Catecholaminergic Polymorphic Ventricular Tachycardia

Actionability Adult Summary Report

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

• Gene: RYR2 (HGNC:10484)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 06/29/2015
• Curation Status: Released (1.2.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
RYR2	N/A (0011484)	604772	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Sudden cardiac death / Beta blockers	3	2N	2B	3	10NB

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence is estimated to be approximately 1 per 10,000. True prevalence is not known.

Clinical Features (Signs / symptoms)

CPVT is 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 ventricular tachycardia. Arrhythmias may self-terminate or ventricular tachycardia 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 ventricular tachycardia during exercise stress testing. Absent emotional or physical stress, CPVT patients have a normal resting 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 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.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

The proportion of de novo RYR2 mutations is estimated at approximately 40%.

Prevalence of Genetic Variants

>1-2 in 100

Approximately 60% of CPVT index cases have a RYR2 mutation.

Tier 2

The prevalence of RYR2 mutations is unknown.

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

>= 40 %

Clinical penetrance for ventricular arrhythmia ranges from 25 to 100%, with an average of 70 to 80%.

Tier 4

Unknown

In one study of 30 clinically identified probands and 118 family members, RyR2 mutations were confirmed in 14 probands and 9 family member carriers. Among these 23, 7 SCDs occurred in individuals less than or equal to , ≤ 40 years of age (30%). No observational time frame was reported.

Tier 5

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

Beta-blockers are recommended for symptomatic patients with CPVT and may be effective in asymptomatic patients with a genetic diagnosis. In a study of 101 CPVT patients, including 50 probands, diagnosed clinically or by genetic mutation in the RYR2 or CASQ2 gene, 81 were administered beta-blockers. 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) In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (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).

Tier 2

Surveillance

Holter recordings and exercise tests should be repeated periodically to assure that the degree of sinus tachycardia that precedes the onset of arrhythmias is known so that in daily life it can be avoided as much as possible.

Tier 2

Resting ECG is also recommended surveillance.

Tier 4

Circumstances to Avoid

Patients with a diagnosis of CPVT should limit/avoid competitive sports, strenuous exercise, exposure to stressful environments, and use of digoxin.

Tier 2

Nature of Intervention

Nature of Intervention

Interventions include non-invasive surveillance and long-term use of beta-blockers.

Context: Adult

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

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			RYR2			604772	0011484	0017990

References List

Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. (2011) HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart rhythm : the official journal of the Heart Rhythm Society. 8(8):1308-39.

Catecholaminergic polymorphic ventricular tachycardia. Orphanet (2021) Accessed: 2021-03-11. URL: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=3286

Napolitano C, Bloise R, Memmi M, Priori SG. (2014) Clinical utility gene card for: Catecholaminergic polymorphic ventricular tachycardia (CPVT). European journal of human genetics : EJHG. 22(1).

Napolitano C, Priori SG, Bloise R. Catecholaminergic Polymorphic Ventricular Tachycardia. (2004) [Updated Mar 06 2014]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1289/

Pedersen CT, Kay GN, Kalman J, Borggrefe M, Della-Bella P, Dickfeld T, Dorian P, Huikuri H, Kim YH, Knight B, Marchlinski F, Ross D, Sacher F, Sapp J, Shivkumar K, Soejima K, Tada H, Alexander ME, Triedman JK, Yamada T, Kirchhof P, Lip GY, Kuck KH, Mont L, Haines D, Indik J, Dimarco J, Exner D, Iesaka Y, Savelieva I. (2014) EHRA/HRS/APHRS expert consensus on ventricular arrhythmias. Heart rhythm : the official journal of the Heart Rhythm Society. 11(10):e166-96.

Pedersen CT, Kay GN, Kalman J, Borggrefe M, Della-Bella P, Dickfeld T, Dorian P, Huikuri H, Kim YH, Knight B, Marchlinski F, Ross D, Sacher F, Sapp J, Shivkumar K, Soejima K, Tada H, Alexander ME, Triedman JK, Yamada T, Kirchhof P, Lip GY, Kuck KH, Mont L, Haines D, Indik J, Dimarco J, Exner D, Iesaka Y, Savelieva I. (2014) EHRA/HRS/APHRS expert consensus on ventricular arrhythmias. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 16(9):1257-83.

Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, DeSimone L, Coltorti F, Bloise R, Keegan R, Cruz Filho FE, Vignati G, Benatar A, DeLogu A. (2002) Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 106(1):69-74.

Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C, Ackerman M, Belhassen B, Estes NA 3rd, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET, Quek SC. (2013) Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 15(10):1389-406.

van der Werf C, Zwinderman AH, Wilde AA. (2012) Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 14(2):175-83.

VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND/OR DILATED CARDIOMYOPATHY; CPVT1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 604772, (2014) World Wide Web URL: http://omim.org/

Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B. (2006) ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death--executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. European heart journal. 27(17):2099-140.