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

Heart Rhythm. 2010 Jan;7(1):22-9. doi: 10.1016/j.hrthm.2009.09.070. Epub 2009 Oct 12.


Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses.

Objective: This study sought to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers.

Methods: Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing.

Results: Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers.

Conclusion: Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Chromatography, High Pressure Liquid
  • Cohort Studies
  • Cytoskeletal Proteins / genetics*
  • Death, Sudden, Cardiac / etiology
  • Desmocollins / genetics*
  • Desmoglein 2 / genetics
  • Desmoplakins / genetics
  • Desmosomes / chemistry
  • Desmosomes / genetics*
  • Female
  • Genetic Testing
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Plakophilins / genetics
  • Risk Assessment
  • Young Adult
  • gamma Catenin


  • Cytoskeletal Proteins
  • DSC2 protein, human
  • DSG2 protein, human
  • DSP protein, human
  • Desmocollins
  • Desmoglein 2
  • Desmoplakins
  • JUP protein, human
  • PKP2 protein, human
  • Plakophilins
  • gamma Catenin