Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: RYR2
Condition: Catecholaminergic Polymorphic Ventricular Tachycardia
GENEDISEASE PAIRS: RYR2604772
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence is estimated to be approximately 1 per 10,000. True prevalence is not known.
1 2 3
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.
4 2 3
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.
4 3 5
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
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)
6 7 8
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)
7 8
Resting ECG is also recommended surveillance. (Tier 4)
3
Family Management
Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the CPVT-causative mutation in an index case. Early CPVT genetic evaluation facilitates pre-symptomatic diagnosis, appropriate counseling, and initiation of prophylactic beta blocker therapy. Due to instances of SIDS associated with RYR2 mutations, confirmatory genetic testing should be performed at birth in families with known mutations. (Tier 2)
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)
9 7
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
The proportion of de novo RYR2 mutations is estimated at approximately 40%.
3
Prevalence of Genetic Mutations
Approximately 60% of CPVT index cases have a RYR2 mutation. (Tier 2)
4
The prevalence of RYR2 mutations is unknown.
 
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Clinical penetrance for ventricular arrhythmia ranges from 25 to 100%, with an average of 70 to 80%. (Tier 4)
10
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)
11
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)
3
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions include non-invasive surveillance and long-term use of beta-blockers.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
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. (Tier 3)
3

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Sudden cardiac death / Beta blockers
3
2N
2B
3
10NB
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Atecholaminergic polymorphic ventricular tachycardia. Orphanet. (2011) Website: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=3286
2. Napolitano C, Bloise R, Memmi M, Priori SG. Clinical utility gene card for: catecholaminergic polymorphic ventricular tachycardia (cpvt). Eur J Hum Genet. (2014) 22(1).
3. Napolitano C, Priori SG, Bloise R. Catecholaminergic polymorphic ventricular tachycardia. 2004 Jun 01 [Updated 2014 Mar 06]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1289
4. 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. 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. (2011) 8(8):1308-39.
5. van der Werf C, Zwinderman AH, Wilde AA. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace. (2012) 14(2):175-83.
6. 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. Ehra/hrs/aphrs expert consensus on ventricular arrhythmias. Heart Rhythm. (2014) 11(10):e166-96.
7. 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. Executive summary: hrs/ehra/aphrs expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace. (2013) 15(10):1389-406.
8. 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. 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. Eur Heart J. (2006) 27(17):2099-140.
9. 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. Ehra/hrs/aphrs expert consensus on ventricular arrhythmias. Europace. (2014) 16(9):1257-83.
10. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Ventricular tachycardia, catecholaminergic polymorphic, 1, with or without atrial dysfunction and/or dilated cardiomyopathy; cpvt1. MIM: 604772: 2014 Nov 11. World Wide Web URL: http://omim.org.
11. 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. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. (2002) 106(1):69-74.
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