CATECHOLAMINERGIC POLYMORPHIC VT

Catecholaminergic Polymorphic Ventricular Tachycardia — sudden cardiac death during exercise or emotional stress in children and young adults with structurally normal hearts and normal resting ECGs.

RYR2 and CASQ2 are on the ACMG SF v3.2 mandatory secondary findings list. Whole genome sequencing identifies all CPVT-associated genetic variants, enabling treatment that can prevent sudden death before it occurs.

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About this condition

Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndrome characterized by stress-induced ventricular arrhythmias in individuals with structurally normal hearts and normal resting ECGs. During physical exercise or acute emotional stress, catecholamine surges trigger abnormal calcium release from the sarcoplasmic reticulum within cardiac myocytes, producing triggered ventricular ectopy that degenerates into bidirectional or polymorphic ventricular tachycardia and ventricular fibrillation. CPVT affects approximately 1 in 10,000 individuals and is responsible for approximately 15% of unexplained sudden cardiac arrest cases in individuals under 40 with normal hearts.

CPVT is genetically heterogeneous. The most common cause is autosomal dominant pathogenic variants in RYR2 (ryanodine receptor 2), which encodes the cardiac sarcoplasmic reticulum calcium release channel and accounts for approximately 60-70% of CPVT cases (CPVT1). RYR2 is a massive gene with 105 exons and over 300 pathogenic variants documented. Autosomal recessive CPVT (CPVT2) is caused by pathogenic variants in CASQ2 (calsequestrin 2) and accounts for approximately 3-5% of cases. Additional CPVT-associated genes include TRDN (triadin), CALM1, CALM2, CALM3, KCNJ2 (Timothy syndrome-related), and ANK2. The CALM genes are now on the ACMG SF v3.2 list, joining RYR2 and CASQ2 as mandatory secondary findings candidates.

The danger of CPVT lies in its deceptive normalcy at rest. Standard cardiac evaluation — ECG, echocardiogram, and Holter monitoring — is uniformly normal in CPVT patients between episodes. The condition is revealed only by exercise stress testing, which provokes the characteristic bidirectional or polymorphic VT. Many cases are diagnosed only after a child or young adult survives an exercise-induced cardiac arrest, or after a first-degree relative dies suddenly during exercise. Beta-blocker therapy (nadolol preferred) substantially reduces arrhythmia burden. ICD implantation is recommended for survivors of cardiac arrest or in patients with breakthrough arrhythmias on optimal medical therapy. Flecainide provides additional antiarrhythmic benefit in combination with beta-blockers.

CPVT1 (RYR2, autosomal dominant) is the most common form. CPVT2 (CASQ2, autosomal recessive) is rarer and often more severe. CALM1/2/3 variants cause a phenotypically overlapping syndrome with additional QT prolongation.

Gene locus
RYR2 (1q43), CASQ2 (1p13.3), CALM1 (14q32.11), CALM2 (2p21), CALM3 (19q13.32)

RYR2 is one of the largest genes in the human genome with 105 exons. Standard CPVT panels sequence RYR2 and CASQ2 but may miss deep intronic variants and rare structural rearrangements in this enormous gene.

RYR2 with 105 exons is one of the most challenging genes to sequence completely — and missed variants have fatal consequences

The RYR2 gene spans over 800 kilobases of genomic DNA with 105 coding exons. Comprehensive RYR2 sequencing is technically demanding, and some gene panel designs use reduced coverage in intronic regions adjacent to hotspot exons. Deep intronic RYR2 variants that create aberrant splice sites have been documented in CPVT patients with initially negative panel results. The clinical consequence of a missed RYR2 variant in CPVT is not an inconvenience — it is an unprotected young person who continues to exercise without diagnosis or treatment, with each vigorous physical activity episode representing a cardiac arrest risk. Whole genome sequencing provides uniform coverage across all 105 RYR2 exons and flanking intronic sequence.

A 'hidden' CPVT diagnosis changes every recommendation — activity, medication, ICD, family cascade testing

Once a CPVT diagnosis is established, management is immediate and comprehensive: beta-blocker therapy (typically nadolol at maximum tolerated dose), activity restriction to avoid vigorous exercise, prohibition of competitive sports, consideration of ICD implantation, and cascade genetic testing of all first-degree relatives. Every first-degree relative who tests positive requires the same management. This cascade has been documented to prevent deaths in relatives identified before their first clinical event. A missed diagnosis — a false-negative panel result that did not fully evaluate RYR2, CASQ2, or the CALM genes — delays all of these protective interventions until a cardiac arrest occurs.

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