Missense Variants in Plakophilin-2 in Arrhythmogenic Right Ventricular Cardiomyopathy Patients – Disease-Causing or Innocent Bystanders?
Key result
PKP2 mutations were found in 15% of ARVC/D patients, but several reported missense mutations were also present in healthy controls, suggesting they may be disease-modifying rather than causative.
Why the study?
Are reported missense variants in the PKP2 gene directly disease-causing or innocent bystanders in ARVC/D patients?
Population
53 unrelated Danish patients fulfilling Task Force criteria for Arrhythmogenic Right Ventricular…
Comparison
Direct sequencing of the plakophilin-2 gene. vs 650 healthy controls.
Design
Case-control
Authors
Discussion
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Member takes
Implication
Conservative PKP2 missense variant classification is warranted in ARVC/D testing; leaves open their role as modifiers versus direct causes.
Study Design
Type
Case-Control (n=703)
Structured PICO
Are reported missense variants in the PKP2 gene directly disease-causing or innocent bystanders in ARVC/D patients?
P
Population
53 unrelated patients fulfilling Task Force criteria for ARVC/D and 650 healthy controls screened for PKP2 mutations.
E
Exposure
Direct sequencing of the plakophilin-2 (PKP2) gene.
C
Comparator
650 healthy controls.
O
Outcome
Presence and frequency of PKP2 mutations.surrogate
The finding of previously reported 'disease-causing' PKP2 missense mutations in healthy controls suggests these variants may be disease-modifying rather than directly pathogenic, highlighting the need for conservative interpretation of genetic testing in ARVC/D.
Cite This Study
Christensen et al. (2009) conducted a case-control in Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (n=703). Plakophilin-2 (PKP2) mutations vs. Healthy controls was evaluated on Presence of PKP2 mutations. PKP2 mutations were found in 15% of ARVC/D patients, but several reported missense mutations were also present in healthy controls, suggesting they may be disease-modifying rather than causative.