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Functional assessment of potential splice site variants in arrhythmogenic right ventricular dysplasia/cardiomyopathy

Judith A Groeneweg1, Amber Ummels2, Marcel Mulder2

  • 1Department of Cardiology, University Medical Center Utrecht and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.

Heart Rhythm
|August 5, 2014
PubMed

Insights

Functional analysis of splice site variants in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) genes identified six pathogenic mutations. This research clarifies genetic variants, improving ARVD/C diagnosis and patient care.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Disease Mechanisms

Background:

  • Interpreting genetic screening results for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is challenging.
  • Software algorithms predict variant pathogenicity, but functional assessment provides definitive evidence.
  • This study focuses on variants of uncertain clinical significance in ARVD/C.

Purpose of the Study:

  • To conduct functional analysis of potential splice site variants in patients diagnosed with or suspected of having ARVD/C.
  • To determine the impact of specific genetic variants on RNA splicing.
  • To clarify the pathogenicity of uncertain variants in ARVD/C.

Main Methods:

  • Analyzed nine potential splice site variants in desmosomal genes (PKP2, JUP, DSG2, DSC2) from ARVD/C patients.
  • RNA was isolated from blood samples and analyzed using reverse transcriptase polymerase chain reaction (RT-PCR).
  • Assessed the effect of variants on mRNA splicing, including exon skipping and altered splice site usage.

Main Results:

  • Software predicted splicing effects for all nine variants.
  • Functional analysis confirmed deleterious splicing effects in six of the nine variants.
  • Five intronic variants severely impaired splicing, while only one of four exonic variants showed a significant effect.

Conclusions:

  • Six variants in PKP2, JUP, and DSG2 genes demonstrated a pathogenic effect on mRNA splicing, confirming them as ARVD/C-related mutations.
  • Functional assessment is crucial for accurately interpreting potential splice site variants.
  • These findings enhance patient care and facilitate cascade screening for ARVD/C.
Abstract

Keywords:
Arrhythmogenic right ventricular dysplasia/cardiomyopathyDesmosomesGeneticsRNA analysisSplice site mutationsVentricular arrhythmias

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