Catecholaminergic Polymorphic Ventricular Tachycardia

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: RYR2 (HGNC:10484) CASQ2 (HGNC:1513) TRDN (HGNC:12261) CALM1 (HGNC:1442) CALM2 (HGNC:1445) CALM3 (HGNC:1449) TECRL (HGNC:27365)
• Mode(s) of Inheritance: Unknown
• Literature Search: 03/11/2021
• Curation Status: Released (2.0.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
RYR2	catecholaminergic polymorphic ventricular tachycardia 1 (0011484)	604772	Strong Actionability
CASQ2	catecholaminergic polymorphic ventricular tachycardia 2 (0012762)	611938	Strong Actionability
TRDN	catecholaminergic polymorphic ventricular tachycardia 5 (0014191)	615441	Strong Actionability
CALM1	catecholaminergic polymorphic ventricular tachycardia 4 (0013966)	614916	Moderate Actionability
CALM2	catecholaminergic polymorphic ventricular tachycardia (0017990)	616249	Moderate Actionability
CALM3	long QT syndrome 16 (0032915)	618782	Moderate Actionability
TECRL	catecholaminergic polymorphic ventricular tachycardia 3 (0013529)	614021	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric. Most scorers asserted CALM1, CALM2, and CALM3 genes as moderate for actionability because of concerns about gene-disease validity as well as whether the evidence related to penetrance and effectiveness could be extrapolated to these genes.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Sudden cardiac death / Antiarrhythmic therapy with beta-blockers and consideration for more intensive therapies as indicated	3	2C	2A	3	10CA
Sudden cardiac death / Avoidance of intense exercise	3	2C	2N	3	10CN

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of catecholaminergic polymorphic ventricular tachycardia (CPVT) is estimated to be approximately 1 per 10,000. True prevalence is not known. High prevalence of simplex cases and lethality at a young age suggest that the overall prevalence of CPVT is significantly lower than that of other inherited arrhythmogenic disorders such as Long QT syndrome.

Clinical Features (Signs / symptoms)

CPVT is an inherited arrhythmogenic disease characterized by episodic syncope occurring during exercise or acute emotion in individuals without structural cardiac abnormalities. The underlying cause of these episodes is the onset of fast (bidirectional or polymorphic) ventricular tachycardia (VT). Arrhythmias may self-terminate, or VT may degenerate into ventricular fibrillation (VF) and cause sudden death if cardiopulmonary resuscitation is not readily available. In other cases, arrhythmias may be well tolerated, with only mild symptoms such as dizziness or feeling faint. Clinical CPVT is defined by premature ventricular contractions or VT during exercise stress testing. In the absence of emotional stress or exercise, patients with CPVT have a normal resting electrocardiogram (ECG).

Natural History (Important subgroups & survival / recovery)

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in TRDN can have muscle weakness. Individuals with pathogenic variants in TECRL can have mildly prolonged QTc interval on baseline electrocardiography, with a paradoxical QT increase during adrenergic simulation. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Likelihood of Outcome

Mode of Inheritance

Unknown

Autosomal dominant and autosomal recessive. The proportion of de novo RYR2 pathogenic variants is estimated at approximately 40-70%.

Prevalence of Genetic Variants

1-2 in 10000

Approximately 50-55% of cases of CPVT are attributed to pathogenic variants in the RYR2 gene; approximately 2-5%, 1-2%, and 1% of cases are attributed to pathogenic variants in the CASQ2, TRDN, and CALM1 genes, respectively.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Tier 3

>= 40 %

The mean penetrance of RYR2 pathogenic variants is 83%.

Tier 4

Unknown

In one study of 30 clinically identified probands and 118 family members, RYR2 pathogenic variants were confirmed in 14 probands and 9 family members. Among these 23 individuals, 7 SCDs occurred in individuals <40 years of age (30%). Five of the 9 genetically confirmed family members had exercise-induced arrhythmias at clinical evaluation. Syncope occurred in 26 of 30 probands and was the first sign of disease in 16 probands. No observational time frame was reported.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on relative risk was not available.

Expressivity

Age at onset is variable extending into adulthood and severity of disease symptoms among different individuals can range from minor dizziness and faintness to the possible outcome of sudden death.

Tier 3

Intervention Effectiveness

Patient Management

To establish the extent of disease and needs in an individual diagnosed with CPVT, the following evaluations are recommended:

• Resting ECG

• Holter monitoring

• Exercise stress test

• Echocardiogram and/or MRI

• Consultation with a clinical geneticist and/or genetic counselor.

Tier 4

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

Tier 1

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. ICD programming should be optimized to deliver therapy for VF and to minimize inappropriate shocks and risk of potentially fatal electrical storms. Flecainide in combination with a beta blocker can suppress ventricular ectopy by as much as 76% in patients with CPVT during exercise testing or clinical follow-up. A systematic review of studies describing 1429 patients with CPVT (defined as a clinical and/or molecular diagnosis of CPVT) found that 503 (35.2%) had an ICD (median age 15.0 years). Among ICD recipients with a reported medication status (n=271), 96.7% were prescribed beta-blockers. During follow-up (duration not able to be reliably determined; longest known ICD follow-up was 6 years), 40.1% of patients had ≥ 1 appropriate shock. Two case series with a median follow-up of 4 years from implantation reported that shocks for VT almost universally failed (71 of 72 [98.6%]) despite being appropriate. Conversely, shocks that occurred for VF were almost always successful (66 of 70 [94.3%]).

Tier 1

Surveillance

Follow-up should include stress tests and/or continuous ECG monitoring (Holter) during leisure-time low-intensity sports activities to ensure control of exercise-induced ventricular arrhythmias.

Tier 2

Circumstances to Avoid

The following lifestyle changes are recommended in patients with a diagnosis of CPVT, especially in those presenting with syncope of suspected arrhythmic etiology: avoidance of competitive sports, strenuous exercise, and stressful environments. One guideline recommends that athletes with phenotype positive CPVT be evaluated by a specialist before considering participating in competitive sports.

Tier 1

Emotional situations, dehydration, electrolyte disturbances, and hyperthermia should be avoided.

Tier 2

Digitalis should also be avoided in all individuals with CPVT, as it may provoke the onset of cardiac arrhythmias.

Tier 4

Nature of Intervention

Nature of Intervention

Identified interventions include non-invasive surveillance and use of beta-blockers and flecainide. Beta-blockers and flecainide are generally well tolerated but can have adverse cardiac and non-cardiac effects. Minor complications of left cardiac sympathetic denervation have been reported to occur in 20-70% of patients. Implantation of an ICD is an intervention which would involve invasive surgery and device maintenance, potentially starting at a young age; those who are young will require multiple device replacements during their lifetime. Inappropriate ICD shocks and device complications can be minimized with concurrent beta-blocker therapy, optimal device programming, and appropriate lead selection. A systematic review of patients (median age 15.0 years) with CPVT (defined as a clinical and/or molecular diagnosis of CPVT) found that 20.8% experienced ≥1 inappropriate shock, 19.6% had electrical storms, and 1.4% died. ICD-associated electrical storm was implicated in 4 of the 434 reported deaths. Additional complications such as lead failure, endocarditis or surgical revisions were observed in 96 of 296 patients (32.4%). In addition, the use of ICD therapy carries a risk for psychological consequences due to fear of being shocked, particularly among patients who have experienced a shock.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Although the mean age of onset of CPVT symptoms occurs in childhood, onset well into adulthood has been reported. Because approximately 30% of affected individuals experience at least one cardiac arrest and sudden death may be the first manifestation of the disease, early detection is essential to guide preventive therapy and behavior.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			RYR2			604772	0011484	0017990
CASQ2			611938	0012762	0017990
TRDN			615441	0014191	0017990
CALM1			614916	0013966	0017990
CALM2			616249	0017990
CALM3			618782	0032915	0017990
TECRL			614021	0013529	0017990

References List

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