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Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Barbara Bauce1, Andrea Nava, Giorgia Beffagna

  • 1Department of Cardiac-Thoracic and Vascular Sciences, University of Padua Medical School, Padua, Italy.

Heart Rhythm
|February 5, 2010
PubMed

Insights

Multiple mutations in desmosomal genes are relevant in arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). Multiple-mutation carriers often exhibit more severe disease and left ventricular involvement compared to single-mutation carriers.

Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) presents a diverse clinical spectrum.
  • Understanding genetic underpinnings is crucial for prognosis and management.

Purpose of the Study:

  • To determine the frequency of compound and double heterozygotes for desmosomal gene mutations in Italian ARVC/D index cases.
  • To evaluate the clinical phenotype associated with these multiple-mutation carriers.

Main Methods:

  • Screening of 42 ARVC/D index cases for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes.
  • Utilized denaturing high-performance liquid chromatography (DHPLC) and direct sequencing for mutation detection.

Main Results:

  • 7.1% of probands with a family history of sudden death carried multiple mutations.
  • Multiple-mutation carriers showed increased left ventricular involvement (P = .025) compared to single-mutation carriers.
  • Compound and double heterozygotes displayed variable clinical expressivity, with some severe cases and increased disease extent.

Conclusions:

  • The presence of compound and double heterozygotes is significant for ARVC/D mutation screening and genetic counseling strategies.
  • Multiple-mutation carriers, despite variable clinical presentation, tend to have a more extensive disease phenotype than single-mutation carriers.
Abstract

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