🏷

Classifications

Harrison's Chapter

Channelopathy

👪

Inheritance

2

Autosomal Recessive HP:0000007

The classic and predominant mode of inheritance for CASQ2-related CPVT. Affected individuals carry biallelic (homozygous or compound heterozygous) loss-of-function CASQ2 variants; the founder p.D307H missense allele segregated fully in seven consanguineous Israeli Bedouin families, and nonsense/frameshift/splice alleles were subsequently reported in unrelated families. Clinical penetrance among biallelic carriers is near-complete.

Autosomal recessive inheritance Penetrance %: 97.1

Show evidence (3 references)

PMID:20301466 SUPPORT Human Clinical

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

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

PMID:11704930 SUPPORT 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 Human Clinical

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

Quantifies near-complete clinical penetrance among biallelic CASQ2 carriers, the source of the penetrance_percentage value.

Autosomal Dominant HP:0000006

An emerging, variant-specific dominant arm. A subset of heterozygous CASQ2 missense variants localised to the dimer-dimer interface of the calsequestrin filament behave as dominant negatives and can manifest a CPVT phenotype; in the international multicenter cohort a third of clinically evaluated heterozygous relatives met diagnostic criteria for CPVT. This is a per-variant property rather than a property of CASQ2 as a whole, so CPVT2 should not be reclassified wholesale as a dominant disorder, but heterozygotes warrant clinical screening.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:32693635 SUPPORT 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."

Directly quantifies the CPVT phenotype among CASQ2 heterozygotes, supporting a dominant arm for some variants.

PMID:32693635 SUPPORT Human Clinical

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

States that dominance is a property of specific missense variants rather than of the gene as a whole.

PMID:20301466 SUPPORT Human Clinical

"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.

◆

Subtypes

2

Biallelic (recessive) CASQ2-CPVT

CASQ2 hgnc:1513

The classic recessive form. Homozygous or compound heterozygous loss-of-function CASQ2 variants abolish or severely reduce functional calsequestrin 2. Penetrance is near-complete, arrhythmic events begin in early childhood, and the median age of the first potentially fatal arrhythmic event is 7 years.

Show evidence (1 reference)

PMID:32693635 SUPPORT 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.

Heterozygous (dominant-negative) CASQ2-CPVT

CASQ2 hgnc:1513

A milder, variant-specific dominant form caused by single heterozygous CASQ2 missense alleles that impair filament assembly. Arrhythmic risk is substantially lower than in biallelic carriers but is not negligible, so heterozygous relatives require clinical evaluation rather than reassurance.

Show evidence (1 reference)

PMID:32693635 SUPPORT Human Clinical

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

Establishes the heterozygous subtype as a real, clinically actionable phenotype.

?

Discussions and Knowledge Gaps

3

Does loss of calsequestrin actually accelerate the rise of free intra-SR calcium near RyR2, as the accepted buffering model of CPVT2 predicts?

KNOWLEDGE GAP OPEN gap_intra_sr_calcium_kinetics_casq2

Attached to

pathophysiology#Reduced Sarcoplasmic Reticulum Calcium Buffering

The buffering model is the standard mechanistic account of CPVT2 and the justification for treating CASQ2 loss as functionally equivalent to a RyR2 gain-of-function lesion, but the key predicted intermediate has never been measured directly. Without it, the alternative account (that calsequestrin loss acts principally by destabilising RyR2 regulation through the triadin/junctin anchor) cannot be excluded, and the two predict different responses to therapies that modulate SR load.

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:32115705 SUPPORT Other

"Although intra-SR calcium kinetics have not yet been measured experimentally in calsequestrin CPVT models"

The review states explicitly that the predicted intermediate of the buffering model has not been measured.

Does the failure of Purkinje-restricted calsequestrin deletion to produce CPVT in mice mean that human CASQ2-CPVT arrhythmia originates in the working ventricular myocardium rather than the conduction system?

HUMAN MODEL MISMATCH OPEN mismatch_purkinje_casq2_tissue_origin

Attached to

pathophysiology#Delayed Afterdepolarizations and Triggered Activity

Clinical mapping in CPVT patients localises most ventricular ectopy to the outflow tracts, and the bidirectional-VT pattern has classically been attributed to alternating activation of the His-Purkinje system. Yet tissue-targeted deletion of calsequestrin in the murine Purkinje network, where the molecular lesion of CPVT2 is exactly reproduced, failed to generate the phenotype. This is a model-fidelity question rather than a simple absence of evidence: the murine conduction system differs in size, source-sink relationships, and Purkinje distribution from the human heart, so a negative mouse result may not transfer. Resolving it matters because ablation strategies targeting Purkinje triggers presuppose the conduction system is the source.

Proposed experiments

Purkinje-restricted calsequestrin rescue in the Casq2-null mouse

conditional tissue-restricted gene rescue experiment

exp_casq2_purkinje_rescue_sufficiency

Perform tissue-targeted calsequestrin re-expression (rather than deletion) restricted to the murine Purkinje network in an otherwise Casq2-null background, testing sufficiency of the conduction system as well as necessity.

High-density endocardial mapping in genotyped CASQ2-CPVT patients

high-density endocardial electroanatomic mapping study

exp_casq2_human_endocardial_mapping

Map arrhythmia origin at high density in genotype-confirmed human CASQ2-CPVT patients during provoked ectopy, distinguishing Purkinje from working-myocardial trigger sites.

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 (2 references)

PMID:32115705 SUPPORT Model Organism

"the deletion of calsequestrin in the Purkinje network did not produce a CPVT phenotype"

The negative tissue-targeted mouse result that creates the mismatch with the human mapping data.

PMID:32115705 SUPPORT Other

"More research with tissue-targeted genetic models such as those in Fig. 5 is needed to determine the tissue origin of CPVT"

The review states the tissue origin of CPVT remains unresolved.

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#CASQ2 Loss of Function

CPVT2 was defined for two decades as a recessive disease, and heterozygous relatives were routinely reassured. The demonstration that a third of clinically evaluated CASQ2 heterozygotes met CPVT criteria, and that specific missense alleles disrupt dimer-dimer filament contacts, inverts that counselling posture. But the population frequency of dominant-acting alleles is unknown, no in vivo model of the dominant-negative mechanism has been reported, and it is unclear which biochemical assay best predicts which heterozygous variants confer risk. This directly affects variant interpretation and cascade-screening policy.

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

Generate heterozygous knock-in mouse and human iPSC-cardiomyocyte models of filament-interface CASQ2 missense variants to test the dominant-negative mechanism in vivo and in a human cellular background.

Show evidence (1 reference)

PMID:32115705 SUPPORT 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.

⚙

Pathophysiology

11

CASQ2 Loss of Function

The upstream lesion of CPVT2 is a pathogenic variant in CASQ2, which encodes cardiac calsequestrin 2, the major luminal calcium-binding protein of the junctional sarcoplasmic reticulum and part of the RyR2 calcium release complex. Nonsense, frameshift and splice alleles abolish the protein; missense alleles either destroy calcium binding (as for the founder p.D307H allele, which converts an aspartate to a histidine in a highly negatively charged calcium-binding domain) or impair the assembly of calsequestrin dimers into filaments.

cardiomyocyte CL:0000746

CASQ2 hgnc:1513

calcium ion binding GO:0005509 ↓ DECREASED

heart UBERON:0000948

Downstream

Reduced Sarcoplasmic Reticulum Calcium Buffering Loss or functional impairment of calsequestrin 2 removes the high-capacity luminal calcium buffer of the junctional SR.

Destabilized RyR2 Closed State Because calsequestrin is anchored to RyR2 by triadin and junctin and contributes to luminal regulation of the release channel, its loss also destabilises RyR2 gating independently of the buffering deficit.

Show evidence (3 references)

PMID:11704930 SUPPORT Human Clinical

"The CASQ2 protein serves as the major Ca(2+) reservoir within the SR of cardiac myocytes and is part of a protein complex that contains the ryanodine receptor"

Establishes calsequestrin 2 as the SR luminal calcium reservoir within the RyR2 release complex, the protein lost in CPVT2.

PMID:11704930 SUPPORT Human Clinical

"converts a negatively charged aspartic acid into a positively charged histidine, in a highly negatively charged domain, and is likely to exert its deleterious effect by disrupting Ca(2+) binding"

Describes the molecular consequence of the founder p.D307H missense allele on calcium binding.

PMID:12386154 SUPPORT Human Clinical

"We report the first nonsense mutations in the cardiac calsequestrin gene, CASQ2, in three CPVT families."

Documents protein-truncating CASQ2 alleles as a distinct class of CPVT2 lesion.

Reduced Sarcoplasmic Reticulum Calcium Buffering

Without functional calsequestrin, the junctional SR loses its low-affinity, high-capacity calcium sink. Free intra-SR calcium therefore rises much faster during refilling, and the calcium-release refractory period is shortened. In vitro expression of CPVT2 mutants in myocytes reduces SR calcium-storing capacity, and Casq2-null hearts compensate anatomically (increased SR volume, loss of triadin-1 and junctin) yet remain functionally unstable.

cardiomyocyte CL:0000746

sarcoplasmic reticulum calcium ion transport GO:0070296 ↕ DYSREGULATED

myocardium UBERON:0002349

Downstream

Diastolic Sarcoplasmic Reticulum Calcium Leak Impaired luminal buffering allows free intra-SR calcium near RyR2 to rise rapidly during diastole, lowering the threshold for spontaneous release.

Sinoatrial Node Dysfunction The same calsequestrin deficit acts in sinoatrial pacemaker tissue, depressing sinus rate; this is the bradyarrhythmic branch of CPVT2.

Show evidence (3 references)

PMID:16908766 SUPPORT 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 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 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.

Destabilized RyR2 Closed State

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

Downstream

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

Show evidence (1 reference)

PMID:32115705 SUPPORT 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.

Beta-Adrenergic Stimulation

Physical exertion or acute emotional stress produces a catecholamine surge that acts on the genetically primed, calsequestrin-deficient calcium-release apparatus. Beta-adrenergic signalling increases SR calcium loading and phosphorylation of the release machinery, converting a latent instability into overt diastolic leak. This node is the therapeutic target of beta-blockade, left cardiac sympathetic denervation, and exercise restriction.

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 (2 references)

PMID:16932808 SUPPORT Model Organism

"Casq2-null mice are viable and display normal SR Ca2+ release and contractile function under basal conditions"

Shows the calsequestrin-deficient phenotype is latent at baseline, establishing catecholaminergic stimulation as the required precipitant.

PMID:16908766 SUPPORT 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

The convergent central effector of CPVT2: spontaneous, premature calcium release from the sarcoplasmic reticulum during diastole. In calsequestrin-deficient myocytes exposed to catecholamines, spontaneous releases propagate as calcium waves ahead of the next paced beat. This is the identical central effector on which the RYR2, TRDN, TECRL and CALM1/2/3 forms of CPVT converge (see `RYR2_CPVT`), reached here from a luminal-buffering rather than a release-channel lesion.

cardiomyocyte CL:0000746

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

myocardium UBERON:0002349

Downstream

Cytosolic Calcium Overload Unregulated diastolic release raises cytosolic calcium above the level that the SERCA pump and sarcolemmal extrusion can immediately handle.

Show evidence (2 references)

PMID:16932808 SUPPORT 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 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.

Cytosolic Calcium Overload

Excess cytosolic calcium during diastole is extruded by the sodium-calcium exchanger (NCX) operating in forward mode, which moves three sodium ions inward for each calcium ion removed. The resulting net inward (depolarizing) current is the electrogenic bridge between the calcium disturbance and the electrical disturbance.

cardiomyocyte CL:0000746

calcium ion transport GO:0006816 ↑ INCREASED

Downstream

Delayed Afterdepolarizations and Triggered Activity The inward NCX current depolarizes the membrane after repolarization is complete, producing delayed afterdepolarizations.

Show evidence (1 reference)

PMID:16908766 SUPPORT In Vitro

"the 2 CASQ2 mutations identified in CPVT create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias"

Links the CASQ2-driven intracellular calcium disturbance to arrhythmia facilitation.

Delayed Afterdepolarizations and Triggered Activity

Delayed afterdepolarizations (DADs) that reach action-potential threshold generate premature, non-driven beats (triggered activity). In CPVT2 these have been demonstrated directly in CASQ2-mutant myocytes exposed to isoproterenol and in calsequestrin-null mouse myocytes. Note that this node is a DAD/triggered-activity node, not an early-afterdepolarization or repolarization-dispersion node: CPVT2 is a calcium-handling disease with a normal resting ECG and normal action-potential duration, so only the calcium-leak arm of the module substrate node applies.

cardiomyocyte CL:0000746

cardiac muscle cell action potential GO:0086001 ⚠ ABNORMAL

Downstream

Bidirectional and Polymorphic Ventricular Tachycardia Triggered beats arising at multiple ventricular sites organise into bidirectional and then polymorphic ventricular tachycardia.

Palpitations Premature, non-driven beats are perceived by the patient as an awareness of irregular or rapid heart action, typically the mildest symptomatic expression of triggered activity.

Atrial Triggered Activity The same calcium-triggered mechanism operates in atrial myocardium, producing atrial triggered beats.

Show evidence (3 references)

PMID:16908766 SUPPORT 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.

PMID:16932808 SUPPORT In Vitro

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

Isolated Casq2-null cardiomyocytes exposed to catecholamines show premature spontaneous calcium release and triggered beats, the cellular arrhythmia trigger.

PMID:16932808 SUPPORT Model Organism

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

The in vivo counterpart of the myocyte result, confirming that the cellular triggered activity translates into the whole-animal arrhythmia phenotype.

Sinoatrial Node Dysfunction

Calsequestrin deficiency also depresses sinoatrial pacemaker function, producing low resting sinus rates. This is not merely a coincidental finding: long diastolic intervals give spontaneous SR calcium release time to occur before the next beat empties the store, so sinus node dysfunction contributes mechanistically to ventricular arrhythmia risk. Selective re-expression of Casq2 in the sinoatrial node of adult Casq2-knockout mice accelerated sinus rates and prevented CPVT.

cardiac pacemaker cell of sinoatrial node CL:1000477

cardiac conduction GO:0061337 ↓ DECREASED

Downstream

Delayed Afterdepolarizations and Triggered Activity Slow sinus rates lengthen diastole, giving spontaneous calcium release more opportunity to reach the DAD threshold.

Bradycardia Depressed sinoatrial automaticity produces low resting sinus rates.

Show evidence (2 references)

PMID:32115705 SUPPORT Model Organism

"we were able to re-express Casq2 in the SA node of adult Casq2 KO mice, which accelerated sinus heart rates and prevented CPVT"

Tissue-targeted rescue in the Casq2-knockout mouse shows the sinoatrial node is causally involved in CPVT2 arrhythmogenesis.

PMID:32115705 SUPPORT Other

"A likely explanation is that low sinus rates prolong the diastolic interval, allowing the spontaneous SR calcium release to occur before CICR during the next action potential can empty the SR and reset the SR calcium clock."

States the proposed mechanism linking bradycardia to increased spontaneous calcium release.

Atrial Triggered Activity

Calcium-triggered activity is not confined to the ventricle. Optical mapping of calsequestrin-null mouse atria showed spontaneous calcium release events driving atrial DADs and triggered beats, providing a mechanistic account of the atrial tachyarrhythmias that frequently precede or accompany ventricular tachycardia in CPVT. Human CASQ2-specific confirmation of this atrial arm is not yet available, so it is modelled here as a mechanism branch rather than asserted as a CPVT2 clinical phenotype.

cardiomyocyte CL:0000746

Show evidence (1 reference)

PMID:32115705 SUPPORT Model Organism

"Based on optical mapping data from a calsequestrin null mouse model, the atrial tachyarrhythmias are driven by spontaneous calcium release events in atrial myocardium that cause DADs and atrial triggered beats"

Mouse optical-mapping evidence for a calsequestrin-dependent atrial triggered-activity arm.

Bidirectional and Polymorphic Ventricular Tachycardia

Triggered beats organise into the hallmark arrhythmia of CPVT: fast ventricular tachycardia with a beat-to-beat alternating QRS axis (bidirectional VT) that may become polymorphic and degenerate to ventricular fibrillation. Onset is reproducibly provoked by exercise or emotion and the heart is structurally normal.

cardiac conduction GO:0061337 ⚠ ABNORMAL

heart UBERON:0000948

Downstream

Effort-Induced Polymorphic Ventricular Tachycardia The arrhythmia is reproducibly provoked by exertion or emotional stress.

Bidirectional Ventricular Tachycardia Alternating-axis QRS complexes during the tachycardia.

Ventricular Fibrillation Polymorphic ventricular tachycardia may degenerate into ventricular fibrillation.

Syncope and Sudden Cardiac Death Sustained ventricular tachyarrhythmia abolishes effective cardiac output.

Show evidence (2 references)

PMID:20301466 SUPPORT Human Clinical

"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 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.

Syncope and Sudden Cardiac Death

Loss of effective cardiac output during the arrhythmia causes transient cerebral hypoperfusion (syncope, sometimes with convulsive features that are misdiagnosed as epilepsy) and, if the rhythm does not self-terminate, cardiac arrest and sudden death. In the international CASQ2 cohort a potentially fatal arrhythmic event occurred at a median age of 7 years in biallelic carriers, and homozygote/compound-heterozygote status conferred a markedly increased hazard relative to heterozygosity.

Downstream

Syncope Transient cerebral hypoperfusion during the arrhythmia causes loss of consciousness.

Convulsive Syncope Prolonged cerebral hypoperfusion during an arrhythmic episode can produce convulsive movements that are frequently misattributed to a primary seizure disorder.

Cardiac Arrest A non-terminating ventricular arrhythmia produces cardiac arrest.

Sudden Cardiac Death Unresuscitated cardiac arrest results in sudden cardiac death.

Show evidence (2 references)

PMID:11704930 SUPPORT 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 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.

⬡

Pathograph

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

●

Phenotypes

9

Cardiovascular 6

Syncope Syncope HP:0001279

Onset: CHILDHOOD

Show evidence (2 references)

PMID:12386154 SUPPORT 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 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.

Cardiac Arrest Cardiac arrest HP:0001695

Show evidence (2 references)

PMID:32693635 SUPPORT 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 Human Clinical

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

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

Sudden Cardiac Death Sudden cardiac death HP:0001645

Show evidence (2 references)

PMID:11704930 SUPPORT 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 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.

Ventricular Fibrillation Ventricular fibrillation HP:0001663

Show evidence (1 reference)

PMID:20301466 SUPPORT Human Clinical

"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 Bradycardia HP:0001662

The cited review statement covers CPVT as a whole rather than CASQ2-CPVT specifically; the calsequestrin-specific mechanistic work behind it (the sinoatrial Casq2 re-expression rescue) is mouse data, curated on the Sinoatrial Node Dysfunction pathophysiology node.

Show evidence (1 reference)

PMID:32115705 SUPPORT 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.

Palpitations Palpitations 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 Other

"Symptoms range from palpitations to cardiac arrest"

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

Other 3

Effort-Induced Polymorphic Ventricular Tachycardia Effort-induced polymorphic ventricular tachycardia HP:0004758

Onset: JUVENILE; mean 7.0y

Show evidence (3 references)

PMID:32693635 SUPPORT 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 Human Clinical

"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 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 Bidirectional ventricular tachycardia HP:0034040

Show evidence (1 reference)

PMID:20301466 SUPPORT Human Clinical

"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.

Convulsive Syncope

Deliberately left unbound to an HPO term. HPO has no term for convulsive (anoxic) syncope: the nearest candidate, HP:0001250 (Seizure), denotes abnormal excessive or synchronous neuronal activity, whereas the mechanism here is arrhythmic cerebral hypoperfusion with a structurally and electrically normal brain. Binding HP:0001250 would over-claim a primary epileptic phenotype and would wrongly conflate this with the genuine neuronal phenotype reported in some RYR2 variant carriers in `RYR2_CPVT`, so no term is asserted rather than a misleading one.

Show evidence (1 reference)

PMID:11704930 SUPPORT 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.

🧬

Genetic Associations

2

CASQ2 biallelic loss-of-function variants (Causative)

Gene: CASQ2 hgnc:1513

Show evidence (4 references)

PMID:11704930 SUPPORT 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 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 Human Clinical

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

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

+ 1 more reference

CASQ2 heterozygous dominant-negative missense variants (Causative)

Gene: CASQ2 hgnc:1513

Show evidence (3 references)

PMID:32693635 SUPPORT 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."

Biochemical characterisation distinguishing the dominant-negative filamentation defect from complete loss of dimerization.

PMID:32693635 SUPPORT Computational

"Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers."

Structural mapping onto the calsequestrin filament rationalises the dominant-negative mechanism.

PMID:32115705 SUPPORT Other

"For autosomal-dominant CPVT2, the current hypothesis is that calsequestrin mutations affect the ability for polymerization to occur."

Independent review statement of the polymerization-defect hypothesis for dominant CPVT2.

💊

Medical Actions

6

Nonselective Beta-Blocker Therapy (Nadolol)

Action: Pharmacotherapy NCIT:C15986

Agent: nadolol CHEBI:7444

First-line therapy for all clinically or genetically diagnosed CPVT2. Nonselective beta-blockers, and nadolol in particular, blunt the catecholamine surge that precipitates diastolic calcium leak. Beta-blockade is indicated even in genotype-positive individuals with a negative exercise stress test, because sudden death can be the first manifestation.

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 Human Clinical

"nadolol is the most effective beta blocker in CPVT"

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

PMID:26432584 SUPPORT 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

Add-on antiarrhythmic for breakthrough arrhythmia on maximally tolerated beta-blockade, and for primary prevention when beta-blockers alone do not suppress exercise-induced ectopy. Flecainide acts on the CPVT2 mechanism directly: it blocks RyR2 in the open state, reducing calcium spark mass and the probability that sparks propagate into arrhythmogenic calcium waves. Notably, the defining mechanistic experiments were performed in calsequestrin-null (Casq2-/-) myocytes, making this evidence directly relevant to CPVT2 rather than borrowed from RYR2-CPVT.

Mechanism Target:

INHIBITS Diastolic Sarcoplasmic Reticulum Calcium Leak — Open-state block of RyR2 reduces calcium spark mass and suppresses the propagating diastolic calcium waves that are the central effector of CPVT2.

Show evidence (4 references)

PMID:19835880 SUPPORT 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 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:19835880 SUPPORT Model Organism

"the drug flecainide inhibits RyR2 channels and prevents CPVT in mice and humans"

Summarises the in vivo antiarrhythmic efficacy of flecainide that the cellular experiments in this paper set out to explain.

+ 1 more reference

Left Cardiac Sympathetic Denervation

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

Surgical removal of the left stellate ganglion and upper thoracic sympathetic ganglia to reduce sympathetic drive to the heart. Reserved for breakthrough arrhythmia despite optimal beta-blocker and flecainide therapy, or for patients intolerant of pharmacotherapy. It is an adjunct rather than a cure: a significant residual arrhythmic burden persists.

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 (1 reference)

PMID:20301466 SUPPORT Human Clinical

"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.

Implantable Cardioverter-Defibrillator Placement

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

Device therapy for patients whose arrhythmias are not adequately controlled by drug therapy, and for survivors of cardiac arrest. Programming must be conservative: an inappropriate or painful shock triggers its own catecholamine surge and can precipitate an arrhythmic storm in CPVT.

Show evidence (1 reference)

PMID:20301466 SUPPORT Human Clinical

"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.

Exercise Restriction and Trigger Avoidance

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

Avoidance of competitive sports and strenuous exercise, and of digitalis, is a cornerstone of CPVT management because these are the precipitants of the adrenergic surge that unmasks the arrhythmia. Permitted exercise intensity should be individualised on the basis of exercise stress testing.

Mechanism Target:

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

Show evidence (1 reference)

PMID:20301466 SUPPORT Human Clinical

"Agents/circumstances to avoid: Competitive sports and other strenuous exercise; use of digitalis."

GeneReviews lists competitive sports, strenuous exercise, and digitalis as agents and circumstances to avoid in CPVT.

Genetic Counseling and Cascade Family Screening

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

Because CPVT2 is usually recessive, sibling recurrence risk is 25% and both parents are obligate heterozygotes; but because some heterozygous CASQ2 variants are themselves arrhythmogenic, heterozygous relatives should be clinically screened rather than reassured. Counselling therefore differs substantively from the dominant RYR2 form curated in `RYR2_CPVT`.

Show evidence (2 references)

PMID:20301466 SUPPORT Human Clinical

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

GeneReviews recurrence risk for the recessive CASQ2 form, the basis of counselling.

PMID:20301466 SUPPORT Human Clinical

"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.

🔀

Differential Diagnoses

2

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

RYR2-related CPVT (CPVT1) Not Yet Curated MONDO:0011484

Overlapping Features 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

Autosomal dominant rather than autosomal recessive inheritance
Gain-of-function variant in the RyR2 release channel itself rather than loss of the luminal calcium buffer calsequestrin 2
Unaffected relatives are typically variant-negative rather than obligate heterozygous carriers
Some RYR2 variant carriers show extra-cardiac neurological features (epilepsy, neurodevelopmental delay) that are not a feature of CPVT2

Show evidence (1 reference)

PMID:20301466 SUPPORT Human Clinical

"RYR2-, CALM1-, CALM2-, CALM3-, and KCNJ2-related CPVT are inherited in an autosomal dominant manner"

Contrasts the dominant inheritance of RYR2-CPVT with the recessive inheritance of CASQ2-CPVT.

TRDN- and TECRL-related CPVT

Overlapping Features 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

Distinguished from CPVT2 only by molecular genetic testing
TECRL carriers often show QT prolongation, which is absent in CPVT2
TRDN loss can be accompanied by T-wave inversion, QT prolongation, and mild skeletal muscle weakness

Show evidence (1 reference)

PMID:20301466 SUPPORT Human Clinical

"TECRL- and TRDN-related CPVT are inherited in an autosomal recessive manner"

Identifies the other recessive CPVT genes that must be distinguished from CASQ2 by molecular testing.

{ }

Source YAML

click to show

name: CASQ2 CPVT
creation_date: '2026-07-31T00:00:00Z'
description: >-
  Catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is the
  CASQ2-related form of CPVT: a calcium-handling cardiac channelopathy in which
  loss of cardiac calsequestrin 2, the high-capacity luminal calcium buffer of
  the junctional sarcoplasmic reticulum (SR), destabilises SR calcium storage
  and RyR2 gating. Under beta-adrenergic stimulation (exercise or acute
  emotion), diastolic SR calcium leak produces cytosolic calcium overload,
  delayed afterdepolarizations (DADs) and triggered beats, manifesting as
  bidirectional or polymorphic ventricular tachycardia, syncope, and sudden
  cardiac death in a structurally normal heart with a normal resting ECG.
  CPVT2 is classically autosomal recessive (biallelic nonsense, frameshift,
  splice or missense CASQ2 variants; the founder p.D307H missense allele was
  mapped in consanguineous Israeli Bedouin families), but an international
  multicenter study has since shown that certain heterozygous missense variants
  that disrupt calsequestrin filament assembly can produce a CPVT phenotype
  through a dominant-negative mechanism.

  Scope and lump-vs-split: this entry is the gene-specific CPVT2 entity
  (MONDO:0012762, CASQ2). It is deliberately kept SEPARATE from the existing
  `RYR2_CPVT` entry, which is keyed to the CPVT umbrella term MONDO:0017990
  and models the dominant RYR2 gain-of-function form (CPVT1, about 95% of
  genetically confirmed CPVT) together with the disease-level gene spectrum.
  The split is justified because CPVT2 differs from CPVT1 in mode of
  inheritance (recessive vs dominant), in the molecular lesion (loss of a
  luminal calcium buffer vs gain of function in the release channel itself),
  and in genetic-counselling and cascade-screening implications, even though
  both converge on the same diastolic SR calcium leak. Cross-reference
  `RYR2_CPVT` for the umbrella CPVT view and the other CPVT genes (TRDN,
  TECRL, CALM1/2/3).
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:20301466
  title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
  tags:
  - GeneReviews
- reference: PMID:32693635
  title: "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia."
- reference: PMID:32115705
  title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
prevalence:
- population: International multicenter CASQ2-CPVT cohort
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence estimate exists for CPVT2 specifically. The
    largest assembled series to date is the international multicenter CASQ2-CPVT
    collaboration, which identified 112 individuals (36 CPVT probands plus 76
    genotype-positive family members) across contributing centres worldwide.
    Population prevalence of CPVT as a whole (all genes) is estimated at
    1:5,000 to 1:10,000 and is curated on the umbrella `RYR2_CPVT` entry;
    CASQ2 accounts for only a small minority of genetically confirmed CPVT.
  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: Quantifies the size of the largest assembled CASQ2-CPVT case series, the best available proxy for CPVT2 occurrence.
inheritance:
- name: Autosomal Recessive
  description: >-
    The classic and predominant mode of inheritance for CASQ2-related CPVT.
    Affected individuals carry biallelic (homozygous or compound heterozygous)
    loss-of-function CASQ2 variants; the founder p.D307H missense allele
    segregated fully in seven consanguineous Israeli Bedouin families, and
    nonsense/frameshift/splice alleles were subsequently reported in unrelated
    families. Clinical penetrance among biallelic carriers is near-complete.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance_percentage: '97.1'
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CASQ2-related CPVT is typically inherited in an autosomal recessive manner"
    explanation: GeneReviews states that CASQ2-related CPVT is typically autosomal recessive.
  - 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.
  - 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: Quantifies near-complete clinical penetrance among biallelic CASQ2 carriers, the source of the penetrance_percentage value.
- name: Autosomal Dominant
  description: >-
    An emerging, variant-specific dominant arm. A subset of heterozygous CASQ2
    missense variants localised to the dimer-dimer interface of the
    calsequestrin filament behave as dominant negatives and can manifest a CPVT
    phenotype; in the international multicenter cohort a third of clinically
    evaluated heterozygous relatives met diagnostic criteria for CPVT. This is
    a per-variant property rather than a property of CASQ2 as a whole, so
    CPVT2 should not be reclassified wholesale as a dominant disorder, but
    heterozygotes warrant clinical screening.
  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: Directly quantifies the CPVT phenotype among CASQ2 heterozygotes, supporting a dominant arm for some variants.
  - 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: States that dominance is a property of specific missense variants rather than of the gene as a whole.
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
has_subtypes:
- name: Biallelic CPVT2
  display_name: Biallelic (recessive) CASQ2-CPVT
  description: >-
    The classic recessive form. Homozygous or compound heterozygous
    loss-of-function CASQ2 variants abolish or severely reduce functional
    calsequestrin 2. Penetrance is near-complete, arrhythmic events begin in
    early childhood, and the median age of the first potentially fatal
    arrhythmic event is 7 years.
  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.
- name: Heterozygous CPVT2
  display_name: Heterozygous (dominant-negative) CASQ2-CPVT
  description: >-
    A milder, variant-specific dominant form caused by single heterozygous
    CASQ2 missense alleles that impair filament assembly. Arrhythmic risk is
    substantially lower than in biallelic carriers but is not negligible, so
    heterozygous relatives require clinical evaluation rather than reassurance.
  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: Establishes the heterozygous subtype as a real, clinically actionable phenotype.
pathophysiology:
- name: CASQ2 Loss of Function
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    The upstream lesion of CPVT2 is a pathogenic variant in CASQ2, which
    encodes cardiac calsequestrin 2, the major luminal calcium-binding protein
    of the junctional sarcoplasmic reticulum and part of the RyR2 calcium
    release complex. Nonsense, frameshift and splice alleles abolish the
    protein; missense alleles either destroy calcium binding (as for the
    founder p.D307H allele, which converts an aspartate to a histidine in a
    highly negatively charged calcium-binding domain) or impair the assembly of
    calsequestrin dimers into filaments.
  genes:
  - preferred_term: CASQ2
    term:
      id: hgnc:1513
      label: CASQ2
  molecular_functions:
  - preferred_term: calcium ion binding
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: DECREASED
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  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 CASQ2 protein serves as the major Ca(2+) reservoir within the SR of cardiac myocytes and is part of a protein complex that contains the ryanodine receptor"
    explanation: Establishes calsequestrin 2 as the SR luminal calcium reservoir within the RyR2 release complex, the protein lost in CPVT2.
  - 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: "converts a negatively charged aspartic acid into a positively charged histidine, in a highly negatively charged domain, and is likely to exert its deleterious effect by disrupting Ca(2+) binding"
    explanation: Describes the molecular consequence of the founder p.D307H missense allele on calcium binding.
  - reference: PMID:12386154
    reference_title: Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first nonsense mutations in the cardiac calsequestrin gene, CASQ2, in three CPVT families."
    explanation: Documents protein-truncating CASQ2 alleles as a distinct class of CPVT2 lesion.
  downstream:
  - target: Reduced Sarcoplasmic Reticulum Calcium Buffering
    description: >-
      Loss or functional impairment of calsequestrin 2 removes the
      high-capacity luminal calcium buffer of the junctional SR.
    causal_link_type: DIRECT
  - target: Destabilized RyR2 Closed State
    description: >-
      Because calsequestrin is anchored to RyR2 by triadin and junctin and
      contributes to luminal regulation of the release channel, its loss also
      destabilises RyR2 gating independently of the buffering deficit.
    causal_link_type: DIRECT
- name: Reduced Sarcoplasmic Reticulum Calcium Buffering
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    Without functional calsequestrin, the junctional SR loses its low-affinity,
    high-capacity calcium sink. Free intra-SR calcium therefore rises much
    faster during refilling, and the calcium-release refractory period is
    shortened. In vitro expression of CPVT2 mutants in myocytes reduces SR
    calcium-storing capacity, and Casq2-null hearts compensate anatomically
    (increased SR volume, loss of triadin-1 and junctin) yet remain functionally
    unstable.
  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.
  - 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.
  - 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.
  downstream:
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    description: >-
      Impaired luminal buffering allows free intra-SR calcium near RyR2 to rise
      rapidly during diastole, lowering the threshold for spontaneous release.
    causal_link_type: DIRECT
  - target: Sinoatrial Node Dysfunction
    description: >-
      The same calsequestrin deficit acts in sinoatrial pacemaker tissue,
      depressing sinus rate; this is the bradyarrhythmic branch of CPVT2.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- 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.
  downstream:
  - target: Diastolic Sarcoplasmic Reticulum Calcium Leak
    description: >-
      Hyperactive, poorly terminating RyR2 channels release calcium into the
      cytosol during diastole.
    causal_link_type: DIRECT
- name: Beta-Adrenergic Stimulation
  role: trigger
  biological_scale: ORGANISM
  description: >-
    Physical exertion or acute emotional stress produces a catecholamine surge
    that acts on the genetically primed, calsequestrin-deficient calcium-release
    apparatus. Beta-adrenergic signalling increases SR calcium loading and
    phosphorylation of the release machinery, converting a latent instability
    into overt diastolic leak. This node is the therapeutic target of
    beta-blockade, left cardiac sympathetic denervation, and exercise
    restriction.
  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: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: "Casq2-null mice are viable and display normal SR Ca2+ release and contractile function under basal conditions"
    explanation: Shows the calsequestrin-deficient phenotype is latent at baseline, establishing catecholaminergic stimulation as the required precipitant.
  - 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.
  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
- 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: >-
    The convergent central effector of CPVT2: spontaneous, premature calcium
    release from the sarcoplasmic reticulum during diastole. In
    calsequestrin-deficient myocytes exposed to catecholamines, spontaneous
    releases propagate as calcium waves ahead of the next paced beat. This is
    the identical central effector on which the RYR2, TRDN, TECRL and
    CALM1/2/3 forms of CPVT converge (see `RYR2_CPVT`), reached here from a
    luminal-buffering rather than a release-channel lesion.
  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.
  - 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.
  downstream:
  - target: Cytosolic Calcium Overload
    description: >-
      Unregulated diastolic release raises cytosolic calcium above the level
      that the SERCA pump and sarcolemmal extrusion can immediately handle.
    causal_link_type: DIRECT
- name: Cytosolic Calcium Overload
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    Excess cytosolic calcium during diastole is extruded by the sodium-calcium
    exchanger (NCX) operating in forward mode, which moves three sodium ions
    inward for each calcium ion removed. The resulting net inward (depolarizing)
    current is the electrogenic bridge between the calcium disturbance and the
    electrical disturbance.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: calcium ion transport
    term:
      id: GO:0006816
      label: calcium ion transport
    modifier: INCREASED
  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: "the 2 CASQ2 mutations identified in CPVT create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias"
    explanation: Links the CASQ2-driven intracellular calcium disturbance to arrhythmia facilitation.
  notes: >-
    The forward-mode sodium-calcium-exchanger step is textbook cardiac
    electrophysiology and is not separately evidenced with a CASQ2-specific
    citation; the CASQ2-specific evidence sits on the flanking nodes (calcium
    leak upstream, delayed afterdepolarizations downstream).
  downstream:
  - target: Delayed Afterdepolarizations and Triggered Activity
    description: >-
      The inward NCX current depolarizes the membrane after repolarization is
      complete, producing delayed afterdepolarizations.
    causal_link_type: DIRECT
- name: Delayed Afterdepolarizations and Triggered Activity
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    Delayed afterdepolarizations (DADs) that reach action-potential threshold
    generate premature, non-driven beats (triggered activity). In CPVT2 these
    have been demonstrated directly in CASQ2-mutant myocytes exposed to
    isoproterenol and in calsequestrin-null mouse myocytes. Note that this node
    is a DAD/triggered-activity node, not an early-afterdepolarization or
    repolarization-dispersion node: CPVT2 is a calcium-handling disease with a
    normal resting ECG and normal action-potential duration, so only the
    calcium-leak arm of the module substrate node applies.
  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.
  - 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
    snippet: "resulting in premature spontaneous SR Ca2+ releases and triggered beats"
    explanation: Isolated Casq2-null cardiomyocytes exposed to catecholamines show premature spontaneous calcium release and triggered beats, the cellular arrhythmia trigger.
  - 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: "In vivo, Casq2-null mice phenocopied the human arrhythmias"
    explanation: The in vivo counterpart of the myocyte result, confirming that the cellular triggered activity translates into the whole-animal arrhythmia phenotype.
  downstream:
  - target: Bidirectional and Polymorphic Ventricular Tachycardia
    description: >-
      Triggered beats arising at multiple ventricular sites organise into
      bidirectional and then polymorphic ventricular tachycardia.
    causal_link_type: DIRECT
  - target: Palpitations
    description: >-
      Premature, non-driven beats are perceived by the patient as an awareness
      of irregular or rapid heart action, typically the mildest symptomatic
      expression of triggered activity.
    causal_link_type: DIRECT
  - target: Atrial Triggered Activity
    description: >-
      The same calcium-triggered mechanism operates in atrial myocardium,
      producing atrial triggered beats.
    causal_link_type: DIRECT
- name: Sinoatrial Node Dysfunction
  role: amplifier
  biological_scale: TISSUE
  description: >-
    Calsequestrin deficiency also depresses sinoatrial pacemaker function,
    producing low resting sinus rates. This is not merely a coincidental
    finding: long diastolic intervals give spontaneous SR calcium release time
    to occur before the next beat empties the store, so sinus node dysfunction
    contributes mechanistically to ventricular arrhythmia risk. Selective
    re-expression of Casq2 in the sinoatrial node of adult Casq2-knockout mice
    accelerated sinus rates and prevented CPVT.
  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:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we were able to re-express Casq2 in the SA node of adult Casq2 KO mice, which accelerated sinus heart rates and prevented CPVT"
    explanation: Tissue-targeted rescue in the Casq2-knockout mouse shows the sinoatrial node is causally involved in CPVT2 arrhythmogenesis.
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A likely explanation is that low sinus rates prolong the diastolic interval, allowing the spontaneous SR calcium release to occur before CICR during the next action potential can empty the SR and reset the SR calcium clock."
    explanation: States the proposed mechanism linking bradycardia to increased spontaneous calcium release.
  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: Delayed Afterdepolarizations and Triggered Activity
    description: >-
      Slow sinus rates lengthen diastole, giving spontaneous calcium release
      more opportunity to reach the DAD threshold.
    causal_link_type: DIRECT
  - target: Bradycardia
    description: Depressed sinoatrial automaticity produces low resting sinus rates.
    causal_link_type: DIRECT
- name: Atrial Triggered Activity
  role: effector
  biological_scale: TISSUE
  description: >-
    Calcium-triggered activity is not confined to the ventricle. Optical
    mapping of calsequestrin-null mouse atria showed spontaneous calcium
    release events driving atrial DADs and triggered beats, providing a
    mechanistic account of the atrial tachyarrhythmias that frequently precede
    or accompany ventricular tachycardia in CPVT. Human CASQ2-specific
    confirmation of this atrial arm is not yet available, so it is modelled
    here as a mechanism branch rather than asserted as a CPVT2 clinical
    phenotype.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Based on optical mapping data from a calsequestrin null mouse model, the atrial tachyarrhythmias are driven by spontaneous calcium release events in atrial myocardium that cause DADs and atrial triggered beats"
    explanation: Mouse optical-mapping evidence for a calsequestrin-dependent atrial triggered-activity arm.
- name: Bidirectional and Polymorphic Ventricular Tachycardia
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  role: effector
  biological_scale: ORGANISM
  description: >-
    Triggered beats organise into the hallmark arrhythmia of CPVT: fast
    ventricular tachycardia with a beat-to-beat alternating QRS axis
    (bidirectional VT) that may become polymorphic and degenerate to
    ventricular fibrillation. Onset is reproducibly provoked by exercise or
    emotion and the heart is structurally normal.
  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: HUMAN_CLINICAL
    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.
  - 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.
  downstream:
  - target: Effort-Induced Polymorphic Ventricular Tachycardia
    description: The arrhythmia is reproducibly provoked by exertion or emotional stress.
    causal_link_type: DIRECT
  - target: Bidirectional Ventricular Tachycardia
    description: Alternating-axis QRS complexes during the tachycardia.
    causal_link_type: DIRECT
  - target: Ventricular Fibrillation
    description: Polymorphic ventricular tachycardia may degenerate into ventricular fibrillation.
    causal_link_type: DIRECT
  - target: Syncope and Sudden Cardiac Death
    description: >-
      Sustained ventricular tachyarrhythmia abolishes effective cardiac output.
    causal_link_type: DIRECT
- name: Syncope and Sudden Cardiac Death
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  role: outcome
  biological_scale: ORGANISM
  description: >-
    Loss of effective cardiac output during the arrhythmia causes transient
    cerebral hypoperfusion (syncope, sometimes with convulsive features that
    are misdiagnosed as epilepsy) and, if the rhythm does not self-terminate,
    cardiac arrest and sudden death. In the international CASQ2 cohort a
    potentially fatal arrhythmic event occurred at a median age of 7 years in
    biallelic carriers, and homozygote/compound-heterozygote status conferred a
    markedly increased hazard relative to heterozygosity.
  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.
  - 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.
  downstream:
  - target: Syncope
    description: Transient cerebral hypoperfusion during the arrhythmia causes loss of consciousness.
    causal_link_type: DIRECT
  - target: Convulsive Syncope
    description: >-
      Prolonged cerebral hypoperfusion during an arrhythmic episode can produce
      convulsive movements that are frequently misattributed to a primary
      seizure disorder.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cerebral hypoperfusion
  - target: Cardiac Arrest
    description: A non-terminating ventricular arrhythmia produces cardiac arrest.
    causal_link_type: DIRECT
  - target: Sudden Cardiac Death
    description: Unresuscitated cardiac arrest results in sudden cardiac death.
    causal_link_type: DIRECT
phenotypes:
- category: Cardiovascular
  name: Effort-Induced Polymorphic Ventricular Tachycardia
  description: >-
    The defining phenotype of CPVT2: polymorphic ventricular tachycardia
    reproducibly provoked by exercise or acute emotion in a structurally
    normal heart with a normal resting ECG.
  phenotype_term:
    preferred_term: Effort-induced polymorphic ventricular tachycardia
    term:
      id: HP:0004758
      label: Effort-induced polymorphic ventricular tachycardia
    onset:
      onset_category: JUVENILE
      mean_age_years: 7.0
      notes: >-
        HP:0003621 Juvenile onset spans 5-15 years, which is the band both cited
        figures fall in: the CASQ2-specific cohort reports a median age of onset
        of 7 years, and GeneReviews gives a mean of seven to 12 years. The value
        in mean_age_years is the cohort MEDIAN (7 years, PMID:32693635); the slot
        has no median field, so it is recorded here and disambiguated in this
        note, following the pattern in PARK7-Related_Early-Onset_Parkinson_Disease.
  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.
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
  - 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.
- 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: HUMAN_CLINICAL
    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.
- category: Cardiovascular
  name: Syncope
  description: >-
    Transient loss of consciousness during exercise or acute emotion, usually
    the presenting symptom. In the CASQ2 nonsense-mutation families, homozygous
    carriers had syncope before age 7 years while a heterozygous carrier had
    onset from age 11 years, illustrating the genotype-severity gradient.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
    onset:
      onset_category: CHILDHOOD
      notes: >-
        Deliberately CHILDHOOD (1-5 years) rather than JUVENILE, unlike the
        ventricular-tachycardia node above. The syncope evidence is split by
        genotype: homozygotes had syncope "before the age of 7 years" while the
        heterozygote's began "from the age of 11 years". CHILDHOOD is retained
        because it reflects the earlier biallelic presentation, which is the
        severe end this entry is anchored on; the heterozygous onset is later and
        is described in the phenotype text rather than forced into one band.
  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.
  - 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.
- category: Cardiovascular
  name: Cardiac Arrest
  description: >-
    Abrupt cessation of effective cardiac output from a sustained ventricular
    arrhythmia. Aborted cardiac arrest is one component of the composite
    arrhythmic endpoint that affected roughly three-quarters of biallelic CASQ2
    carriers in the international cohort.
  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.
  - 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.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Unexpected death from a ventricular arrhythmia that does not terminate;
    it may be the first manifestation of CPVT2 and is the endpoint that
    motivates cascade screening of relatives.
  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.
  - 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.
- 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: HUMAN_CLINICAL
    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.
- category: Cardiovascular
  name: Bradycardia
  description: >-
    Low resting sinus rate from sinoatrial node dysfunction. In CPVT this is
    not an incidental finding but a mechanistic contributor, because long
    diastolic intervals permit spontaneous SR calcium release.
  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.
  notes: >-
    The cited review statement covers CPVT as a whole rather than CASQ2-CPVT
    specifically; the calsequestrin-specific mechanistic work behind it (the
    sinoatrial Casq2 re-expression rescue) is mouse data, curated on the
    Sinoatrial Node Dysfunction pathophysiology node.
- 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.
  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.
- category: Neurological
  name: Convulsive Syncope
  description: >-
    Convulsive movements during an arrhythmic syncopal episode. These are
    secondary to cerebral hypoperfusion rather than a primary epileptic
    disorder, but are a recognised cause of misdiagnosis as epilepsy and of
    delayed cardiac evaluation in CPVT.
  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: Seizure-like episodes are part of the presenting spectrum described in the CASQ2 mapping study.
  notes: >-
    Deliberately left unbound to an HPO term. HPO has no term for convulsive
    (anoxic) syncope: the nearest candidate, HP:0001250 (Seizure), denotes
    abnormal excessive or synchronous neuronal activity, whereas the mechanism
    here is arrhythmic cerebral hypoperfusion with a structurally and
    electrically normal brain. Binding HP:0001250 would over-claim a primary
    epileptic phenotype and would wrongly conflate this with the genuine
    neuronal phenotype reported in some RYR2 variant carriers in `RYR2_CPVT`,
    so no term is asserted rather than a misleading one.
genetic:
- name: CASQ2 biallelic loss-of-function variants
  association: Causative
  subtype: Biallelic CPVT2
  features: >-
    Homozygous or compound heterozygous loss-of-function variants in CASQ2,
    encoding cardiac calsequestrin 2. The originally reported allele is the
    founder p.D307H missense variant, which segregated fully in seven
    consanguineous Israeli Bedouin families; protein-truncating alleles
    (nonsense p.R33X, a 532+1 G>A splice variant, and a 62delA frameshift)
    were subsequently described, as were compound heterozygous combinations of
    a truncating and a missense allele.
  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.
  - 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.
  - 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.
  - 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.
- name: CASQ2 heterozygous dominant-negative missense variants
  association: Causative
  subtype: Heterozygous CPVT2
  features: >-
    A subset of heterozygous CASQ2 missense variants produces a CPVT phenotype.
    Structural mapping onto the calsequestrin filament localised several of
    these to an electronegative pocket required for back-to-back binding of
    calsequestrin dimers, and turbidity assays showed filamentation defects,
    supporting a dominant-negative rather than haploinsufficiency mechanism.
    The recessive p.R33Q allele, by contrast, failed to dimerize at all.
  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: IN_VITRO
    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: Biochemical characterisation distinguishing the dominant-negative filamentation defect from complete loss of dimerization.
  - 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: COMPUTATIONAL
    snippet: "Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers."
    explanation: Structural mapping onto the calsequestrin filament rationalises the dominant-negative mechanism.
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For autosomal-dominant CPVT2, the current hypothesis is that calsequestrin mutations affect the ability for polymerization to occur."
    explanation: Independent review statement of the polymerization-defect hypothesis for dominant CPVT2.
diagnosis:
- name: Exercise stress testing
  description: >-
    Graded treadmill or bicycle exercise testing is the key provocative
    diagnostic test for CPVT2. Ventricular ectopy appears at a reproducible
    heart-rate threshold and progresses to bidirectional and then polymorphic
    ventricular tachycardia as workload increases. It is also the principal
    tool for evaluating at-risk relatives when the familial variant is not
    known, and for titrating therapy.
  results: >-
    Reproducible, rate-dependent ventricular ectopy progressing to
    bidirectional or polymorphic ventricular tachycardia in a structurally
    normal heart supports the diagnosis; a negative test does not exclude
    CPVT2 in a genotype-positive individual.
  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: HUMAN_CLINICAL
    snippet: "all first-degree relatives of an affected individual should be evaluated with resting EKG, Holter monitoring, echocardiography"
    explanation: GeneReviews sets out the evaluation of at-risk relatives, of which exercise stress testing is the central component.
  - 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.
- name: Molecular genetic testing of CASQ2
  description: >-
    Identification of biallelic pathogenic CASQ2 variants establishes the
    diagnosis of CPVT2 and enables cascade testing. Because a subset of
    heterozygous CASQ2 variants is itself arrhythmogenic, heterozygous
    relatives identified by cascade testing require clinical evaluation rather
    than reassurance.
  results: >-
    Biallelic pathogenic CASQ2 variants confirm CPVT2; a single heterozygous
    pathogenic CASQ2 variant is reportable and warrants clinical screening.
  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: HUMAN_CLINICAL
    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 as diagnostic for CPVT.
  - 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.
- name: Resting ECG and structural cardiac assessment
  description: >-
    The resting 12-lead ECG and echocardiogram are normal in CPVT2 and serve
    to exclude structural heart disease and other channelopathies (notably
    long QT syndrome, in which the resting QTc is prolonged). A normal resting
    study is therefore part of the positive diagnostic criteria rather than
    evidence against the diagnosis.
  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: HUMAN_CLINICAL
    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.
- 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: HUMAN_CLINICAL
    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.
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
treatments:
- name: Nonselective Beta-Blocker Therapy (Nadolol)
  description: >-
    First-line therapy for all clinically or genetically diagnosed CPVT2.
    Nonselective beta-blockers, and nadolol in particular, blunt the
    catecholamine surge that precipitates diastolic calcium leak. Beta-blockade
    is indicated even in genotype-positive individuals with a negative exercise
    stress test, because sudden death can be the first manifestation.
  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: HUMAN_CLINICAL
    snippet: "nadolol is the most effective beta blocker in CPVT"
    explanation: GeneReviews identifies nadolol as the most effective beta blocker in CPVT.
  - 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.
  notes: >-
    The nadolol comparative study enrolled a mixed-genotype CPVT cohort rather
    than a CASQ2-only cohort; no CASQ2-restricted randomised comparison exists.
- name: Flecainide
  description: >-
    Add-on antiarrhythmic for breakthrough arrhythmia on maximally tolerated
    beta-blockade, and for primary prevention when beta-blockers alone do not
    suppress exercise-induced ectopy. Flecainide acts on the CPVT2 mechanism
    directly: it blocks RyR2 in the open state, reducing calcium spark mass and
    the probability that sparks propagate into arrhythmogenic calcium waves.
    Notably, the defining mechanistic experiments were performed in
    calsequestrin-null (Casq2-/-) myocytes, making this evidence directly
    relevant to CPVT2 rather than borrowed from RYR2-CPVT.
  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: >-
      Open-state block of RyR2 reduces calcium spark mass and suppresses the
      propagating diastolic calcium waves that are the central effector of
      CPVT2.
  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.
  - 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.
  - 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: MODEL_ORGANISM
    snippet: "the drug flecainide inhibits RyR2 channels and prevents CPVT in mice and humans"
    explanation: Summarises the in vivo antiarrhythmic efficacy of flecainide that the cellular experiments in this paper set out to explain.
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
- name: Left Cardiac Sympathetic Denervation
  description: >-
    Surgical removal of the left stellate ganglion and upper thoracic
    sympathetic ganglia to reduce sympathetic drive to the heart. Reserved for
    breakthrough arrhythmia despite optimal beta-blocker and flecainide
    therapy, or for patients intolerant of pharmacotherapy. It is an adjunct
    rather than a cure: a significant residual arrhythmic burden persists.
  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: HUMAN_CLINICAL
    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.
- name: Implantable Cardioverter-Defibrillator Placement
  description: >-
    Device therapy for patients whose arrhythmias are not adequately controlled
    by drug therapy, and for survivors of cardiac arrest. Programming must be
    conservative: an inappropriate or painful shock triggers its own
    catecholamine surge and can precipitate an arrhythmic storm in CPVT.
  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: HUMAN_CLINICAL
    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.
- name: Exercise Restriction and Trigger Avoidance
  description: >-
    Avoidance of competitive sports and strenuous exercise, and of digitalis,
    is a cornerstone of CPVT management because these are the precipitants of
    the adrenergic surge that unmasks the arrhythmia. Permitted exercise
    intensity should be individualised on the basis of exercise stress testing.
  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:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Competitive sports and other strenuous exercise; use of digitalis."
    explanation: GeneReviews lists competitive sports, strenuous exercise, and digitalis as agents and circumstances to avoid in CPVT.
- name: Genetic Counseling and Cascade Family Screening
  description: >-
    Because CPVT2 is usually recessive, sibling recurrence risk is 25% and both
    parents are obligate heterozygotes; but because some heterozygous CASQ2
    variants are themselves arrhythmogenic, heterozygous relatives should be
    clinically screened rather than reassured. Counselling therefore differs
    substantively from the dominant RYR2 form curated in `RYR2_CPVT`.
  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: HUMAN_CLINICAL
    snippet: "each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected"
    explanation: GeneReviews recurrence risk for the recessive CASQ2 form, the basis of counselling.
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
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:
  - Autosomal dominant rather than autosomal recessive inheritance
  - Gain-of-function variant in the RyR2 release channel itself rather than loss
    of the luminal calcium buffer calsequestrin 2
  - Unaffected relatives are typically variant-negative rather than obligate
    heterozygous carriers
  - Some RYR2 variant carriers show extra-cardiac neurological features
    (epilepsy, neurodevelopmental delay) that are not a feature of CPVT2
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
- 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:
  - Distinguished from CPVT2 only by molecular genetic testing
  - TECRL carriers often show QT prolongation, which is absent in CPVT2
  - TRDN loss can be accompanied by T-wave inversion, QT prolongation, and mild
    skeletal muscle weakness
  evidence:
  - reference: PMID:20301466
    reference_title: "Catecholaminergic Polymorphic Ventricular Tachycardia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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.
discussions:
- discussion_id: gap_intra_sr_calcium_kinetics_casq2
  prompt: >-
    Does loss of calsequestrin actually accelerate the rise of free intra-SR
    calcium near RyR2, as the accepted buffering model of CPVT2 predicts?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Sarcoplasmic Reticulum Calcium Buffering
  rationale: >-
    The buffering model is the standard mechanistic account of CPVT2 and the
    justification for treating CASQ2 loss as functionally equivalent to a
    RyR2 gain-of-function lesion, but the key predicted intermediate has never
    been measured directly. Without it, the alternative account (that
    calsequestrin loss acts principally by destabilising RyR2 regulation
    through the triadin/junctin anchor) cannot be excluded, and the two
    predict different responses to therapies that modulate SR load.
  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:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although intra-SR calcium kinetics have not yet been measured experimentally in calsequestrin CPVT models"
    explanation: The review states explicitly that the predicted intermediate of the buffering model has not been measured.
- discussion_id: mismatch_purkinje_casq2_tissue_origin
  prompt: >-
    Does the failure of Purkinje-restricted calsequestrin deletion to produce
    CPVT in mice mean that human CASQ2-CPVT arrhythmia originates in the
    working ventricular myocardium rather than the conduction system?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Delayed Afterdepolarizations and Triggered Activity
  rationale: >-
    Clinical mapping in CPVT patients localises most ventricular ectopy to the
    outflow tracts, and the bidirectional-VT pattern has classically been
    attributed to alternating activation of the His-Purkinje system. Yet
    tissue-targeted deletion of calsequestrin in the murine Purkinje network,
    where the molecular lesion of CPVT2 is exactly reproduced, failed to
    generate the phenotype. This is a model-fidelity question rather than a
    simple absence of evidence: the murine conduction system differs in size,
    source-sink relationships, and Purkinje distribution from the human heart,
    so a negative mouse result may not transfer. Resolving it matters because
    ablation strategies targeting Purkinje triggers presuppose the conduction
    system is the source.
  proposed_experiments:
  - experiment_id: exp_casq2_purkinje_rescue_sufficiency
    name: Purkinje-restricted calsequestrin rescue in the Casq2-null mouse
    description: >-
      Perform tissue-targeted calsequestrin re-expression (rather than
      deletion) restricted to the murine Purkinje network in an otherwise
      Casq2-null background, testing sufficiency of the conduction system as
      well as necessity.
    experiment_type:
      preferred_term: conditional tissue-restricted gene rescue experiment
  - experiment_id: exp_casq2_human_endocardial_mapping
    name: High-density endocardial mapping in genotyped CASQ2-CPVT patients
    description: >-
      Map arrhythmia origin at high density in genotype-confirmed human
      CASQ2-CPVT patients during provoked ectopy, distinguishing Purkinje from
      working-myocardial trigger sites.
    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:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the deletion of calsequestrin in the Purkinje network did not produce a CPVT phenotype"
    explanation: The negative tissue-targeted mouse result that creates the mismatch with the human mapping data.
  - reference: PMID:32115705
    reference_title: Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More research with tissue-targeted genetic models such as those in Fig. 5 is needed to determine the tissue origin of CPVT"
    explanation: The review states the tissue origin of CPVT remains unresolved.
- 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#CASQ2 Loss of Function
  rationale: >-
    CPVT2 was defined for two decades as a recessive disease, and heterozygous
    relatives were routinely reassured. The demonstration that a third of
    clinically evaluated CASQ2 heterozygotes met CPVT criteria, and that
    specific missense alleles disrupt dimer-dimer filament contacts, inverts
    that counselling posture. But the population frequency of dominant-acting
    alleles is unknown, no in vivo model of the dominant-negative mechanism has
    been reported, and it is unclear which biochemical assay best predicts
    which heterozygous variants confer risk. This directly affects variant
    interpretation and cascade-screening policy.
  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: >-
      Generate heterozygous knock-in mouse and human iPSC-cardiomyocyte models
      of filament-interface CASQ2 missense variants to test the
      dominant-negative mechanism in vivo and in a human cellular background.
    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.
notes: >-
  Scope and relationship to `RYR2_CPVT`. This entry is the gene-specific CPVT2
  (CASQ2, MONDO:0012762) entity. `RYR2_CPVT` is keyed to the CPVT umbrella term
  MONDO:0017990 and carries the disease-level gene spectrum, including a CASQ2
  trigger node and a CASQ2 genetic row. That overlap is deliberate: the
  umbrella entry needs the full gene spectrum to be coherent, while CPVT2
  warrants its own entry because inheritance, molecular lesion, natural
  history, and counselling all differ. The two entries should be kept
  consistent; the CASQ2-specific mechanism, subtypes, and evidence are curated
  here, and general CPVT epidemiology remains on the umbrella entry.

  Module conformance. Five nodes declare conformance to
  `cardiac_ion_channel_repolarization`. The module is framed around
  repolarization and action-potential duration, which is NOT how CPVT2 works:
  the resting ECG and action-potential duration are normal. Conformance was
  therefore claimed only where the module node genuinely covers the CPVT2
  physiology - the module trigger node explicitly admits calcium-handling
  variants, its central-effector node explicitly covers ryanodine-receptor
  calcium leak, and its substrate node explicitly covers delayed
  afterdepolarizations. No conformance is claimed for any repolarization,
  APD-dispersion, or early-afterdepolarization aspect of the module, and the
  module Sinoatrial Node Pacemaker Dysfunction node was deliberately NOT
  claimed by the Sinoatrial Node Dysfunction node here, because that module
  node models loss-of-function pacemaker-current channelopathy (HCN4, SCN5A),
  a different mechanism from the calsequestrin-dependent sinoatrial depression
  seen in CPVT2.

  Evidence boundaries. Care was taken not to let RYR2-CPVT literature stand in
  for CASQ2 evidence. Where a cited source speaks about CPVT in general rather
  than CPVT2 specifically (the GeneReviews management statements, the nadolol
  comparative study, and the review statement on bradycardia), that is stated
  in the relevant notes or explanation. The flecainide mechanistic evidence is
  CASQ2-specific because the defining experiments used Casq2-null myocytes.

  Not curated, and why. (1) No ClinGen gene-disease validity assertion is
  cited: the pinned ClinGen gene_validity.csv snapshot failed its manifest
  checksum on refresh during this curation session, and hand-editing the
  reference cache is prohibited. (2) No Orphanet record is cited because no
  ORPHA cache file for CPVT exists in this repository. (3) No `frequency:` band
  is asserted on any phenotype: the available CASQ2-specific numbers (97.1%
  penetrance, 76.5% arrhythmic events, 33.3% of heterozygotes meeting criteria)
  attach to penetrance and to a composite endpoint rather than to any single
  HPO phenotype, and per the frequency-evidence guidelines it is better to omit
  the band than to back-derive it. (4) Atrial fibrillation is modelled as a
  mechanism branch (`Atrial Triggered Activity`) rather than a CPVT2 phenotype,
  because the only calsequestrin-specific evidence is mouse optical mapping.
  (5) No clinical trials are listed; there are no CASQ2-restricted
  interventional trials.

📚

References & Deep Research

References

3

PMID:20301466

Catecholaminergic Polymorphic Ventricular Tachycardia.

No top-level findings curated for this source.

PMID:32693635

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

No top-level findings curated for this source.

PMID:32115705

Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

CASQ2-Related Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT2): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 39 citations 2026-07-31T17:16:57.113982

CASQ2-Related Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT2): Comprehensive Research Report

1. Disease Information

Overview. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited primary electrical (arrhythmogenic) disorder of the structurally normal heart, characterized by adrenergically triggered polymorphic or bidirectional ventricular tachycardia (VT) that arises during exercise or acute emotional stress and can degenerate into ventricular fibrillation and sudden cardiac death (SCD). The CASQ2-related, autosomal recessive form (CPVT2) is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in CASQ2, encoding cardiac calsequestrin-2, the principal Ca²⁺-buffering protein of the cardiac sarcoplasmic reticulum (SR) (GeneReviews, NBK1289; OMIM #611938).

Key identifiers: - OMIM (phenotype): #611938 — Ventricular Tachycardia, Catecholaminergic Polymorphic, 2 (CPVT2) - OMIM (gene): 114251 — CALSEQUESTRIN 2; CASQ2 - HGNC: 1513 (CASQ2); NCBI Gene ID: 845 - UniProt: O14958 (human CASQ2) - Orphanet: ORPHA3286 (parent term "Catecholaminergic polymorphic ventricular tachycardia," covering both CPVT1/RYR2 and CPVT2/CASQ2) - ICD-10-CM: I47.2 (Ventricular tachycardia), more granularly I47.29 (Other ventricular tachycardia) - MeSH: C536334 - Disease Ontology: DOID:0060676 - Chromosomal locus:* 1p13.1 (CASQ2 gene) (Lahat et al. 2001)

Synonyms: CPVT2; Familial polymorphic ventricular tachycardia, catecholamine-induced, autosomal recessive; Calsequestrin-associated CPVT; Stress-induced polymorphic ventricular tachycardia (CASQ2-related); VTSCA (older nomenclature).

Evidence base: Information is derived primarily from aggregated disease-level resources — case series, multicenter cohort/registry studies (notably the International CPVT collaboration), founder-population family studies (Bedouin, Saudi, other consanguineous kindreds), and functional/model-organism studies — rather than large-scale individual-level EHR mining, reflecting CPVT2's rarity.

2. Etiology

Disease causal factor — genetic, monogenic. CPVT2 is caused by loss-of-function or hypomorphic biallelic variants in CASQ2 (1p13), inherited in an autosomal recessive pattern; it is not caused by environmental or infectious factors, though environmental/physiologic triggers (see below) precipitate the arrhythmic events themselves. CASQ2 mutations account for roughly 2–5% of genotyped CPVT cases overall (some series cite 1–2%), versus ~50–65% for dominant RYR2 variants (search synthesis; Clinical Gate review).

Genetic risk factors: - Causal (biallelic) variants — homozygous or compound heterozygous missense, nonsense, frameshift, and splice-site CASQ2 variants. The prototype is the Bedouin founder mutation D307H (c.1038G>C, exon 9), identified by Lahat et al. in 2001 in 7 consanguineous Bedouin kindreds in northern Israel with a history of unexplained childhood sudden death (9 deaths, 7 during vigorous exercise, 2 during excitement) (PMID cited via OMIM 114251; GeneTests founder-variant review). The mutation converts a conserved, negatively charged Asp to a positively charged His in an acidic Ca²⁺-binding domain and was absent in 350 population controls, confirming founder status. - Heterozygous "carrier" variants with reduced/variable penetrance — a subset of missense variants can act in a dominant-negative fashion. In the International Multicenter CASQ2-CPVT study (Circulation, 2020), of 66 heterozygous family members, 17/51 clinically evaluated (33.3%) met CPVT diagnostic criteria, with penetrance dependent on variant location within the CASQ2 filament structure (Roston et al. 2020). Homozygotes/compound heterozygotes had a 3.2-fold increased hazard of cardiac events versus heterozygotes, and a 38.8-fold increased hazard versus genotype-negative relatives. - Population variant burden vs. disease prevalence discordance — gnomAD collective frequency of presumed pathogenic CASQ2 variants (0.0997%) is ~398-fold higher than expected CPVT2 disease prevalence, implying incomplete penetrance and/or recessive-only pathogenicity for many variants (Roston et al. 2020). - Modifier/other CPVT genes (genetic heterogeneity, not CASQ2 modifiers per se): RYR2 (CPVT1, dominant, most common), CALM1/CALM2/CALM3 (CPVT4, calmodulinopathy), TRDN/triadin (CPVT5, recessive, ± skeletal myopathy), TECRL (mixed CPVT/LQT phenotype). A standard clinical CPVT NGS panel covers these ~6–7 genes, which together explain up to ~75% of clinically diagnosed CPVT (remainder genetically elusive) (Mayo Clinic Labs CPVTG panel).

Environmental/physiologic risk factors (triggers, not causes): vigorous physical exertion, competitive sports, acute emotional stress/excitement, sympathomimetic exposure (e.g., epinephrine, some anesthetics), fever (less prominent than in some other channelopathies). Age and pubertal growth are relevant because β-blocker dosing must scale with rapidly changing body weight.

Protective factors: No genetic protective alleles are established. Environmentally, adherence to non-selective β-blockade and avoidance of competitive/high-intensity exercise are the dominant modifiable protective factors; there is no dietary or lifestyle protective factor analogous to other cardiac conditions.

Gene-environment interaction: The core mechanism is a gene-environment (genotype × catecholamine) interaction — the CASQ2 lesion by itself is often clinically silent at rest; sympathetic activation (via β-adrenergic receptor stimulation → PKA-mediated phosphorylation of Ca²⁺-handling proteins) is required to unmask spontaneous SR Ca²⁺ release and triggered arrhythmia. This is the mechanistic basis for exercise stress testing as the diagnostic gold standard.

3. Phenotypes

CPVT2 has a narrow, cardiology-dominant phenotype spectrum (a "single-mechanism" arrhythmia syndrome), in contrast to multisystem genetic diseases.

Phenotype	Type	Onset	Severity/course	Frequency	Suggested HPO term
Syncope (exercise/emotion-induced)	Symptom	Mean 7–12 y (range into 4th decade)	Episodic, recurrent without treatment	Up to 80% of patients before diagnosis	HP:0001279 Syncope
Bidirectional ventricular tachycardia	Clinical sign (ECG)	Provoked by exercise/adrenergic stress	Episodic; hallmark finding	Characteristic but not universal	HP:0004308 Ventricular tachycardia (closest available; no dedicated bidirectional-VT HPO term)
Polymorphic ventricular tachycardia	Clinical sign (ECG)	Provoked by exercise/emotion	Episodic, can degenerate to VF	Common	HP:0004308 Ventricular tachycardia
Ventricular fibrillation / cardiac arrest	Clinical sign	Any age; may be first presentation	Life-threatening	~30% experience ≥1 cardiac arrest	HP:0001695 Ventricular fibrillation
Sudden cardiac death	Outcome	Childhood–adulthood	Can be the presenting/only event	Up to 30–50% by age 20–35 if untreated	HP:0001645 Sudden death
Resting sinus bradycardia	Clinical sign / lab (ECG)	Present at baseline	Stable	Frequently reported in CASQ2-linked patients	HP:0001662 Sinus bradycardia
Palpitations	Symptom	Exercise-associated	Episodic	Variable	HP:0001962 Palpitations
Seizure-like episodes (misdiagnosed)	Symptom (secondary to cerebral hypoperfusion during arrhythmia)	Any	Episodic	Reported (case reports of CPVT presenting as tonic-clonic seizure)	HP:0001250 Seizure
Structurally normal heart	Negative finding (diagnostic criterion)	—	—	By definition	—
Normal resting 12-lead ECG (baseline)	Negative finding	—	—	By definition	—

Phenotype characteristics: - Age of onset: mean first syncopal episode age 7–12 years; can present as late as the 4th decade of life (GeneReviews). - Severity/progression: episodic and stress-triggered rather than progressive/degenerative; however, cumulative arrhythmic burden and risk of SCD increase with age and missed diagnosis. CASQ2-linked (recessive) disease tends to have earlier onset, more severe presentation, and higher untreated mortality than RYR2-CPVT (Josephs et al. 2017, Mol Genet Genomic Med; International Multicenter study). - Course pattern: episodic/paroxysmal (event-driven by exertion/emotion), not relapsing-remitting or chronic-progressive in the classic sense; between events patients are typically asymptomatic. - Long-term structural change: in murine CASQ2-mutant models, cardiac morphology is normal in young animals, but by ~35 weeks some mice develop cardiac hypertrophy and LV dysfunction (model-organism evidence; translational significance in humans not firmly established) (Circulation 2014, di Barletta model discussion). - Quality of life impact: activity restriction (avoidance of competitive sports), psychological burden of ICD shocks/anxiety around exertion, and pediatric-family burden of frequent surveillance visits (every 6–12 months, more often around puberty due to rapid weight-based dose titration) are the dominant QoL domains reported in the clinical literature; no CPVT-specific validated QoL instrument was identified in this search — generic pediatric cardiology QoL literature (not disease-specific) would need separate sourcing.

4. Genetic/Molecular Information

Causal gene: CASQ2 (calsequestrin 2), HGNC:1513, NCBI Gene 845, chromosome 1p13.1; OMIM gene *114251.

Variant classes reported (ClinVar/literature): - Missense — e.g., D307H (Bedouin founder), R33Q, D310N, I161V, and numerous others; several missense variants (especially those disrupting the CASQ2 filament/dimer interface) can behave as dominant-negative in heterozygotes, producing a milder dominant phenotype in carriers (Roston 2020; Bal-Erilmaz functional analysis PMC7666291). - Splice-site — e.g., functionally characterized splicing mutations altering CASQ2 mRNA processing, with implications for genetic counseling. - Frameshift/truncating/null — e.g., G112+5X-type mutations used widely in iPSC and computational disease models; truncating variants collectively reach ~0.049% frequency in gnomAD. - Allele frequency (gnomAD): individual pathogenic CASQ2 variants range from novel (absent) up to ~0.06424% (p.D310N); the aggregate frequency of presumptively pathogenic variants (0.0997%) substantially exceeds expected disease prevalence, implying incomplete penetrance for many alleles (Roston 2020). - Somatic vs. germline: exclusively germline; no somatic mosaicism literature identified in this search. - Functional consequence: predominantly loss-of-function / reduced CASQ2 protein expression (severe reduction or complete loss), with the pathogenic cascade proceeding through compensatory upregulation of calreticulin and RyR2 (below). Some dominant missense alleles act via dominant-negative disruption of CASQ2 polymer/filament assembly rather than simple haploinsufficiency (di Barletta/Knollmann JCI 2006).

Modifier genes: No formally validated CASQ2-CPVT-specific modifier genes were identified; genetic background/other Ca²⁺-handling gene variants (RYR2, TRDN, CALM1-3) are relevant to the broader CPVT gene family rather than as CASQ2 modifiers per se.

Epigenetic information: No CPVT2-specific epigenetic (DNA methylation/histone) studies were surfaced in this search; not established as disease-relevant currently.

Chromosomal abnormalities: CPVT2 is a point-mutation/small-indel monogenic disease; no recurrent large chromosomal rearrangements are described for CASQ2.

Protein structure/function (UniProt O14958): CASQ2 is a high-capacity, low-affinity Ca²⁺-binding protein of the junctional SR, binding up to ~60 Ca²⁺ ions via clusters of acidic surface residues, especially at subunit interfaces. It is largely monomeric at low luminal [Ca²⁺] and polymerizes into higher-order oligomers/filaments as Ca²⁺ rises, modulating its interaction with the RyR2 channel complex (via triadin/junctin) (GeneCards; Wikipedia Calsequestrin). Mutations at the interdimer/filament interface (e.g., near Tyr180) disrupt this Ca²⁺-dependent polymerization.

5. Environmental Information

CPVT2 is a purely genetic, monogenic disorder — there are no known toxic, infectious, or occupational causal exposures. The relevant "environmental" factors are physiologic triggers rather than disease causes: - Exercise/exertion — the principal, near-universal trigger of arrhythmic events and the basis of exercise stress testing for diagnosis. - Acute emotional stress/excitement — second major trigger; historically some Bedouin sudden deaths occurred "during excitement" rather than exertion. - Catecholamine/sympathomimetic exposure — iatrogenic epinephrine, certain anesthetic/perioperative catecholamine surges, and possibly stimulant use are theoretically arrhythmogenic, though not systematically studied for CASQ2-CPVT specifically. - No infectious agent involvement.

6. Mechanism / Pathophysiology

Overall causal chain: CASQ2 loss-of-function/dominant-negative variant → reduced/dysfunctional SR Ca²⁺ buffering capacity in the junctional SR → compensatory post-transcriptional upregulation of calreticulin and RyR2 (a paradoxical adaptive response) → increased RyR2 "leakiness" (heightened sensitivity to Ca²⁺-induced Ca²⁺ release even at low diastolic cytosolic Ca²⁺) → spontaneous diastolic SR Ca²⁺ release events ("Ca²⁺ sparks/waves") especially under β-adrenergic stimulation → activation of the electrogenic Na⁺/Ca²⁺ exchanger (NCX1; 3 Na⁺ in for 1 Ca²⁺ out) → delayed afterdepolarizations (DADs) → if DAD amplitude reaches threshold, triggered activity → bidirectional/polymorphic ventricular tachycardia → possible degeneration to ventricular fibrillation and sudden death (JCI 2006, Knollmann/Song; PMC8867003 RyR2 molecular changes; PMC3433449 cell model DADs).

Direct quote: "Adaptive changes to CASQ2 deficiency increased posttranscriptional expression of calreticulin and RyR2, which maintained electrical-mechanical coupling but increased RyR2 leakiness, a paradoxical response further exacerbated by stress." This unifies the CASQ2 mechanism with the RyR2 (CPVT1) mechanism at the level of RyR2 channel dysfunction — "The central role of RyR2 dysfunction in CASQ2 deficiency unifies the pathophysiologic mechanism underlying CPVT due to RyR2 or CASQ2 mutations."

Molecular pathways: cardiac excitation-contraction (EC) coupling pathway; β-adrenergic receptor–PKA signaling (phosphorylation of RyR2 at Ser2808 is reported to be increased, with decreased binding of the stabilizing subunit FKBP12.6/calstabin2, further destabilizing the channel's closed state) (PMC2525570; mechanism reviews). Relevant GO biological process terms: GO:0086029 (SR Ca²⁺ release for cardiac muscle contraction), GO:0086036 (regulation of cardiac muscle cell membrane potential), GO:0002027 (regulation of heart rate by epinephrine-norepinephrine).

Cellular processes: disrupted Ca²⁺-induced Ca²⁺ release (CICR); triggered activity (afterdepolarizations) rather than reentry as the dominant arrhythmia mechanism; no apoptosis/inflammation/fibrosis is centrally implicated (structurally normal myocardium is a diagnostic hallmark), though chronic murine models show late hypertrophic remodeling.

Protein dysfunction: loss of Ca²⁺-buffering capacity and disrupted Ca²⁺-dependent polymerization/filament formation of CASQ2 within the SR lumen; secondary structural/functional destabilization of the RyR2 macromolecular complex (RyR2–triadin–junctin–CASQ2 "quaternary complex" at the junctional SR-T-tubule interface).

Biochemical/ion channel abnormality: functionally, this is a calcium-release channelopathy — the defect is not in a voltage-gated channel itself but in luminal Ca²⁺ sensing/buffering that gates RyR2 opening. Suggested GO Cellular Component terms: GO:0016529 (sarcoplasmic reticulum), GO:0014701 (junctional sarcoplasmic reticulum membrane), GO:0034704 (calcium channel complex).

Molecular/cellular profiling: Patient-derived iPSC-cardiomyocyte models (e.g., homozygous CASQ2-D307H, CASQ2-G112+5X) recapitulate decreased Ca²⁺ transient amplitude, elevated diastolic Ca²⁺, faster Ca²⁺ transient rise, delayed afterdepolarizations, oscillatory prepotentials, and after-contractions — directly mirroring RYR2-CPVT iPSC phenotypes and validating the RyR2-convergent mechanism (PMC4549051; Cell Death & Disease 2016). AAV-mediated wild-type CASQ2 gene delivery to these iPSC-CMs restores calsequestrin expression and rescues the DAD/Ca²⁺-transient phenotype, supporting a gene-replacement therapeutic rationale.

Advanced technologies: guinea-pig computational (in silico) ventricular myocyte models have been used to dissect pacing-dependent arrhythmogenic mechanisms of the CASQ2-G112+5X mutation (PMC9858930) — a COMPUTATIONAL evidence-source example.

7. Anatomical Structures Affected

Organ level (primary): heart (cardiac conduction/electrical system); specifically ventricular myocardium. No other organ system is primarily affected — CPVT2 is a "pure" primary electrical disease of the structurally normal heart (UBERON:0000948 heart).
Secondary/complication-level involvement: cerebral hypoperfusion during arrhythmic events can produce syncope or seizure-like activity (secondary, not a direct disease target); chronic murine models show secondary ventricular hypertrophy/dysfunction with age.
Body systems: cardiovascular system (primary); nervous system only secondarily via hypoperfusion-related syncope/seizures.
Tissue/cell level: cardiac muscle tissue (UBERON:0003104 cardiac muscle tissue); specific cell population — cardiac muscle cell / cardiomyocyte (Cell Ontology CL:0000746, cardiac muscle cell of ventricle: CL:0002131 or CL:0000746 depending on specificity). Both atrial and ventricular myocytes express CASQ2, but the ventricular myocyte is the disease-relevant cell type given the ventricular arrhythmia phenotype.
Subcellular level: the junctional sarcoplasmic reticulum (GO:0014701) and the SR-T-tubule dyad/triad junction where the RyR2-CASQ2-triadin-junctin macromolecular Ca²⁺-release complex resides (GO:0016529 sarcoplasmic reticulum; GO:0033017 sarcoplasmic reticulum membrane).
Localization: diffuse throughout ventricular (and to a lesser extent atrial) myocardium — not focal/lateralized; the disease is bilateral/global in the sense that it affects the whole ventricular myocardium's excitability, producing the characteristic bidirectional VT pattern (alternating QRS axis on ECG reflecting alternating right/left ventricular ectopic foci or Purkinje-fiber triggered beats).

8. Temporal Development

Onset: mean age of first syncope 7–12 years (pediatric-onset predominant); can rarely present as late as the 4th decade. Onset pattern is acute/episodic (a discrete syncopal or arrhythmic event), not insidious.
Progression: the underlying molecular lesion is present from birth (congenital, though clinically silent at rest); the clinical course is not classically "progressive" in a structural sense but the cumulative risk of a fatal event increases with age/exposure to triggers if undiagnosed/untreated. Some murine and possibly human evidence suggests late secondary structural remodeling (hypertrophy) with age.
Disease course pattern: episodic/paroxysmal — patients are asymptomatic between adrenergically triggered events; this is a "channelopathy" pattern (crisis-driven) rather than relapsing-remitting or steadily progressive.
Disease duration: chronic, lifelong (genetic, incurable at present outside of experimental gene therapy); however, well-managed patients on adequate therapy can have long event-free intervals.
Remission patterns: no spontaneous remission; treatment (β-blockade ± flecainide ± LCSD ± ICD) substantially reduces but does not eliminate arrhythmic risk. Some published guidance indicates "a significant burden of life-threatening arrhythmias persists after left cardiac sympathetic denervation" even with maximal adjunctive therapy.
Critical periods: puberty is a clinically important critical/vulnerable window because rapid weight gain requires frequent β-blocker dose re-titration (surveillance recommended every 6–12 months, more frequently through puberty) — a window of relative under-dosing risk if not actively managed (GeneReviews).

9. Inheritance and Population

Epidemiology: - Overall CPVT (all genetic causes combined) prevalence estimated at ~1:10,000 or less, though the true prevalence is not firmly established (GeneReviews; Orphanet). - CASQ2-related (recessive) cases represent a minority subset — roughly 2–5% of genotyped CPVT (some sources state 1–2%), making CPVT2 itself an ultra-rare disease. - CPVT overall is implicated in ~12% of autopsy-negative sudden deaths and ~1.5% of sudden infant deaths in some series.

Inheritance pattern: primarily autosomal recessive (biallelic pathogenic variants required for the classic phenotype); however, a clinically important minority of heterozygous carriers manifest a milder/variable CPVT phenotype (apparent semi-dominant/dominant-negative behavior for specific missense alleles), so genetic counseling and clinical screening of heterozygotes is recommended (Roston et al. 2020, Circulation; GeneReviews).

Penetrance: biallelic CASQ2 pathogenic variants have been reported as 100% penetrant in published cohorts (GeneReviews). Heterozygous penetrance is incomplete and variant-dependent (~33% met diagnostic criteria in the largest multicenter series).

Expressivity: variable, especially among heterozygotes and even among biallelic carriers (age of onset, event severity vary between families/individuals).

Genetic anticipation: not described for CASQ2-CPVT (this is a point-mutation/protein-dysfunction disease, not a repeat-expansion disorder).

Germline mosaicism: not specifically documented in the literature surfaced here.

Founder effects: well documented — the D307H founder mutation in a consanguineous Bedouin population in northern Israel (Lahat et al. 2001) is the paradigm example; additional founder/recurrent variants have been reported in Saudi Arabian and other consanguineous kindreds, and in Chinese and Japanese pediatric cohorts (case reports of homozygous CASQ2 mutations) (PMC6825949 Chinese cohort; PMC6341267 Japanese case; Saudi family).

Consanguinity role: strongly relevant — because CPVT2 is autosomal recessive, it is markedly enriched in populations/kindreds with high consanguinity rates (Bedouin, some Middle Eastern populations), consistent with the founder-mutation pattern above.

Carrier frequency: not precisely established population-wide; gnomAD-derived aggregate carrier frequency for presumed-pathogenic CASQ2 alleles is ~0.0997% (collectively), substantially exceeding the expected disease-allele frequency implied by CPVT2's rarity — again pointing to incomplete penetrance of many heterozygous variants rather than an unexpectedly high true carrier rate for fully penetrant recessive alleles.

Population demographics: - Affected populations: enriched in consanguineous/founder populations (Bedouin of northern Israel; some Saudi, Chinese, Japanese kindreds reported), but not restricted to any single ethnicity. - Geographic distribution: worldwide,但 with notable founder clusters in the Middle East (Bedouin D307H). - Sex ratio: CPVT overall appears to affect males and females roughly equally; unlike some earlier suggestions that males with RYR2-CPVT face higher SCD risk, more recent data have not confirmed a strong sex-based risk difference. CASQ2-specific sex-ratio data were not identified as distinct from the general CPVT literature in this search. - Age distribution: predominantly pediatric/young-adult presentation (mean first-symptom age 7–12 years), consistent with an early-onset, often more severe phenotype relative to RYR2-CPVT.

10. Diagnostics

Clinical diagnostic criteria (EHRA/HRS/APHRS consensus, as applied to CPVT generally, including CASQ2-CPVT): clinical diagnosis is established in individuals <40 years old with a structurally normal heart, normal resting ECG, and exercise- or emotion-induced polymorphic ventricular premature beats/polymorphic VT/bidirectional VT reproducing symptoms — OR in any individual (regardless of phenotype) found to carry biallelic pathogenic CASQ2 variants (or a pathogenic RYR2 variant) (GeneReviews).

Clinical tests: - Exercise stress test (EST) — the gold-standard provocative test; typically the onset of ventricular arrhythmia occurs at a heart rate of ~90–120 bpm. Note: single-test sensitivity is imperfect (repeatability of arrhythmia score is only moderate), so serial/repeat EST is sometimes used for both diagnosis and treatment titration (PMC12645809 narrative review 2024; serial EST study). - Resting 12-lead ECG — typically normal (may show sinus bradycardia); used to exclude other channelopathies (long QT, Brugada, ATS). - Ambulatory Holter monitoring — can capture spontaneous ectopy/bidirectional VT, especially during activity. - Echocardiography — used to confirm structurally normal heart (exclusion of cardiomyopathy). - Epinephrine/catecholamine provocation testing — alternative pharmacologic provocation when exercise testing is not feasible. - Electrophysiology study — not typically diagnostic (CPVT arrhythmias are not reliably induced by programmed stimulation), used more for risk stratification/ablation planning in refractory cases.

Genetic testing: - First-line: targeted multigene CPVT panel — typically covers RYR2, CASQ2, CALM1, CALM2, CALM3, TRDN, TECRL (~6–7 genes explaining up to ~75% of clinically diagnosed CPVT) (Mayo Clinic Labs CPVTG). - Single-gene testing of CASQ2 is appropriate when phenotype (early recessive-pattern disease, consanguinity, or known familial variant) suggests CASQ2-CPVT specifically. - WES/WGS may be used when panel testing is uninformative, particularly research-context. - Chromosomal microarray, karyotyping, FISH, and mitochondrial DNA testing are not indicated — this is a single-gene point-mutation disorder without chromosomal or mitochondrial basis.

Genetic variant interpretation: ACMG/AMP classification via ClinVar/ClinGen; the ClinGen Cardiovascular Domain Gene Curation Expert Panel has curated CASQ2-CPVT gene-disease validity (HGNC:1513).

Differential diagnosis: Long QT syndrome (especially LQT7/Andersen-Tawil syndrome, a recognized clinical phenocopy of CPVT when extracardiac ATS features are subtle/absent), Brugada syndrome (a heterozygous CASQ2 variant has even been reported in a large Brugada-phenotype kindred, indicating some channelopathy phenotypic overlap), idiopathic ventricular fibrillation, short-coupled variant of torsade de pointes, and other causes of exertional syncope (structural cardiomyopathies, coronary anomalies, primary seizure disorders — since CPVT can be misdiagnosed as epilepsy when hypoperfusion produces convulsive syncope) (MDPI review; Wikipedia CPVT; PMC11275647 CASQ2-Brugada kindred).

Screening: cascade family screening is essential given autosomal recessive inheritance with reduced heterozygote penetrance — first-degree relatives should undergo exercise stress testing (most sensitive), resting ECG, Holter, echocardiogram, and targeted genetic testing for the known familial variant(s).

11. Outcome/Prognosis

Untreated natural history is life-threatening: - Mortality up to ~30–50% by age 20–35 if untreated (multiple concordant estimates: 31% by age 30; up to 50% by age 20; 30–50% by age 35) (search synthesis, multiple concordant sources). - Estimated 4- and 8-year cardiac event rates of 33% and 58% respectively in cohorts without β-blocker therapy. - ~30% of patients experience at least one cardiac arrest; up to 80% have ≥1 syncopal episode before diagnosis; sudden death can be the first manifestation in previously asymptomatic individuals. - CASQ2 (recessive) genotype is associated with earlier onset, more severe phenotype, and higher untreated mortality than RYR2 (dominant) genotype (Josephs et al. 2017). - Age of first syncope correlates inversely with prognosis — earlier first-syncope age predicts a worse disease course.

With treatment: β-blocker therapy (particularly nadolol) markedly reduces mortality; contemporary combination therapy (β-blocker + flecainide ± LCSD ± ICD) further reduces — but does not eliminate — breakthrough arrhythmic events. Long-term (>10 year) follow-up cohorts describe an ongoing, non-trivial residual event rate even under optimized management (PMC11573199, 10-year follow-up).

Morbidity: primarily arrhythmia-related — syncope-associated injury, psychological burden/anxiety, exercise restriction impacting normal childhood/adolescent activity, and the physical/psychological impact of ICD implantation and shocks (including risk of ICD-shock-triggered further arrhythmia in CPVT, a recognized management pitfall).

Prognostic factors: genotype (CASQ2 biallelic > CASQ2 heterozygous > general population risk gradient established in the 2020 international multicenter cohort — hazard ratios of 3.2 and 38.8 respectively), age at first symptom, history of cardiac arrest/aborted SCD as index event, adequacy of β-blocker dosing (especially through pubertal growth), and adherence.

12. Treatment

Pharmacotherapy (first-line): - Non-selective β-adrenergic blockers — nadolol (1–2.5 mg/kg/day) is considered the most effective agent; non-selective agents (nadolol, propranolol) outperform cardioselective β-blockers (GeneReviews). NCIT term: NCIT:C15986 (Pharmacotherapy) as treatment_term with therapeutic_agent bound to CHEBI (e.g., nadolol CHEBI:7477) or NCIT class term for beta-adrenergic antagonist. - Flecainide (100–300 mg/day, adjunctive) — added when β-blockade alone fails to control arrhythmia on exercise testing; flecainide is thought to act partly via direct RyR2 channel-stabilizing effects beyond its Na⁺-channel blocking action. Recent cohort data associate flecainide use with a lower incidence of arrhythmic events (Scientia Salut PDF, flecainide cohort).

Interventional/device therapy: - Left cardiac sympathetic denervation (LCSD) — adjunct for patients with breakthrough life-threatening arrhythmia despite β-blocker + flecainide, or ICD shocks; reduces but does not eliminate residual arrhythmic burden (PMC3536998). NCIT candidate: surgical/procedural term (no highly specific NCIT LCSD term identified; general "Surgical Procedure" NCIT:C15329 with therapeutic_modality: SURGERY as fallback). - Implantable cardioverter-defibrillator (ICD) — reserved for arrhythmias not adequately controlled by drug therapy, given known risk that ICD shocks themselves can trigger further catecholamine surge and arrhythmic storm in CPVT (a distinctive management caveat versus other channelopathies). therapeutic_modality: DEVICE.

Advanced/experimental therapeutics: - AAV-mediated CASQ2 gene replacement therapy — demonstrated in CASQ2-knockout/knock-in mouse models (single AAV9-CASQ2 delivery cured the arrhythmic phenotype from birth to advanced age) and in patient-derived iPSC-cardiomyocyte models (restored CASQ2 expression, rescued Ca²⁺-transient and DAD abnormalities) (Circulation 2013 mouse study; Cell Death & Disease 2016 iPSC study). This is a strong preclinical (MODEL_ORGANISM/IN_VITRO) rationale for gene therapy, with associated patent filings (e.g., US Patents 8859517, 9700636, 10195292, 11173215, "Method of gene transfer for the treatment of recessive catecholaminergic polymorphic ventricular tachycardia (CPVT)") but no completed human clinical trial identified in this search — treat as preclinical/experimental only (therapeutic_modality: GENE_THERAPY, NCIT:C15238). - Engineered calmodulin constructs for "ryanopathies" — patent-level preclinical work targeting the broader RyR2-dysfunction disease class (not CASQ2-CPVT-specific human trial data identified).

Supportive/lifestyle: - Activity restriction — avoidance of competitive/high-intensity sports is a mainstay of supportive management (behavioral intervention; NCIT:C181743 behavioral counseling / therapeutic_modality: BEHAVIORAL). - Genetic counseling — NCIT:C15240, recommended for probands and at-risk family members given autosomal recessive inheritance with reduced heterozygote penetrance.

Treatment outcomes/adverse events: β-blocker non-adherence and under-dosing (especially through pubertal weight gain) are recognized drivers of breakthrough events; ICD shocks carry a specific CPVT-relevant adverse-event profile (catecholamine-surge-induced arrhythmic storm post-shock).

Treatment algorithm: stepwise — (1) non-selective β-blocker (nadolol first-line) → (2) add flecainide if breakthrough arrhythmia on serial exercise testing → (3) consider LCSD for continued breakthrough events → (4) ICD reserved for those not adequately controlled by 1–3, used cautiously given shock-triggered arrhythmia risk.

Clinical trials: an identified relevant trial is NCT02927223 ("Atropine in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)"), investigating the paradoxical/diagnostic use of vagolytic agents in CPVT (general CPVT, not CASQ2-specific) (clinicaltrials.gov).

13. Prevention

Primary prevention: not possible in the classic sense for a monogenic recessive disease — prevention centers on genetic counseling and reproductive risk assessment in consanguineous families/known-carrier couples (25% recurrence risk for biallelic-affected offspring, 50% heterozygous-carrier risk, 25% unaffected/non-carrier per GeneReviews Mendelian recurrence risk).
Secondary prevention (early detection): cascade genetic and clinical (exercise stress test) screening of first-degree relatives of an index case is the principal secondary-prevention strategy, allowing pre-symptomatic identification and prophylactic β-blockade before a first life-threatening event.
Tertiary prevention: the entire pharmacologic/device treatment algorithm above (β-blocker, flecainide, LCSD, ICD) functions as tertiary prevention — preventing sudden death and recurrent events in already-diagnosed individuals.
Genetic/reproductive options: carrier screening in high-consanguinity or founder-mutation populations (e.g., Bedouin community screening for D307H), and prenatal/preimplantation genetic diagnosis are reproductive-option considerations for known-carrier couples, though this search did not surface CPVT2-specific PGD program data.
Prophylaxis: prophylactic β-blockade in genotype-positive, phenotype-negative (asymptomatic) relatives is a recognized preventive strategy given the potential for sudden death as a first presentation.
Public health/behavioral: activity/sports restriction counseling (avoidance of competitive athletics) functions as an ongoing behavioral primary-prevention measure against triggering the first or subsequent events, alongside emergency-preparedness counseling (family CPR/AED training) for at-risk households.

14. Other Species / Natural Disease

Taxonomy: disease modeling has been performed in Mus musculus (NCBITaxon:10090) extensively; guinea pig (Cavia porcellus, NCBITaxon:10141) computational/electrophysiological modeling; and human iPSC-derived cardiomyocyte systems.
Zebrafish (Danio rerio, NCBITaxon:7955): casq2 and ryr2b orthologs are expressed in zebrafish heart, but no zebrafish model has yet reported CASQ2-linked cardiac arrhythmias specifically (unlike the well-characterized tremblor mutant, which is an ncx1-related Ca²⁺-handling arrhythmia model, not CASQ2) (PMC8779270 zebrafish arrhythmia review).
Naturally occurring canine/other veterinary CASQ2-CPVT: this search did not identify confirmed naturally occurring CASQ2-CPVT in dogs (e.g., German Shepherd inherited sudden death, a well-known distinct polygenic canine arrhythmia syndrome, does not appear to be CASQ2-linked based on available search results) or other companion/livestock species. No OMIA entry was surfaced confirming a natural CASQ2 veterinary disease — this should be treated as not established rather than affirmatively absent, pending a dedicated OMIA search.
Gene orthology: mouse Casq2 (MGI:1309469) is the standard ortholog used in genetic (knockout/knock-in/point-mutant) modeling.
Comparative pathology: the fundamental Ca²⁺-handling/RyR2-CASQ2-triadin macromolecular complex is highly conserved across vertebrate cardiac muscle, supporting strong translational validity of mouse and iPSC models for the core arrhythmogenic mechanism, though whole-organism phenotype penetrance/timing (e.g., late hypertrophy at 35 weeks in mice) may not map precisely onto human disease timelines.

15. Model Organisms

Mouse models (primary model system):
Casq2 knockout (null) mice — under resting conditions, 100% of Casq2-null mice exhibit bidirectional ventricular tachycardia (versus 0% in WT), closely recapitulating the human resting-bradycardia-plus-stress-induced-bidirectional-VT phenotype (Circulation 2013 AAV rescue study).
Casq2-D307H knock-in mice — recapitulate impaired SR Ca²⁺ handling and complex ventricular arrhythmias, directly modeling the human Bedouin founder mutation (PMC2717009).
Conditional ablation/rescue (cell-type- and developmentally-controlled) Casq2 models — used to dissect the developmental timing and cell-type specificity (cardiomyocyte-restricted) requirement for Casq2 in producing the CPVT2 phenotype (Human Molecular Genetics 2018).
CRISPR/Cas9-generated novel CPVT mouse models — recent efforts to generate additional Casq2 (and related) mutant lines for mechanistic study (bioRxiv 2021).
Phenotype recapitulation: excellent for the core electrophysiological phenotype (resting bradycardia, exercise/catecholamine-induced bidirectional VT); models also reveal late (35-week) cardiac hypertrophy/LV dysfunction not yet fully characterized as a human correlate.
Limitations: murine cardiac electrophysiology (heart rate, ion channel repertoire) differs quantitatively from human; late structural remodeling seen in mice is not yet confirmed as a robust human CASQ2-CPVT feature (a candidate HUMAN_MODEL_MISMATCH consideration for dismech curation).
AAV gene-therapy rescue in mice: single neonatal or even adult AAV9-mediated CASQ2 gene delivery to knock-in mice normalized the arrhythmic phenotype "from birth to advanced age," a key translational proof-of-concept (Circulation 2013).
Human iPSC-derived cardiomyocyte (iPSC-CM) models:
Patient-specific iPSC-CMs carrying homozygous CASQ2-D307H or CASQ2-G112+5X mutations recapitulate decreased Ca²⁺ transient amplitude, elevated diastolic Ca²⁺, delayed afterdepolarizations, oscillatory prepotentials, and after-contractions — a strong IN_VITRO human-cell-based model with direct disease-mechanism concordance to the mouse/RyR2 literature (PMC4549051; Cell Death & Disease 2016).
AAV-CASQ2 gene delivery to these iPSC-CMs rescues the functional Ca²⁺-handling and DAD defects, mirroring the mouse gene-therapy rescue data and strengthening translational confidence.
Computational/in silico models:
A guinea-pig ventricular myocyte computational model has been used to dissect pacing-rate-dependent arrhythmogenic mechanisms specific to the CASQ2-G112+5X mutation, representing a COMPUTATIONAL evidence-source complement to the wet-lab models (PMC9858930).
Resources: MGI (Casq2, MGI:1309469) for mouse allele/phenotype data; no dedicated ZFIN CASQ2 arrhythmia model identified; IMPC/KOMP not specifically searched for a validated Casq2 line in this pass.

Summary of Key Citations (PMIDs and identifiers referenced or implied)

Lahat H et al. 2001 — Bedouin D307H founder mutation (OMIM 114251/611938 primary reference)
Postma AV et al. / Viatchenko-Karpinski S et al. — RYR2 and CASQ2 mutation comparative clinical series (Circulation)
di Barletta MR et al. 2006 — Clinical phenotype and functional characterization of CASQ2 mutations (Circulation 2006;114:1012, PMID 16908766)
Knollmann BC et al. 2006 — Casq2 point mutation impairs SR Ca²⁺ handling in mice (JCI 2006, PMID for JCI article 31080)
Song L et al. 2007 — CASQ2 mutations increase calreticulin/RyR2 expression (JCI, PMID 17607358)
Josephs K et al. 2017 — Compound heterozygous CASQ2 mutations, long-term course (Mol Genet Genomic Med, PMID 29178653)
Roston TM et al. 2020 — International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-CPVT (Circulation 2020;142:2005)
GeneReviews — Catecholaminergic Polymorphic Ventricular Tachycardia (NBK1289), Roston/Sanatani et al., updated periodically
Priori SG, Napolitano C et al. — foundational CPVT clinical/genetic reviews
Chen et al. — CASQ2 variants in Chinese children with CPVT (PMC6825949)
Faggioni M, Kryshtal DO, Knollmann BC — mechanistic reviews on calstabin/RyR2 phosphorylation and DAD generation

All specific numeric claims above should be independently re-verified against cached PubMed abstracts (via just fetch-reference PMID:XXXX) before being committed as dismech evidence snippets, per this repository's evidence SOP — this report is a research synthesis and lead list, not pre-verified curation-ready evidence.

Sources: - OMIM #611938 — CPVT2 - OMIM *114251 — CASQ2 - GeneReviews — Catecholaminergic Polymorphic Ventricular Tachycardia (NBK1289) - Orphanet — CPVT (ORPHA3286) - Roston et al. 2020, Circulation — International Multicenter CASQ2-CPVT study - Josephs et al. 2017, Mol Genet Genomic Med — Compound heterozygous CASQ2 - di Barletta et al. 2006, Circulation — Clinical Phenotype and Functional Characterization - Knollmann/Song, JCI 2006 — Calsequestrin mutations increase calreticulin/RyR2 - Circulation 2013 — AAV-mediated CASQ2 gene transfer in knock-in mice - Cell Death & Disease 2016 — AAV-CASQ2 rescue in patient-specific iPSC model - PMC7666291 — Molecular adaptation to CASQ2 R33Q and D307H mutants - PMC4549051 — Functional abnormalities in iPSC-CMs from CPVT1/CPVT2 patients - PMC2717009 — CASQ2-D307H knock-in mouse model - Human Molecular Genetics 2018 — Conditional Casq2 ablation/rescue models - PMC9858930 — Guinea pig computational model of CASQ2-G112+5X - PMC6825949 — CASQ2 variants in Chinese children with CPVT - PMC6341267 — Homozygous CASQ2 mutation, Japanese patient - PubMed 22650415 — CASQ2 mutation in a Saudi family - PMC11275647 — CASQ2 variant causing Brugada syndrome phenotype - PMC3536998 — Left cardiac sympathetic denervation in CPVT/LQTS - Flecainide cohort study 2023 (Scientia Salut repository PDF) - PMC12645809 — CPVT narrative review 2024/2025 - MDPI 2024 — CPVT clinical characteristics, diagnosis, therapy review - Mayo Clinic Labs — CPVT gene panel (CPVTG) - NCBI Gene — CASQ2 (Gene ID 845) - GeneCards — CASQ2 - Wikipedia — Calsequestrin - Wikipedia — Catecholaminergic polymorphic ventricular tachycardia - ClinicalTrials.gov NCT02927223 — Atropine in CPVT - NBK583118 — Founder variants common in the Bedouin population

CASQ2 CPVT

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

CASQ2-Related Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT2): Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Citations (PMIDs and identifiers referenced or implied)