Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: RYR2, CASQ2, TRDN, CALM1, CALM2, CALM3, TECRL
• Condition: Catecholaminergic Polymorphic Ventricular Tachycardia
• Mode(s) of Inheritance: Unknown

Actionability Assertion

• RYR2 ⇔ 0011484 (ventricular tachycardia, catecholaminergic polymorphic, 1, with or without atrial dysfunction and/or dilated cardiomyopathy; cpvt1): Strong Actionability
• CASQ2 ⇔ 0012762 (ventricular tachycardia, catecholaminergic polymorphic, 2; cpvt2): Strong Actionability
• TRDN ⇔ 0014191 (ventricular tachycardia, catecholaminergic polymorphic, 5, with or without muscle weakness; cpvt5): Strong Actionability
• CALM1 ⇔ 0013966 (ventricular tachycardia, catecholaminergic polymorphic, 4; cpvt4): Strong Actionability
• CALM2 ⇔ 0017990 (long qt syndrome 15; lqt15): Strong Actionability
• CALM3 ⇔ 0032915 (long qt syndrome 16; lqt16): Strong Actionability
• TECRL ⇔ 0013529 (ventricular tachycardia, catecholaminergic polymorphic, 3; cpvt3): Strong Actionability

Actionability Rationale

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

Final Consensus Scores

Gene Condition Pairs: RYR2 ⇔ 0011484 (OMIM:604772) CASQ2 ⇔ 0012762 (OMIM:611938) TRDN ⇔ 0014191 (OMIM:615441) CALM1 ⇔ 0013966 (OMIM:614916) CALM2 ⇔ 0017990 (OMIM:616249) CALM3 ⇔ 0032915 (OMIM:618782) TECRL ⇔ 0013529 (OMIM:614021)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Sudden cardiac death / Antiarrhythmic therapy with beta-blockers and consideration for more intensive therapies as indicated	3	3C	3A	3	12CA
Sudden cardiac death / Avoidance of intense exercise	3	3C	2N	3	11CN

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

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. [1, 2, 3, 4, 5, 6]

Clinical Features

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). [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11]

Natural History

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. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15]

2. How effective are interventions for preventing harm?

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) [6]

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) [4, 5, 8]

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) [4, 5, 7, 8, 16]

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) [3]

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) [4, 5]

Emotional situations, dehydration, electrolyte disturbances, and hyperthermia should be avoided. (Tier 2) [3]

Digitalis should also be avoided in all individuals with CPVT, as it may provoke the onset of cardiac arrhythmias. (Tier 4) [6]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Unknown
Autosomal dominant and autosomal recessive. The proportion of de novo RYR2 pathogenic variants is estimated at approximately 40-70%. [1, 2, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]

Prevalence of Genetic Variants

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) [4, 6, 7]

Penetrance

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) [11]

The mean penetrance of RYR2 pathogenic variants is 83%. (Tier 4) [6]

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) [17]

Relative Risk

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) [6]

4. What is the Nature of the 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. [4, 5, 7, 8, 16, 18]

5. Would the underlying risk or condition escape detection prior to harm in the setting 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) [1, 2, 6, 8]

Date of Search: 03.11.2021

Reference List

1. Catecholaminergic polymorphic ventricular tachycardia. Orphanet. (2021) Accessed: 2021-03-11. 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. Heidbuchel H, Arbelo E, D'Ascenzi F, Borjesson M, Boveda S, Castelletti S, Miljoen H, Mont L, Niebauer J, Papadakis M, Pelliccia A, Saenen J, Sanz de la Garza M, Schwartz PJ, Sharma S, Zeppenfeld K, Corrado D. Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part 2: ventricular arrhythmias, channelopathies, and implantable defibrillators. Europace. (2021) 23(1532-2092):147-148.

4. Shen WK, Sheldon RS, Benditt DG, Cohen MI, Forman DE, Goldberger ZD, Grubb BP, Hamdan MH, Krahn AD, Link MS, Olshansky B, Raj SR, Sandhu RK, Sorajja D, Sun BC, Yancy CW. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. (2017) 136(1524-4539):e60-e122.

5. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace. (2015) 17(11):1601-87.

6. 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; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1289

7. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes NA 3rd, Ferguson TB Jr, Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. (2013) 61(3):e6-75.

8. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. Circulation. (2018) 138(13):e272-e391.

9. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 4; CPVT4. MIM: 614916: 2014 Nov 11. World Wide Web URL: http://omim.org.

10. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 2; CPVT2. MIM: 611938: 2021 Mar 19. World Wide Web URL: http://omim.org.

11. 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.

12. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 3; CPVT3. MIM: 614021: 2020 Feb 29. World Wide Web URL: http://omim.org.

13. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. LONG QT SYNDROME 16; LQT16. MIM: 618782: 2021 Mar 19. World Wide Web URL: http://omim.org.

14. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. LONG QT SYNDROME 15; LQT15. MIM: 616249: 2020 Feb 26. World Wide Web URL: http://omim.org.

15. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 5, WITH OR WITHOUT MUSCLE WEAKNESS; CPVT5. MIM: 615441: 2013 Oct 02. World Wide Web URL: http://omim.org.

16. Roston TM, Jones K, Hawkins NM, Bos JM, Schwartz PJ, Perry F, Ackerman MJ, Laksman ZWM, Kaul P, Lieve KVV, Atallah J, Krahn AD, Sanatani S. Implantable cardioverter-defibrillator use in catecholaminergic polymorphic ventricular tachycardia: A systematic review. Heart Rhythm. (2018) 15(1556-3871):1791-1799.

17. 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.

18. Olde Nordkamp LR, Postema PG, Knops RE, van Dijk N, Limpens J, Wilde AA, de Groot JR. Implantable cardioverter-defibrillator harm in young patients with inherited arrhythmia syndromes: A systematic review and meta-analysis of inappropriate shocks and complications. Heart Rhythm. (2016) 13(2):443-54.