SickKids

Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
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Arrhythmogenic Right Ventricular Cardiomyopathy

Background
Who should be tested?
Testing Methodology
Potential Outcomes Interpretation of Test Results
Cautions
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Background

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a progressive disorder caused by fatty replacement of muscle tissue that predisposes to ventricular tachycardia and sudden death. It primarily affects the right ventricle. The presentation of the disease is highly variable within affected individuals and their families.

ARVC is an autosomal dominantly inherited condition, which is genetically heterogeneous. Mutations in several different genes are known to cause ARVC, including: DSP (locus name ARVD8), located on chromosome 6 which encodes the protein desmoplakin; PKP2 (locus name ARVD9), located on chromosome 12 which encodes the desmodermal protein plakophilin-2; and DSG2 (locus name ARVD10), located on chromosome 18 which encodes the protein desmoglein-2 and the DSC2 (locus name ARVD11), located on chromosome 18 which encodes the protein desmocollin-2. Approximately 45% of ARVC patients will have mutations in the DSP, PKP2, DSG2 or DSC2 gene. Many cases of ARVC are due to mutations in unknown genes. Molecular testing for ARVC consists of complete sequencing of the coding region and flanking exon/intron boundaries of the many genes listed above to detect mutations.

ARVC is present when an individual has one copy of the defective DSP/PKP2/DSG2/DSC2 gene. Affected individuals have a 50% chance of transmitting the disorder to each child. There is a 50% chance that the affected individual’s offspring will not be affected with ARVC.

Who should be tested?

  • individuals clinically suspected of being affected with ARVC
  • individuals with a family history of ARVC, to determine the carrier status of unaffected individuals
  • pregnancies at increased risk of being affected with ARVC

Testing Methodology

Direct Mutation Analysis: Direct sequencing to identify point mutations in the DSP, PKP2, DSG2 and DSC2 genes

Sensitivity of the Test: Approximately 45% of ARVC patients will have mutations in the DSP, PKP2, DSG2 or DSC2 gene.

Note: Sequence changes detected by these tests may be interpreted as disease causing mutations because they will clearly disrupt the protein or have been previously associated with the disease. Other sequence changes may be interpreted as benign polymorphisms because they have been detected in unaffected individuals. However in some patients a change in the gene sequence may be detected but the laboratory may not be able to determine if this change causes disease because it is not clear that the sequence affects protein function, the change has not previously been reported in the literature to cause disease nor been described as a benign polymorphism. These “variants of unknown significance” could potentially be a disease causing mutation or could be benign polymorphism and should be interpreted in the context of clinical findings, family history and other experimental data.

Potential Outcomes & Interpretation of Test Results

Reason for referral

Gene Mutations
allele 1 / allele 2

Explanation

diagnosis

none detected / none detected

  • This result does not support a diagnosis of ARVC.

diagnosis

mutation detected / none detected

  • This result supports a diagnosis of ARVC.

presymptomatic testing

none detected / none detected

  • This individual is unlikely to develop ARVC.

presymptomatic testing

mutation detected / none detected

  • This individual has a DSP/PKP2/DSG2/DSC2 mutation, and may develop ARVC and transmit a mutation to offspring.

Cautions

  1. Current molecular testing will not detect all possible mutations in these genes. A negative result does not rule out the possibility that the individual carries a rare DSP, PKP2, DSG2 or DSC2 gene mutation not detected by this assay.
  2. About 60% of ARVC cases are caused by mutations in unknown genes which will not be detected by this assay
  3. The clinical course or severity of symptoms cannot be predicted by molecular analysis.
  4. Test results should be interpreted in the context of clinical findings, family history, ethnic background and other laboratory data.
  5. This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

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