Comprehensive exonic sequence analysis of the known desmosomal ARVD/C-related genes currently identifies a responsible mutation in approximately 50% of ARVD/C probands. Recognition of additional genes associated with this condition, improved techniques for identifying large deletions or gene rearrangements, and lower cost sequence analysis should all improve the diagnostic yield of genetic testing in the future.
Patients and their physicians may seek clinical genetic testing for ARVD/C for several reasons. In our experience, the most common reason cited is identification of individuals related to someone with ARVD/C who may be at increased risk of sudden cardiac death or of developing the disorder. In such cases, the affected proband should be tested first and if a mutation is identified, at-risk family members can also seek testing. Genetic diagnosis before implantation is possible, but depends on the policies in the clinical laboratory performing the test. We discourage testing requested simply on the basis of curiosity or to confirm a diagnosis, as imaging and arrhythmia testing have greater diagnostic utility at this point. When the diagnostic criteria for this disorder are revised, inclusion of desmosome gene mutations in establishing this diagnosis might lead to increased ARVD/C genetic testing in the clinic.
Clinical genetic testing for ARVD/C is currently available in at least two laboratories in the US, both of which meet the Clinical Laboratory Improvement Amendments: the Johns Hopkins DNA Diagnostic Laboratory and the Harvard Laboratory for Molecular Medicine. Clinicians and patients who seek such testing should be aware of the possible outcomes, including the distinct possibility of finding a sequence variant of uncertain or unknown significance in one or more of these genes. Accordingly, genetic counseling is essential with such testing. Mutations resulting in insertions, deletions, frameshift, or premature termination are frequently found in this disorder, each of which dramatically alters the predicted protein. Even if they have not been previously reported, mutations may be more easily inferred as pathogenic by a clinical laboratory. Missense substitutions can be harder to interpret without extensive analysis in unaffected populations and functional assessment of these alterations (). Clinical genetic testing laboratories are not typically able to perform such analyses.
Figure 3 Tallies of the types of unique mutations found in each of the five desmosomal genes mutated in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Shown are missense, nonsense, and insertion/deletion or frameshift mutations. Abbreviations: DSC2 (more ...)
In our experience, PKP2
mutations are not typically found among individuals with sub-clinical manifestations of ARVD/C, but are far more common in those who satisfy the current clinical criteria.34
As such, use of such clinical genetic testing in an individual who does not meet the diagnostic criteria for ARVD/C is unlikely to result in a clear diagnosis.34
As the criteria used in the diagnosis of this condition evolve, genetic testing is likely to provide information that is additive to that provided by family history of ARVD/C.
Several reports have demonstrated probands and families with ARVD/C in whom more than one pathogenic mutation has been identified. 37,44,45
This possibility must also be considered when advising a proband or family member about the likelihood of identifying those in the family who are at highest risk of developing ARVD/C. As previously noted, penetrance of ARVD/C is low and variable expressivity is widely seen.39
Accordingly, identification of a genetic predisposition to ARVD/C should be viewed as only one factor contributing to ARVD/C, and does not independently lead to a diagnosis.