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: PKP2, DSP, DSC2, TMEM43, DSG2
Condition: Arrhythmogenic Right Ventricular Dysplasia
GENEDISEASE PAIRS: PKP2609040 DSP607450 DSC2610476 TMEM43604400 DSG2610193
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 1,000 to 5,000 individuals in the general population worldwide. Higher numbers may be found in specific regions.
1 2 3
Clinical Features
(Signs / symptoms)
Arrhythmogenic right ventricular dysplasia or cardiomyopathy (here referred to as ARVD) is characterized by structural and functional abnormalities of the right ventricle, with or without concomitant left ventricular disease. Clinical diagnosis is based on demonstration of characteristic electrocardiogram (ECG), arrhythmic, structural, and/or histological abnormalities along with family history of sudden cardiac death (SCD) or a disease-causing mutation.
4 3 5 1
Natural History
(Important subgroups & survival / recovery)
Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Among 100 ARVD patients from a US registry, the most common presenting symptoms were palpitations, syncope, and sudden cardiac death in 27%, 26%, and 23% of patients, respectively. Estimates of the annual incidence of SCD vary from 0.08% to 9%. In the early 'concealed' phase, individuals are often asymptomatic, but may still be at risk of SCD, especially during exertion. However, SCD with no apparent provocation is not uncommon. In the symptomatic phase, individuals present with arrhythmias and right ventricular morphological abnormalities discernible by conventional imaging. Later, diffuse disease may result in heart failure while ventricular arrhythmias may or may not be present.
4 3 6 5 7
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Antiarrhythmic medication (beta-blockers, the anti-arrhythmic beta-blocker sotalol, amiodarone) can be used to prevent ventricular arrhythmias. In one study of patients with ARVD neither beta blocker therapy (n=58) nor sotalol (n=38) were protective against ventricular arrhythmias. However, amiodarone was associated with lower risk for any clinically relevant arrhythmias. Larger studies are needed to confirm this finding. (Tier 3)
3
Implantable cardioverter defibrillators (ICD) can be effective for the prevention of SCD in ARVD patients with extensive disease, 1 or more affected family members with SCD, or undiagnosed syncope when VT or VF has not been excluded as the cause of syncope, who are receiving chronic optimal medical therapy. However, there is not clear consensus among guidelines on the specific risk factors that identify those ARVD patients in whom the probability of SCD is sufficiently high to warrant an ICD for primary prevention. Individualized decisions for primary prevention of SCD must be based on experience, judgment, and the available data. (Tier 3)
8 6 7
In a systematic review of 18 cohort studies enrolling 610 patients who had received an ICD for primary or secondary prevention of SCD, the appropriate and inappropriate annual ICD intervention rates were 9.5% and 3.7%, respectively. (Tier 1)
9
Electrophysiological (EP) testing might be useful for risk assessment of SCD in patients with ARVD. The prognostic role of EP testing in patients presenting with isolated PVCs or NSVT is not known. The response to EP testing may be influenced by the severity of the disease. In one study EP testing in 17 patients with "mild" dysplasia and induced VT only in patients with spontaneous sustained VT. VT was induced in 90% of 12 patients with spontaneous sustained VT. The positive predictive value for recurrent VT was only 55%. In a second study, sustained VT could not be induced in 20 patients presenting with NSVT. In this study, inducibility was 88% in 24 of 27 patients presenting with sustained VT. (Tier 2)
7
Surveillance
Clinical screening for cardiomyopathy is recommended at yearly intervals after age 10 to age 50 in asymptomatic individuals known to carry a disease-causing mutation(s) or at any time that signs or symptoms appear. Consider repeat screening at 1 year for any abnormal clinical screening test. Recommended screening consists of clinical history and physical exam; electrocardiogram and echocardiogram; Holter monitoring; and imaging. In an analysis of a registry of ARVD patients, all 69 patients who were diagnosed with ARVD while living demonstrated one or more ECG abnormality characteristic of ARVD. In another study, MRI was found to be 100% sensitive to those meeting ARVD diagnostic criteria. (Tier 2)
10
Family Management
Mutation-specific genetic testing is recommended for appropriate family members following the identification of the ARVD-causative mutation in an index case. (Tier 2)
4 11 2
Clinical screening for cardiomyopathy (as described in Surveillance) is recommended in asymptomatic at-risk relatives who are known to carry the disease-causing mutation(s). (Tier 2)
11 10
In situations where genetic testing has not been performed or has not identified a disease causing mutation, screening is recommended at least every 5 years starting at age 10. Whether screening may be discontinued is uncertain as the age of complete penetrance is not known. (Tier 2)
11 10
Circumstances to Avoid
ARVD is present in 4% to 22% of athletes with sudden cardiac death. There is some debate over whether high-intensity endurance exercise can cause development of ARVD and therefore should be avoided. (Tier 3)
3
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Autosomal recessive has also been described. Up to 57% of persons with ARVD have been shown to have compound heterozygosity or digenic heterozygosity.
3 6
Prevalence of Genetic Mutations
Overall yield of genetic testing for all available genes in probands who meet diagnostic criteria for ARVD approximates 50% with the majority of mutations (11-51%) occurring in PKP2. Exceptions include a founder mutation in the TMEM43 gene in the Newfoundland, Canada population.
 
Information on the prevalence of genetic mutations associated with ARVD in the general population was not available. (Tier 3)
3 1
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
In a study of 35 PKP2 mutation carriers among 9 unrelated families (including probands) 49% met criteria for ARVD. Excluding probands, 31% were clinically diagnosed with ARVD. (Tier 3)
 
Clinical evaluation of 24 family members of 9 probands, all with DSG2 mutations, demonstrated penetrance of 58 to 75% depending on diagnostic criteria. (Tier 3)
 
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)
 
In a single family with DSP mutation carriers, penetrance was estimated at 50%. (Tier 3)
 
Penetrance is age-related and often incomplete as late as 50-60 years of age. (Tier 3)
12 13 11 14 3
Information on the penetrance of SCD is limited. In a study of 130 probands fulfilling clinical criteria for ARVD, there were 7 SCDs (4.4%) over a mean followup of 8 years. In a study of 100 persons in 9 families with genetically confirmed ARVD (diagnosed clinically or via autopsy), 31 experienced sudden cardiac death. In a study of 11 families with members at risk for mutations in TMEM43, 31% of 197 individuals at high risk of a mutation died of SCD. In these last two studies, no time frame for observation was provided. (Tier 3)
 
Studies of genetic variation in ARVD-related genes in healthy population controls suggest that variants that would be considered rare and pathogenic may be common and penetrance depends on type of mutation. (Tier 3)
3
Information on relative risk was not available.
 
 
Expressivity
Disease expression is variable with regard to age at onset and severity. (Tier 3)
4 11 5
ARVD patients carrying more than one disease-associated mutation may show a more severe phenotype characterized by a younger age of onset and worse prognosis. (Tier 3)
1
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 moderate risk and burden.
 
Based on data from the National ICD Registry, more than 25% of procedures are to replace devices.
15
Among patients receiving replacement ICDs between 2005 and 2010 and reported to the National ICD Registry, the median time to replacement was 4.6 years (25-75% Interquartile Range 3.7-5.8) for all types of replaced devices.
16
In one study of 132 ARVD patients followed for a mean of 39 months, 16% of patients per year experienced an inappropriate ICD shock. In a second study, 23% of patients received inappropriate shocks during a mean follow-up period of almost 7 years.
17 18
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
SCD may be the first manifestation of disease. Among 100 ARVD patients from a US registry, 23% of cases were identified after SCD. Establishing a presymptomatic diagnosis among family members allows monitoring for disease development and genetic counseling. (Tier 2)
3 7

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Sudden cardiac death / ICD implantation
3
2C
2A
2
9CA
Sudden cardiac death / Anti-arrhythmic therapy
3
2C
1C
2
8CC
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
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