ACTIONABILITY KNOWLEDGE REPOSITORY ACTIONABILITY CURATION INTERFACE

Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released Status (Pediatric): Passed (Consensus scoring is Complete) P

GENE/GENE PANEL: PKP2, DSP, DSC2, TMEM43, DSG2, JUP
Condition: Arrhythmogenic Right Ventricular Dysplasia
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
PKP20012180 (arrhythmogenic right ventricular dysplasia, familial, 9; arvd9)
Moderate Actionability
DSP0011831 (arrhythmogenic right ventricular dysplasia, familial, 8; arvd8)
Moderate Actionability
DSC20012506 (arrhythmogenic right ventricular dysplasia, familial, 11; arvd11)
Moderate Actionability
TMEM430011459 (arrhythmogenic right ventricular dysplasia, familial, 5; arvd5)
Moderate Actionability
DSG20012434 (arrhythmogenic right ventricular dysplasia, familial, 10; arvd10)
Moderate Actionability
JUP0012684 (arrhythmogenic right ventricular dysplasia, familial, 12; arvd12)
Moderate Actionability
Actionability Rationale
The consensus assertion was moderate. However, there was support from some scorers regarding a strong assertion due to the possiblity of Sudden cardiac death, given a reasonably effective screening protocol for evalutating and managing arrhythmias.
Final Consensus Scoresa
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Gene Disease Pairs: PKP20012180 DSP0011831 DSC20012506 TMEM430011459 DSG20012434 JUP0012684
Sudden cardiac death / Surveillance to detect disease manifestations [cardiac arrhythmias and structural disease] to guide treatment including antiarrhythmic medications
3
1C
2A
3
9CA

 
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 of arrhythmogenic right ventricular cardiomyopathy (ARVC; previously known as arrhythmogenic right ventricular dysplasia) is estimated to be approximately 1 per 1,000 to 5,000 individuals in the general population worldwide. Higher numbers may be found in specific regions; in Italy and Greece (Island of Naxos), it can be as high as 0.4%-0.8%.
1 2 3 4
Clinical Features
(Signs / symptoms)
ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Other clinical manifestations include palpitations, syncope, and occasionally development of heart failure. Clinical diagnosis of ARVC is based on the presence of a combination of major and minor diagnostic criteria across a range of groups: global or regional dysfunction and structural alterations; tissue characterization of the wall myocardium; repolarization abnormalities; arrhythmias; and family history (which includes the presence of a pathogenic variant). Importantly, the presence of a pathogenic variant alone is not sufficient for a clinical diagnosis of ARVC. (see Marcus et al. Circulation 2010; 121:1533-1541 for more detailed diagnosis criteria)
1 2 3 5 6 7
Natural History
(Important subgroups & survival / recovery)
There are four stages of ARVC: 1) concealed phase (no clinical manifestations, but potential risk of SCD); 2) overt electrical disorder (characterized by symptomatic arrhythmias); 3) right ventricular failure; and 4) biventricular pump failure. Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. The most common presenting symptoms are heart palpitations, syncope, and SCD Estimates of the annual incidence of SCD vary from 0.08% to 5%. However, SCD with no apparent provocation is not uncommon. Identified risk factors for SCD include history of aborted SCD, syncope, young age, male sex, specific electrocardiographic findings (e.g., T wave inversion in certain ECG leads, non-sustained VT), left ventricular dysfunction, right ventricular dysfunction, and inducibility of VA on electrophysiological (EP) study, premature ventricular contraction (PVC) burden on Holter. Disease progression may result in right or biventricular heart failure. In long-term studies, survival is greater than 72% after 6 years of follow up.
 
A meta-analysis of 11 studies indicated that ARVC due to a desmosomal gene variants (e.g., PKP2, DSP, DSG2, DSC2, JUP) had a younger age of onset of ARVC, a higher incidence of T wave inversion on right precordial leads, and a family history of ARVC compared to ARVC due to non-desmosomal genes variants (e.g., TMEM43). Some individuals who carry a variant associated with ARVC may not meet the clinical criteria for ARVC; however, such individuals may still be at risk for cardiovascular events including VA. In most studies, digenic/biallelic carriers have a more severe arrythmia phenotype.
1 2 3 4 5 6 7 8
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Individuals identified to have a variant associated with ARVC should be referred to a center with expertise in the evaluation, diagnosis, and management of genetic heart disease and undergo cardiovascular phenotyping, including:
 
• Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, thromboembolism
 
• Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected
 
• Electrocardiography
 
• Cardiovascular imaging. (Tier 2)
9
Guidelines are conflicting on whether EP studies may be meaningful for risk assessment of SCD in patients with ARVC. EP studies induce sustained VT in approximately 60% of patients, many of whom have had prior spontaneous episodes of sustained VT. However, studies are conflicting on the accuracy of EP studies in identifying those at risk of SCD with differing results on whether inducible sustained VT was predictive of appropriate implantable cardioverter defibrillator (ICD) shocks in symptomatic patients. In addition, the value of EP study is uncertain in asymptomatic patients with preserved ventricular functioning in predicting risk for SCD as most studies include a majority of symptomatic patients. (Tier 1)
10 11
Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. (Tier 2)
7
In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. An observational registry-based study of 95 patients reported a lower risk of clinically relevant VA (defined as sustained VT or ICD therapy) in patients taking atenolol (HR=0.25, 95% CI=0.08-0.80) or amiodarone (HR=0.03, 95% CI=0.01-0.64), while sotalol was associated with no effect or increased arrhythmia. In patients with ARVC without VA, a beta-blocker may also be useful. (Tier 1)
10
Prophylactic ICD implantation is not recommended in patients with ARVC who are asymptomatic with no risk factors or healthy gene carriers. (Tier 2)
7
Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. The risk of ICD therapy, including long-term complications, and the benefits to the patient should be balanced. A meta-analysis of 18 studies included 610 patients with ARVC who had received an ICD for primary or secondary prevention of SCD. During the 3.8-year follow-up, the appropriate and inappropriate annual ICD intervention rates were 9.5% and 3.7%, respectively. In a second study of 60 patients with ARVC, the estimated benefit of ICD implantation in preventing potentially fatal events was 21%, 32%, 36%, and 35% after 1, 3, 5, and 7 years of follow-up, respectively. (Tier 1)
12 3 10 11
In a retrospective study that included 188 patients referred to a specialized inherited arrhythmia clinic (IAC) for ARVC, 115 received a definite or probable diagnosis. Referral to the clinic was based on suspicion of an inherited cardiac disease, patients with unexplained cardiac arrest, family members of SCD victims, and family members identified through cascade testing. Management included appropriate exercise prescription, recommendations for medications, option of ICD, and drug avoidance. Asymptomatic ARVC patients with positive genetic findings underwent repeat magnetic resonance imaging at 3- to 5-year intervals. 104 patients (53% women and average age at first encounter of 40±16 years) had long-term follow up either due to definite/possible ARVC or positive genetic findings. During a median period of 3.8 years, 3 had documented sustained VA or syncope thought to be of arrhythmic origin, 30 had ICD implantation (7 for primary prevention), 8 had an appropriate ICD shock (all had received ICD for secondary prevention), and no SCD was seen. In the 17 patients followed for genetic findings alone, with a median follow-up period of 2.8 years, no cardiac events were documented. Compared to reported rates of SCD of 5.4% during 8 years of follow-up in patients with ARVC, the effective management in a specialized IAC clinic may explain the low incidence of SCD in this study. (Tier 5)
13
Surveillance
Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including:
 
• Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism
 
• Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected
 
• Electrocardiography
 
• Cardiovascular imaging. (Tier 2)
9
Circumstances to Avoid
Avoiding intensive exercise is recommended given patients with ARVC have a significantly increased risk of SCD during exertion. A study of patients with ARVC and their family members, athletes (defined as patients with ≥4 hours of exercise per week) were found to have reduced biventricular function compared with nonathletes. (Tier 1)
10 11
Restriction from competitive sports activity may be considered in healthy gene carriers. (Tier 2)
7
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Autosomal dominant. It can also be inherited in a digenic or autosomal recessive manner. Up to 47% of persons with ARVC have been shown to have compound heterozygosity or digenic heterozygosity.
2 4
Prevalence of Genetic Mutations
Estimates of pathogenic variants detected in ARVC cases are 11-74% for PKP2, 1-39% DSP, 3-26% in DSG2, 0.5-16% in JUP, and 1-7% in DSC2. Pathogenic variants in TMEM43 are rare, but there is a founder variant in Newfoundland, Canada. (Tier 3)
1 2
A study genotyped 5 ARVC genes (PKP2, DSP, DSG2, DSC2, and TMEM43) in 427 healthy individuals of which 69 (16.2%) had a genetic variant which would have been a “positive” finding in a patient with ARVC. Of these variants, 19.7% were in PKP2, 32.9% in DSP, 21.1% in DSG, 14.5% in DSC2, and 11.8% in TMEM43. (Tier 5)
14
Penetrance
(Include any high risk racial or ethnic subgroups)
In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years. (Tier 3)
2
Exercise-induced abnormalities during exercise treadmill testing were compared in 30 asymptomatic ARVC gene carriers and 30 healthy controls. Depolarization abnormalities were more frequent in gene carriers compared to controls: epsilon waves in 14% vs 0% (p=0.048), PVCs in 57% vs. 10% (p=0.0003), and new QRS terminal activation duration ≥55 ms in 32% vs. 7% (p=0.03). Superior axis PVCs occurred only in gene carriers. (Tier 5)
15
In a study of 35 PKP2 variant carriers among 9 unrelated families (including probands) 49% met criteria for ARVC. Excluding probands, 31% were clinically diagnosed with ARVC. (Tier 3)
16
Clinical evaluation of 24 family members of 9 probands, all with DSG2 variants, demonstrated penetrance of 58-75% depending on diagnostic criteria. Morphologic abnormalities of the right ventricle were evident in 66%, left ventricular involvement in 25%, classic right precordial T-wave inversion in 26%, and sustained VA in 8%. (Tier 3)
17
In 15 unrelated families from Newfoundland, penetrance was 100% in males and females carrying the S358L variant in the TMEM43 gene by ages 63 and 76 years, respectively. (Tier 3)
18
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available.
 
 
Expressivity
The presentation of diseases is highly variable even within families and some affected individuals may not meet clinical criteria for ARVC. (Tier 3)
1 2
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions include non-invasive surveillance, long-term pharmacotherapy, and possible ICD implantation which may be associated with low-moderate risk and burden.
 
In a meta-analysis of 18 studies, 20% of patients had ICD-related complications that consisted of difficult lead placement (18%), lead malfunction (10%), infection (1%), and lead displacement (3%). A second meta-analysis that included 710 patients with ARVC reported that 24% experienced ICD-related complications, with inappropriate shocks in 19% and ICD-related mortality in 0.5%.
12 19
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
ARVC management is focused on prevention of SCD, which may be the first manifestation of disease. In addition, SCD may occur during the asymptomatic phase. (Tier 2)
2
 
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.

 
Gene Disease Associations
Gene
Disease Associations
Primary MONDO Identifier
Additional MONDO Identifiers
OMIM Identifier
Reference List
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3. 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). Eur Heart J. (2015) 36(41):2793-867.
4. Arrhythmogenic right ventricular cardiomyopathy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=247
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6. Bosman LP, Sammani A, James CA, Cadrin-Tourigny J, Calkins H, van Tintelen JP, Hauer RNW, Asselbergs FW, Te Riele ASJM. Predicting arrhythmic risk in arrhythmogenic right ventricular cardiomyopathy: A systematic review and meta-analysis. Heart Rhythm. (Year2018Month07) 15(1556-3871):1097-1107.
7. Corrado D, Wichter T, Link MS, Hauer RN, Marchlinski FE, Anastasakis A, Bauce B, Basso C, Brunckhorst C, Tsatsopoulou A, Tandri H, Paul M, Schmied C, Pelliccia A, Duru F, Protonotarios N, Estes NM, McKenna WJ, Thiene G, Marcus FI, Calkins H. Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: An International Task Force Consensus Statement. Circulation. (Day04Year2015MonthAug) 132(1524-4539):441-53.
8. Xu Z, Zhu W, Wang C, Huang L, Zhou Q, Hu J, Cheng X, Hong K. Genotype-phenotype relationship in patients with arrhythmogenic right ventricular cardiomyopathy caused by desmosomal gene mutations: A systematic review and meta-analysis. Sci Rep. (Month01Year2017Day25) 7(2045-2322):41387.
9. Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline. J. Card. (Fail)
10. 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: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. (2018) 15(10):e73-e189.
11. Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. (Month11Year2019) 16(1556-3871):e301-e372.
12. Schinkel AF. Implantable cardioverter defibrillators in arrhythmogenic right ventricular dysplasia/cardiomyopathy: patient outcomes, incidence of appropriate and inappropriate interventions, and complications. Circ Arrhythm Electrophysiol. (2013) 6(3):562-8.
13. Adler A, Sadek MM, Chan AY, Dell E, Rutberg J, Davis D, Green MS, Spears DA, Gollob MH. Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. Circ Arrhythm Electrophysiol. (2016) 9(1):e003440.
14. Kapplinger JD, Landstrom AP, Salisbury BA, Callis TE, Pollevick GD, Tester DJ, Cox MG, Bhuiyan Z, Bikker H, Wiesfeld AC, Hauer RN, van Tintelen JP, Jongbloed JD, Calkins H, Judge DP, Wilde AA, Ackerman MJ. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J. Am. Coll. (Cardiol)
15. Perrin MJ, Angaran P, Laksman Z, Zhang H, Porepa LF, Rutberg J, James C, Krahn AD, Judge DP, Calkins H, Gollob MH. Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy. J. Am. Coll. (Cardiol)
16. Dalal D, James C, Devanagondi R, Tichnell C, Tucker A, Prakasa K, Spevak PJ, Bluemke DA, Abraham T, Russell SD, Calkins H, Judge DP. Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J. Am. Coll. (Cardiol)
17. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10; ARVD10. MIM: 610193: 2015 Jan 06. World Wide Web URL: http://omim.org.
18. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 5; ARVD5. MIM: 604400: 2013 Dec 02. World Wide Web URL: http://omim.org.
19. 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.
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