What is the clinical evidence from this study?

Study design: Observational. Population: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Intervention: plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C. Primary outcome: Presence of aberrant messenger RNA and clinical manifestations.

What question did this study set out to answer?

To investigate the clinical and genetic characteristics of a plakophilin-2 (PKP2) splice site mutation (c.2489+4A>C) identified in four unrelated Dutch families with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

January 1, 2012CardiologyOpen Access

Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation

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Key result

The PKP2 splice site mutation c.2489+4A>C leads to aberrant mRNA and a wide range of disease severity in carriers, demonstrating variable expression and incomplete penetrance in ARVD/C.

Population

4 separately ascertained Dutch families with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Design

Cohort

Authors

JSJasper J. van der SmagtUniversity Medical Center Utrecht PZPaul A. van der ZwaagUniversity Medical Center Groningen JTJ. Peter van TintelenHeart Failure & Transplant

Discussion

Member takes

Implication

Supports cautious genetic counseling for ARVD/C families given incomplete penetrance; leaves open identification of disease modifiers in PKP2 carriers.

Key Points

To investigate the clinical and genetic characteristics of a plakophilin-2 (PKP2) splice site mutation (c.2489+4A>C) identified in four unrelated Dutch families with arrhythmogenic right ventricular dysplasia/cardiomyopathy.
Conducted genealogical investigations and haplotype sharing analyses across four independently ascertained Dutch families.
Screened five desmosomal genes and performed reverse transcriptase PCR (RT-PCR) with direct sequencing to evaluate PKP2 messenger RNA expression.
Identified an identical c.2489+4A>C splice donor site mutation in intervening sequence 12 of PKP2 in all four families, tracing back to a common ancestral founder over seven generations ago.
Demonstrated through RT-PCR that the mutation produces aberrant messenger RNA, predicted to encode a dysfunctional PKP2 protein rather than causing total protein loss.
Observed wide clinical variability and incomplete penetrance among carriers, spanning from severe arrhythmogenic cardiomyopathy to completely asymptomatic phenotypes in elderly carriers.

Study Design

Type

Observational

Structured PICO

Population

Members of 4 Dutch families with arrhythmogenic right ventricular dysplasia/cardiomyopathy carrying a plakophilin-2 (PKP2) splice site mutation.

Outcome

Identification and characterization of a plakophilin-2 (PKP2) splice site mutation (c.2489+4A>C)

A founder splice site mutation in PKP2 causes ARVD/C with highly variable expression and incomplete penetrance, suggesting additional factors are required for disease manifestation.

Cite This Study

Smagt et al. (2012) conducted an observational in Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C was evaluated on Presence of aberrant messenger RNA and clinical manifestations. The PKP2 splice site mutation c.2489+4A>C leads to aberrant mRNA and a wide range of disease severity in carriers, demonstrating variable expression and incomplete penetrance in ARVD/C.

synapsesocial.com/papers/6a98ccef164ba63a391fe9f8 https://doi.org/10.1159/000342717

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Implication

Supports cautious genetic counseling for ARVD/C families given incomplete penetrance; leaves open identification of disease modifiers in PKP2 carriers.

Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation

Discussion

Member takes

Implication

Key Points

Study Design

Structured PICO

Cite This Study

Clinical and Genetic Characterization of Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Caused by a Plakophilin-2 Splice Mutation

Discussion

Member takes

Implication

Key Points

Study Design

Structured PICO

Cite This Study

Also Consider

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