was assessed over shorter intervals. This is preclinical evidence, not established treatment of CASQ2-CPVT patients.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: AAV-mediated CASQ2 gene replacement
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Reduced CASQ2 Protein Abundance
    treatment_effect: RESTORES
    description: AAV-mediated wild-type CASQ2 delivery improves protein expression and arrhythmia readouts in R33Q, D307H and null mice and in G112+5X patient-derived cardiomyocytes. Neonatal R33Q treatment was followed for one year; adult rescue was assessed over shorter intervals. This is preclinical evidence, not established treatment of CASQ2-CPVT patients.
  evidence:
  - reference: PMID:24888331
    reference_title: Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin
    explanation: Mouse neonatal prevention and adult rescue experiments.
  - reference: PMID:28336343
    reference_title: Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Lower levels of expression prevented sustained VT in AAVCASQ2-treated mice (0 of 26; P < .001 vs controls).
    explanation: Lower transgene expression prevented sustained VT but did not necessarily suppress all premature beats or nonsustained VT.
  - reference: PMID:27711080
    reference_title: Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: from 78%, 17/22 in HO cells to 22%, 2/9 in HO-CASQ2
    explanation: DAD/triggered-activity incidence was reduced, not abolished, in patient-derived cells.
- name: Experimental Calpain Inhibition
  description: Calpain inhibition in the R33Q model restores triadin and CASQ2 abundance and reduces isolated-cell triggered activity and mouse ventricular tachycardia. The September 2026 abstract does not establish a human drug, dose or clinical benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Calpain-Dependent Triadin Degradation
    treatment_effect: INHIBITS
    description: Calpain inhibition in the R33Q model restores triadin and CASQ2 abundance and reduces isolated-cell triggered activity and mouse ventricular tachycardia. The September 2026 abstract does not establish a human drug, dose or clinical benefit.
  evidence:
  - reference: PMID:42770222
    reference_title: Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: calpain inhibition restored CASQ2 and TRDN protein levels, decreased triggered activity in isolated cardiomyocytes, and reduced ventricular tachycardia episodes in vivo in Casq2R33Q/R33Q mice.
    explanation: Combined preclinical intervention result; clinical efficacy is untested.
- name: Experimental ent-Verticilide B1
  description: The RyR2 inhibitor ent-B1 reduces spontaneous release in null myocytes and catecholamine-induced arrhythmia burden in mice. Its mouse half-life was about 45 minutes; the significant antiarrhythmic response at the highest tested dose did not abolish all ectopy. No human efficacy is established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Destabilized RyR2 Closed State
    treatment_effect: INHIBITS
    description: The RyR2 inhibitor ent-B1 reduces spontaneous release in null myocytes and catecholamine-induced arrhythmia burden in mice. Its mouse half-life was about 45 minutes; the significant antiarrhythmic response at the highest tested dose did not abolish all ectopy. No human efficacy is established.
  evidence:
  - reference: PMID:38253398
    reference_title: ent-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Casq2 (-/-) Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In vivo, ent-B1 significantly reduced catecholamine-induced ventricular arrhythmias in Casq2 -/- mice in a dose-dependent manner.
    explanation: Mouse arrhythmia reduction, not complete clinical protection.
- name: Experimental SK-Channel Enhancement with NS309
  description: NS309 partially reduces arrhythmia burden in Casq2-null mice and improves repolarizing current, calcium handling and mitochondrial readouts. Protection was transient and absent by 18 hours; pharmacology suggests both sarcolemmal and mitochondrial contributions without establishing their separate clinical effects.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Reduced Sarcolemmal SK Current
    treatment_effect: RESTORES
    description: NS309 partially reduces arrhythmia burden in Casq2-null mice and improves repolarizing current, calcium handling and mitochondrial readouts. Protection was transient and absent by 18 hours; pharmacology suggests both sarcolemmal and mitochondrial contributions without establishing their separate clinical effects.
  evidence:
  - reference: PMID:40438932
    reference_title: Pharmacological Enhancement of Small Conductance Ca(2+)-Activated K(+) Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Bidirectional and polymorphic ventricular tachycardias in CASQ2 KO mice induced by stress challenge (epinephrine+caffeine cocktail) were attenuated by injection of NS309, a specific SK channel enhancer.
    explanation: Whole-animal stress-provocation result.
differential_diagnoses:
- name: RYR2-related CPVT (CPVT1)
  disease_term:
    preferred_term: catecholaminergic polymorphic ventricular tachycardia 1
    term:
      id: MONDO:0011484
      label: catecholaminergic polymorphic ventricular tachycardia 1
  description: >-
    Clinically indistinguishable at the bedside: identical exercise-induced
    bidirectional/polymorphic ventricular tachycardia, structurally normal
    heart, and normal resting ECG. RYR2 gain-of-function accounts for the large
    majority of genetically confirmed CPVT. Curated in this knowledge base as
    `RYR2_CPVT`, which also serves as the CPVT umbrella entry.
  distinguishing_features:
  - RYR2-associated CPVT is usually autosomal dominant; the established CASQ2 association is usually recessive.
  - The primary lesion affects the release channel in RYR2 disease and its luminal regulatory protein in CASQ2 disease.
  - Molecular testing and variant-specific interpretation distinguish clinically overlapping forms.
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RYR2-, CALM1-, CALM2-, CALM3-, and KCNJ2-related CPVT are inherited in an autosomal dominant manner"
    explanation: Contrasts the dominant inheritance of RYR2-CPVT with the recessive inheritance of CASQ2-CPVT.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- name: TRDN- and TECRL-related CPVT
  description: >-
    The other autosomal recessive CPVT genes. TRDN encodes triadin, which
    anchors calsequestrin to the RyR2 complex, so triadin loss produces a
    closely related junctional-SR lesion; TECRL-related disease overlaps
    clinically with long QT syndrome.
  distinguishing_features:
  - Molecular genetic testing distinguishes these overlapping recessive calcium-handling disorders.
  - QT prolongation can accompany TECRL- and TRDN-associated disease.
  - TRDN loss may also involve skeletal-muscle weakness.
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TECRL- and TRDN-related CPVT are inherited in an autosomal recessive manner"
    explanation: Identifies the other recessive CPVT genes that must be distinguished from CASQ2 by molecular testing.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
discussions:
- discussion_id: gap_intra_sr_calcium_kinetics_casq2
  prompt: >-
    How do allele-specific buffering, release-channel regulation and SR compensation combine to determine spontaneous release?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Sarcoplasmic Reticulum Calcium Buffering
  rationale: >-
    Free luminal calcium has been measured in a heterozygous null model and was unchanged despite increased leak. Complete-null hearts also compensate by increasing SR volume. These observations support a regulatory contribution alongside buffering and leave variant-specific dynamic release thresholds unresolved.
  proposed_experiments:
  - experiment_id: exp_casq2_luminal_calcium_kinetics
    name: Direct luminal calcium kinetics in calsequestrin-deficient cardiomyocytes
    description: >-
      Measure free intra-SR calcium kinetics with a targeted luminal calcium
      sensor in calsequestrin-deficient versus wild-type cardiomyocytes during
      beta-adrenergic stimulation, testing whether free luminal calcium near
      RyR2 rises faster and reaches the spontaneous-release threshold sooner.
    experiment_type:
      preferred_term: luminal sarcoplasmic reticulum calcium imaging experiment
  - experiment_id: exp_casq2_truncating_vs_missense_kinetics
    name: Truncating versus filament-defective CASQ2 allele comparison
    description: >-
      Compare intra-SR calcium kinetics between truncating CASQ2 alleles
      (complete protein loss) and missense alleles that retain protein but
      impair filament assembly, to separate the pure buffering deficit from
      the RyR2-regulatory deficit.
    experiment_type:
      preferred_term: allele-series calcium handling comparison
  evidence:
  - reference: PMID:17656677
    reference_title: Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction.
    explanation: A measured negative result contradicts a blanket claim that all relevant luminal-calcium measurements are absent.
- discussion_id: mismatch_purkinje_casq2_tissue_origin
  prompt: >-
    How do cardiac conduction-system and working-myocardial contributions to arrhythmia differ between Casq2 mice and human CASQ2 disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Triggered Cardiomyocyte Action Potentials
  - pathophysiology#Sinoatrial Node Dysfunction
  rationale: >-
    The 2018 conditional study found that concurrent loss in the conduction system and working myocardium was needed for CPVT, while conduction-system rescue prevented it. The targeted system includes sinoatrial tissue and is not equivalent to the Purkinje network alone. These mouse results do not establish the tissue origin in genotype-confirmed human CASQ2 disease, and general CPVT mapping studies should not be assumed to be CASQ2-specific.
  proposed_experiments:
  - experiment_id: exp_casq2_human_endocardial_mapping
    name: High-density endocardial mapping in genotyped CASQ2-CPVT patients
    description: >-
      Where electrophysiological mapping is clinically indicated, compare trigger localization in genotype-confirmed CASQ2 cases, separating conduction-system from working-myocardial origins without extrapolating from mixed-genotype CPVT series.
    experiment_type:
      preferred_term: high-density endocardial electroanatomic mapping study
  - experiment_id: exp_casq2_ipsc_conduction_vs_working
    name: CASQ2-mutant iPSC cardiomyocyte lineage comparison
    description: >-
      Compare triggered-activity thresholds in patient-derived CASQ2-mutant
      iPSC cardiomyocytes differentiated toward conduction-system versus
      working-myocardial identity, in a human cellular background.
    experiment_type:
      preferred_term: iPSC-derived cardiomyocyte lineage comparison experiment
  evidence:
  - reference: PMID:29452352
    reference_title: Conditional ablation and conditional rescue models for Casq2 elucidate the role of development and of cell-type specific expression of Casq2 in the CPVT2 phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Our study shows that the CPVT phenotype is dependent upon concurrent loss of Casq2 function in both the CCS and in working cardiomyocytes. Accordingly, restoration of Casq2 in only the CCS prevents CPVT.
    explanation: The study already performed conduction-system rescue; proposed work must address the remaining human or lineage-specific uncertainty.
- discussion_id: gap_dominant_casq2_prevalence_mechanism
  prompt: >-
    How common are dominant-acting CASQ2 variants, and by what mechanism does a
    single defective allele impair calsequestrin filament function enough to
    cause CPVT?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired CASQ2 Filament Assembly
  - genetic#CASQ2 heterozygous variants
  rationale: >-
    The selected 2020 families and the K180R pedigree support a heterozygous association but do not measure population penetrance. Biochemical filamentation defects do not directly test wild-type/mutant interference, and a corrected K180R iPSC resource is available without reported functional rescue in that resource paper. Variant-specific segregation, isogenic physiology and population ascertainment remain important.
  proposed_experiments:
  - experiment_id: exp_casq2_dominant_allele_penetrance
    name: Population-scale penetrance estimation for candidate dominant CASQ2 alleles
    description: >-
      Ascertain CASQ2 missense carriers at population scale and phenotype them
      by exercise stress testing, to estimate the penetrance of candidate
      dominant-acting alleles independently of clinically ascertained families.
    experiment_type:
      preferred_term: population-scale genotype-first penetrance study
  - experiment_id: exp_casq2_heterozygous_knockin_model
    name: Heterozygous filament-interface CASQ2 knock-in models
    description: >-
      Use isogenic mutant/corrected human cardiomyocytes, including the available K180R control resource, and selected heterozygous knock-in models to distinguish dominant interference from dosage effects under matched maturation and adrenergic protocols.
    experiment_type:
      preferred_term: heterozygous knock-in disease model
  evidence:
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More work is needed to understand the physiological role of calsequestrin in the EC coupling cycle, to determine the prevalence of autosomal-dominant calsequestrin mutations, and to understand how they cause CPVT."
    explanation: The review names the prevalence and mechanism of dominant CASQ2 variants as explicit open questions.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
notes: >-
  This entry represents the CASQ2-specific CPVT2 disease (MONDO:0012762). Most detailed molecular findings derive from mutant proteins, patient-derived cardiomyocytes or engineered mouse models and are not direct measurements in patient hearts. GeneReviews supplies the broader CPVT clinical baseline; the 2025 AHA/ACC statement updates exercise-participation guidance. The 2020 multicenter family cohort is clinically ascertained and includes uncertain variants, so its fractions are not population penetrance. ClinGen distinguishes Definitive recessive validity from Moderate dominant validity. Contemporary human trials with a CASQ2 transgene may target RYR2-associated disease and do not thereby establish eligibility or efficacy in CASQ2-CPVT. The Korean case reporting apparent homozygous Glu74* had a heterozygous father and a variant-negative mother without resolved deletion/UPD/technical testing. The 2026 convulsive-syncope report also contains discordant nucleotide/protein notation. These reports support their observed clinical presentations without establishing the uncertain segregation or exact variant annotation.
clinical_trials:
- name: NCT01117454
  description: Completed randomized placebo-controlled crossover trial of flecainide added to standard beta-blocker therapy. One of 13 treated participants had CASQ2-associated disease; 12 had paired outcome tests. Exercise ectopy improved in the mixed cohort, but the trial did not establish a CASQ2-specific effect or reduction in sudden death.
  phase: NOT_APPLICABLE
  status: COMPLETED
  evidence:
  - reference: clinicaltrials:NCT01117454
    reference_title: A Prospective Randomized Crossover Trial of Oral Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The purpose of this study is to test whether the addition of oral flecainide to standard therapy will reduce ventricular ectopy on exercise test compared to placebo plus standard therapy in patients with Catecholaminergic Polymorphic Ventricular Tachycardia.
    explanation: Registry describes the add-on trial question.
  - reference: PMID:28492868
    reference_title: 'Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Putative pathogenic mutations were present in RYR2 in 10 patients and CASQ2 in 1; 2 patients had negative genetic findings.
    explanation: The randomized trial included one CASQ2 participant; the pooled response cannot be interpreted as a CASQ2-specific effect estimate.
  notes: The registry status and eligibility were checked on October 1, 2026. The original ICD-therapy endpoint was replaced with an exercise-ectopy endpoint after recruitment fell short. Contemporary SGT-501 (NCT07148089) and AGP100 (NCT07263139) trials require an RYR2 mutation and are not CASQ2-eligible trials, even though SGT-501 delivers CASQ2.
animal_models:
- name: Casq2 Promoter/Exon-1 Null Mouse
  species: Mouse
  genotype: Homozygous targeted deletion abolishing Casq2
  publication: PMID:16932808
  description: The complete-null model retains basal contractile function despite loss of the principal SR calcium buffer. SR enlargement partly preserves content, while adrenergic stimulation promotes spontaneous release and ventricular tachyarrhythmia.
  modeled_mechanisms:
  - target: Sarcoplasmic Reticulum Volume Expansion
    description: Structural SR enlargement in the complete-null heart.
    evidence:
    - reference: PMID:16932808
      reference_title: Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin
      explanation: Mouse ultrastructural and protein-complex response.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Triadin/junctin and calreticulin changes differ across lines and assays; these are not established universal human adaptations.
    fidelity: MODERATE
  - target: Bidirectional and Polymorphic Ventricular Tachycardia
    description: Stress-provoked ventricular rhythms reproduce a central human manifestation.
    evidence:
    - reference: PMID:16932808
      reference_title: Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In vivo, Casq2-null mice phenocopied the human arrhythmias
      explanation: Whole-animal arrhythmic phenotype.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    limitations: The study did not reproduce spontaneous sudden death or ventricular fibrillation; basal contractility was largely preserved.
    fidelity: MODERATE
  notes: ''
- name: D307H Knock-In and Exon-9 Null Mice
  species: Mouse
  genotype: Homozygous D307H or exon-9 deletion
  publication: PMID:17607358
  description: The 2007 study compared D307H and exon-9-null models. Both had severe protein depletion, calreticulin/RyR2 increases and stress-related arrhythmia. Older animals developed hypertrophy and impaired function, unlike the usually structurally normal human presentation.
  modeled_mechanisms:
  - target: Reduced CASQ2 Protein Abundance
    description: Protein depletion with retained D307H transcript supports post-transcriptional instability.
    evidence:
    - reference: PMID:17607358
      reference_title: Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Mutant myocytes had reduced CASQ2 and increased calreticulin and RyR2
      explanation: Reports protein changes in these particular lines.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: MOLECULAR
    limitations: Calreticulin elevation was not reproduced at eight weeks in a later D307H study; age, line and assay context matter.
    fidelity: MODERATE
  - target: Bidirectional and Polymorphic Ventricular Tachycardia
    description: Stress-provoked arrhythmia occurred before late structural remodeling.
    evidence:
    - reference: PMID:17607358
      reference_title: Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Young mutant mice had structurally normal hearts but stress-induced ventricular arrhythmias
      explanation: Mouse age-dependent phenotype.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    limitations: Late mouse hypertrophy does not establish CASQ2-related human hypertrophic cardiomyopathy.
    fidelity: MODERATE
  notes: ''
- name: Heterozygous Casq2 Null Mouse
  species: Mouse
  genotype: Casq2+/−, approximately 25% protein reduction
  publication: PMID:17656677
  description: A modest dosage reduction increases stress-induced ventricular ectopy despite unchanged SR volume, other measured SR proteins and free luminal calcium.
  modeled_mechanisms:
  - target: Destabilized RyR2 Closed State
    description: Leak increases without a detectable change in free luminal calcium.
    evidence:
    - reference: PMID:17656677
      reference_title: Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction.
      explanation: Isolated cells demonstrate the negative luminal-calcium result.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: A dosage model does not directly test dominant-negative effects of a human missense allele.
    fidelity: MODERATE
  - target: Premature Ventricular Contractions
    description: Whole-animal ventricular ectopy increases under stress.
    evidence:
    - reference: PMID:17656677
      reference_title: Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Casq2+/- mice (n=35) challenged with isoproterenol displayed 3-fold higher rates of ventricular ectopy than Casq2+/+ mice
      explanation: Direct stress-provocation comparison.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    limitations: Protocol-dependent susceptibility is not a population risk estimate for human heterozygotes.
    fidelity: MODERATE
  notes: ''
- name: Conditional Conduction-System Deletion and Rescue
  species: Mouse
  genotype: Conditional Casq2 deletion/rescue in cardiac conduction system and working myocardium
  publication: PMID:29452352
  description: Genetic timing and tissue targeting separate developmental effects on resting rate from the requirements for stress arrhythmia.
  modeled_mechanisms:
  - target: Bidirectional and Polymorphic Ventricular Tachycardia
    description: Conduction-system restoration prevents CPVT in the conditional experiment.
    evidence:
    - reference: PMID:29452352
      reference_title: Conditional ablation and conditional rescue models for Casq2 elucidate the role of development and of cell-type specific expression of Casq2 in the CPVT2 phenotype.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: restoration of Casq2 in only the CCS prevents CPVT.
      explanation: Tissue-targeted rescue has already been demonstrated.
    relationship: RESCUES
    model_scale: ORGANISM
    limitations: The targeted conduction system includes sinoatrial tissue and is not a Purkinje-only intervention; human tissue origin remains uncertain.
    fidelity: MODERATE
  - target: Sinoatrial Node Dysfunction
    description: Resting-rate effects depend on conduction-system expression and developmental timing.
    evidence:
    - reference: PMID:29452352
      reference_title: Conditional ablation and conditional rescue models for Casq2 elucidate the role of development and of cell-type specific expression of Casq2 in the CPVT2 phenotype.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: resting heart rate depends upon Casq2 gene activity only in the CCS and upon developmental history.
      explanation: Conditional genetics distinguishes basal rate from CPVT timing.
    relationship: PERTURBS
    model_scale: ORGANISM
    limitations: Whole-conduction-system targeting does not isolate the sinoatrial cell lineage.
    fidelity: MODERATE
  notes: ''
- name: R33Q Proteostasis and Calpain Model
  species: Mouse
  genotype: Casq2R33Q/R33Q
  publication: PMID:42770222
  description: The September 2026 study examines couplon-protein degradation and its reversibility in mutant hearts, neonatal cells and isolated adult cardiomyocytes.
  modeled_mechanisms:
  - target: Calpain-Dependent Triadin Degradation
    description: Triadin loss precedes CASQ2 loss, and calpain inhibition restores both proteins.
    evidence:
    - reference: PMID:42770222
      reference_title: Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: TRDN degradation preceded CASQ2 loss
      explanation: Temporal order supports an upstream triadin destabilization process.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: MOLECULAR
    limitations: Available cached source is the abstract; pharmacological specificity and full experimental details cannot be assessed from it alone.
    fidelity: MODERATE
  - target: Bidirectional and Polymorphic Ventricular Tachycardia
    description: Calpain inhibition reduces ventricular tachycardia episodes.
    evidence:
    - reference: PMID:42770222
      reference_title: Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: reduced ventricular tachycardia episodes in vivo in Casq2R33Q/R33Q mice
      explanation: Whole-mouse intervention endpoint.
    relationship: RESCUES
    model_scale: ORGANISM
    limitations: Reduction in events is not a demonstrated cure or human treatment effect.
    fidelity: MODERATE
  notes: ''
- name: Adult and Neonatal AAV-CASQ2 Rescue Models
  species: Mouse
  genotype: R33Q/R33Q treated with AAV9 wild-type CASQ2
  publication: PMID:24888331
  description: Neonatal treatment prevented severe manifestations during follow-up to one year; adult administration was assessed after two months.
  modeled_mechanisms:
  - target: Reduced CASQ2 Protein Abundance
    description: Wild-type gene delivery restores release-complex protein expression.
    evidence:
    - reference: PMID:24888331
      reference_title: Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin
      explanation: Mouse prevention and adult rescue protocols.
    relationship: RESCUES
    model_scale: MOLECULAR
    limitations: Durability differs by treatment age and follow-up window; this does not establish lifelong protection or human dosing.
    fidelity: MODERATE
  notes: ''
- name: Casq2 Null Mouse with Conditional Mcu Deletion
  species: Mouse
  genotype: Casq2−/− with inducible cardiac Mcu knockout
  publication: PMID:39691471
  description: A mitochondrial-calcium-uptake perturbation tests compensatory adaptation rather than reproducing the usual human genotype. Surviving animals show heterogeneous remodeling and greater oxidative stress.
  modeled_mechanisms:
  - target: Increased Mitochondrial Reactive Oxygen Species
    description: Additional Mcu loss aggravates oxidative stress and calcium-handling abnormalities.
    evidence:
    - reference: PMID:39691471
      reference_title: Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Live-cell imaging identified altered Ca2+ handling and increased oxidative stress in CASQ2-/--MCUCKO myocytes.
      explanation: Cellular readout from double-mutant animals.
    relationship: PERTURBS
    model_scale: CELLULAR
    limitations: Severe early mortality creates survivor selection. Remodeling occurred in 6/12 examined double mutants and mean fractional shortening was not significantly different; neither Mcu loss nor this structural phenotype is established as typical human CASQ2 disease.
    fidelity: MODERATE
  notes: CaMKII/calcineurin activation and the usual fetal-gene program were not increased. Greater spontaneous waves were pacing-dependent (2 Hz rather than 0.5 Hz).
- name: Eight-Week D307H Knock-In Proteostasis Model
  species: Mouse
  genotype: Homozygous D307H knock-in
  publication: PMID:32902830
  description: Male eight-week D307H hearts, four per group, retained approximately 14.4% of control CASQ2 protein. Calreticulin, GRP78 and GRP94 were not significantly increased, unlike some other Casq2 models. Protein-marker measurements do not by themselves demonstrate increased degradation or autophagic flux.
  modeled_mechanisms:
  - target: Reduced CASQ2 Protein Abundance
    description: The age-specific D307H heart measurements demonstrate severe protein depletion.
    evidence:
    - reference: PMID:32902830
      reference_title: 'Molecular adaptation to calsequestrin 2 (CASQ2) point mutations leading to catecholaminergic polymorphic ventricular tachycardia (CPVT): comparative analysis of R33Q and D307H mutants.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: we confirmed the drastic reduction of expression of D307H CASQ2, as compared to control (14.4 ± 1.5%, p < 0.005)
      explanation: Protein measurement in young D307H knock-in hearts.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: MOLECULAR
    limitations: Small male-only group and a specific age; findings should not be combined uncritically with older D307H or R33Q hearts.
    fidelity: MODERATE
  evidence:
  - reference: PMID:32902830
    reference_title: 'Molecular adaptation to calsequestrin 2 (CASQ2) point mutations leading to catecholaminergic polymorphic ventricular tachycardia (CPVT): comparative analysis of R33Q and D307H mutants.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The conspicuous decrease of D307H CASQ2 protein was not accompanied by up-regulation of ER stress markers
    explanation: Negative marker finding limits generalization of an ER-stress response across alleles and ages; it does not refute the R33Q-specific node.
experimental_models:
- name: G112+5X Patient-Derived Cardiomyocytes and AAV Rescue
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:27711080
  description: Two clones per donor from a homozygous child, a healthy heterozygous father and an unrelated control. Adrenergic DADs and triggered activity were reduced after wild-type CASQ2 gene delivery.
  cell_source: Patient and family iPSC-derived cardiomyocytes
  modeled_mechanisms:
  - target: Delayed Afterdepolarizations
    description: Homozygous patient-derived cells exhibit adrenergic DADs.
    evidence:
    - reference: PMID:27711080
      reference_title: Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: HO-CMs displayed delayed afterdepolarizations (DADs) and, less frequently, triggered activity (TA)
      explanation: Patient-specific cellular arrhythmia readout.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Immature cells, donor differences and few clones limit transfer to adult myocardium.
    fidelity: MODERATE
  - target: Delayed Afterdepolarizations
    description: AAV9-CASQ2 reduced DAD/triggered-activity-positive cells from 17/22 to 2/9.
    evidence:
    - reference: PMID:27711080
      reference_title: Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: from 78%, 17/22 in HO cells to 22%, 2/9 in HO-CASQ2
      explanation: Rescue was substantial but not absolute; empty vector did not reproduce it.
    relationship: RESCUES
    model_scale: CELLULAR
    limitations: Small cell counts and incomplete rescue; no clinical gene-transfer outcome was studied.
    fidelity: MODERATE
  notes: ''
- name: D307H Patient-Derived Cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:26153920
  description: 'Cardiomyocytes from four patients, two overlapping an earlier report, were compared with non-isogenic controls. Isoproterenol produced heterogeneous responses: arrhythmia, no response or raised diastolic calcium.'
  cell_source: D307H patient iPSC-derived cardiomyocytes
  modeled_mechanisms:
  - target: Diastolic Cytosolic Calcium Elevation
    description: Mutant cells can develop diastolic calcium elevation or arrhythmia under adrenergic stimulation.
    evidence:
    - reference: PMID:26153920
      reference_title: Functional abnormalities in iPSC-derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: in the mutated cardiomyocytes isoproterenol was either ineffective, caused arrhythmias, or markedly increased diastolic
      explanation: Heterogeneous responses; sustained bulk calcium overload is not required in every arrhythmic recording.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Immature non-isogenic cells. Augmented caffeine responses do not by themselves establish increased total SR calcium; mean peripheral SR width was not significantly different.
    fidelity: MODERATE
  notes: ''
- name: Directed-Maturation CASQ2 Knockout Cardiac Organoids
  experimental_model_type: ORGANOID
  publication: PMID:40562874
  description: Three engineered knockout clones in an isogenic pluripotent-cell background were matured with AMPK/ERR activation. Organoids showed reduced spontaneous rate, preserved force and more ectopic activity after rest under If blockade.
  cell_source: Isogenic PB006.6 pluripotent cells with engineered CASQ2 knockout
  modeled_mechanisms:
  - target: Triggered Cardiomyocyte Action Potentials
    description: Engineered CASQ2-deficient cardiac organoids exhibit pro-arrhythmic contraction patterns.
    evidence:
    - reference: PMID:40562874
      reference_title: Maturation of human cardiac organoids enables complex disease modeling and drug discovery.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: when derived from calsequestrin 2 (CASQ2) and ryanodine receptor 2 (RYR2) mutant hPS cells exhibit a pro-arrhythmia phenotype.
      explanation: The paper includes a distinct CASQ2-knockout organoid arm.
    - reference: PMID:40562874
      reference_title: Maturation of human cardiac organoids enables complex disease modeling and drug discovery.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Using the post-rest-potentiation protocol, there was increased ectopy in CASQ2 ... DM-hCOs
      explanation: The full-text result localizes the pro-arrhythmia readout to the post-rest protocol; the omitted text includes the separate RYR2 comparison.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: TISSUE
    limitations: Engineered knockout rather than a patient allele; neural and immune compartments are absent. BET-inhibitor rescue in this paper concerns DSP cardiomyopathy, not CASQ2.
    fidelity: MODERATE
  notes: ''
- name: K180R Isogenic Corrected iPSC Resource
  experimental_model_type: IPSC_DERIVED_MODEL
  publication: PMID:39826349
  description: A CRISPR-corrected control line, CIAUi003-A-1, complements the parental heterozygous K180R line. The resource paper reports genetic correction, not rescue of a cardiac electrophysiological phenotype.
  cell_source: CIAUi003-A patient line and CRISPR-corrected isogenic control
  modeled_mechanisms: []
  notes: No RESCUES mechanism link is assigned because functional rescue was not reported.
  evidence:
  - reference: PMID:39826349
    reference_title: Generation of an isogenic CRISPR/Cas9-corrected control induced pluripotent stem cell line from a patient with autosomal dominant catecholaminergic polymorphic ventricular tachycardia with a heterozygous variant in cardiac calsequestrin-2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: creating a CRISPR-corrected isogenic control line (CIAUi003-A-1)
    explanation: Documents availability of the isogenic resource without claiming functional rescue.
- name: Recombinant Candidate Dominant CASQ2 Proteins
  experimental_model_type: OTHER
  publication: PMID:32693635
  description: Purified proteins were examined by turbidity, size-exclusion and structural mapping. Assays identify assembly defects but do not directly model mixed mutant/wild-type filaments in human cardiomyocytes.
  cell_source: Recombinant CASQ2 proteins
  modeled_mechanisms:
  - target: Impaired CASQ2 Filament Assembly
    description: Candidate missense proteins show assay-dependent filamentation defects.
    evidence:
    - reference: PMID:32693635
      reference_title: An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize.
      explanation: Purified-protein assembly result.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: MOLECULAR
    limitations: R251H required acidic pH, Y55C showed disulfide-related behavior and W361R could not be expressed. Dominant interference was not directly tested by protein mixing.
    fidelity: MODERATE
  notes: ''
- name: G112+5X and L167H Expression in Rat Myocytes
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:16908766
  description: Expression of two mutant proteins distinguishes calcium binding from effective store capacity.
  cell_source: Rat cardiomyocytes expressing mutant CASQ2
  modeled_mechanisms:
  - target: Reduced Sarcoplasmic Reticulum Calcium Buffering
    description: Both variants reduce calcium-storing capacity despite differing calcium-binding effects.
    evidence:
    - reference: PMID:16908766
      reference_title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca2+-storing capacity
      explanation: Mutant expression perturbs SR storage.
    relationship: PERTURBS
    model_scale: CELLULAR
    limitations: Heterologous expression and dosage may differ from patient cardiomyocytes; normal binding by L167H excludes universal binding loss as an explanation.
    fidelity: MODERATE
  notes: ''
- name: Casq2 Null Myocytes for Flecainide Mechanism Dissection
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:33297863
  description: Permeabilized cells, sodium-channel blockade and flecainide analogues separate sodium-channel from RyR2 contributions.
  cell_source: Isolated Casq2-null mouse ventricular myocytes
  modeled_mechanisms:
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    description: Flecainide inhibits spontaneous release even without functional sarcolemmal sodium channels.
    evidence:
    - reference: PMID:33297863
      reference_title: RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In membrane-permeabilized Casq2-/- cardiomyocytes-lacking intact sarcolemma and devoid of sodium channel contribution-flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations.
      explanation: Direct intracellular mechanism experiment.
    relationship: PERTURBS
    model_scale: CELLULAR
    limitations: Demonstrates an independent RyR2 contribution in this assay, not an exclusive mechanism in treated patients.
    fidelity: MODERATE
  notes: ''
- name: Casq2 Null Myocytes for SK and Mitochondrial Studies
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:40438932
  description: Voltage clamp, calcium imaging and mitochondrial assays assess NS309 responses in null ventricular myocytes.
  cell_source: Isolated Casq2-null mouse ventricular myocytes
  modeled_mechanisms:
  - target: Reduced Sarcolemmal SK Current
    description: Reduced current was measured directly by voltage clamp.
    evidence:
    - reference: PMID:40438932
      reference_title: Pharmacological Enhancement of Small Conductance Ca(2+)-Activated K(+) Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Voltage-clamp experiments in isolated VMs treated with β-adrenergic agonist isoproterenol showed a reduction of sarcolemmal SK channel current (ISK) density in CPVT VMs.
      explanation: Reduced functional SK current despite increased surface SK3 protein in the detailed study.
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Increased surface SK3 protein does not imply increased current; mitochondrial effects complicate drug specificity.
    fidelity: MODERATE
  - target: Increased Mitochondrial Reactive Oxygen Species
    description: NS309 reduces excess mitochondrial ROS.
    evidence:
    - reference: PMID:40438932
      reference_title: Pharmacological Enhancement of Small Conductance Ca(2+)-Activated K(+) Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: SK channel enhancement reversed the increased rate of reactive oxygen species production by mitochondria in CPVT VMs.
      explanation: Null-mouse ventricular myocytes show excess mitochondrial ROS, reduced by NS309.
    relationship: RESCUES
    model_scale: CELLULAR
    limitations: Incomplete antagonism by membrane-impermeable apamin suggests a mitochondrial component, but does not genetically isolate it.
    fidelity: MODERATE
  notes: ''
computational_models:
- name: Stochastic CASQ2-Deficient Guinea-Pig Myocyte Simulation
  model_type: PHYSIOLOGICAL
  publication: PMID:36672764
  description: A stochastic local-control ventricular-myocyte model approximates G112+5X-associated changes in CASQ2 buffering and calcium-release-unit parameters. Rapid pacing with adrenergic stimulation produces alternans; a rapid-to-slow transition produces EADs, not a direct experimental demonstration of DADs.
  modeled_mechanisms:
  - target: Reduced Sarcoplasmic Reticulum Calcium Buffering
    description: The model varies luminal-buffer and release parameters to explore instability.
    evidence:
    - reference: PMID:36672764
      reference_title: Pacing Dynamics Determines the Arrhythmogenic Mechanism of the CPVT2-Causing CASQ2(G112+5X) Mutation in a Guinea Pig Ventricular Myocyte Computational Model.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In the simulation studies under rapid pacing (6 Hz), electromechanically concordant cellular alternans appeared under β-adrenergic stimulation in the CPVT mutant but not in the wild-type nor in the non-β-stimulated mutant.
      explanation: Computational alternans under a defined pacing protocol.
    relationship: PERTURBS
    model_scale: CELLULAR
    limitations: Species and parameter assumptions, no modeled calcium-wave propagation, and protocol-dependent EADs limit transfer to human DAD-mediated disease.
    fidelity: MODERATE
- name: Multiscale RyR2 Open- and Closed-Block Model
  model_type: KINETIC
  publication: PMID:42363594
  description: The 2026 dynamic model couples experimentally determined RyR2 gating with SERCA uptake to explain why flecainide and tetracaine can differ despite both inhibiting channels.
  modeled_mechanisms:
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    description: Different blocking kinetics produce different steady-state spark and SR-load behavior.
    evidence:
    - reference: PMID:42363594
      reference_title: Different actions of RyR2 open and closed channel block explained by a multiscale Ca(2+) release model.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Acute closed block also decreased spark frequency due to reduced frequency of RyR2 opening. This resulted in a much stronger inhibition of overall spark Ca2+ leak and a larger increase in SR load to achieve a new steady state.
      explanation: A model prediction explaining compensation to closed-channel block.
    relationship: PERTURBS
    model_scale: CELLULAR
    limitations: Permeabilized-cell calcium-release model, not a whole-heart arrhythmia or clinical drug-efficacy trial.
    fidelity: MODERATE
datasets:
- accession: bioproject:PRJNA916203
  title: Mouse sequence data
  description: The WT and Casq2-null RNA-seq subset used in the mitochondrial-uptake study. The project also contains CypD and double-knockout samples not included in this contrast.
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:39691471
  evidence:
  - reference: PMID:39691471
    reference_title: Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All the sequencing data were deposited in the NCBI sequence Read Archive (SRA) database under the Bioproject acession number PRJNA916203 (WT and CASQ2-/- samples) and PRJNA623119 (MCUCKO and CASQ2-/--MCUCKO samples)
    explanation: The paper identifies genotype-specific subsets from two BioProjects.
  notes: NCBI BioProject and ENA run metadata were verified on October 1, 2026. The 13 runs associated with each project are not all samples from this specific comparison; no aggregate sample count is assigned.
- accession: bioproject:PRJNA623119
  title: Gene regulation in CPVT model
  description: The conditional Mcu-knockout and Casq2/Mcu double-knockout RNA-seq subset. The broader project also includes earlier SERCA2a-related experiments.
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:39691471
  evidence:
  - reference: PMID:39691471
    reference_title: Conditional ablation of MCU exacerbated cardiac pathology in a genetic arrhythmic model of CPVT.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All the sequencing data were deposited in the NCBI sequence Read Archive (SRA) database under the Bioproject acession number PRJNA916203 (WT and CASQ2-/- samples) and PRJNA623119 (MCUCKO and CASQ2-/--MCUCKO samples)
    explanation: The paper identifies genotype-specific subsets from two BioProjects.
  notes: NCBI BioProject and ENA run metadata were verified on October 1, 2026. The 13 runs associated with each project are not all samples from this specific comparison; no aggregate sample count is assigned.

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References & Deep Research

References

PMID:32693635

An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.