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

Received 23 June 2009; accepted 26 September 2009. published online 12 October 2009.

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.

Keywords: Arrhythmia, Arrhythmogenic cardiomyopathy, Sudden death, Cell adhesion molecules, Gene mutations, Compound genotypes

Abbreviations: ARVC/D, arrhythmogenic right ventricular cardiomyopathy/dysplasia, ECG, electrocardiogram, DHPLC, denaturing high-performance liquid chromatography, ICD, implantable cardioverter-defibrillator, RPD, repeat domains, RV, right ventricular, VT, ventricular tachycardia

⁎ Department of Cardiac-Thoracic and Vascular Sciences, University of Padua Medical School, Padua, Italy

† Department of Biology, University of Padua, Padua, Italy

‡ Department of Medical-Diagnostic Sciences and Special Therapies, University of Padua Medical School, Padua, Italy

§ Department of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, Texas

Address reprint requests and correspondence: Dr. Alessandra Rampazzo, Department of Biology, University of Padua, Via U. Bassi 58/B, 35131 Padua, Italy

This study was supported by Telethon, Rome, Italy (GGP07220 and GGP05261); Fifth Framework Program European Commission (QLG1-CT-2000-01091), Bruxelles, Belgium; National Institutes of Health (U04HL 65652), Bethesda, Maryland, USA; Ministry of Health, MIUR (2006061007_002), Rome, Italy; and Fondazione CA.RI.PA.RO, Padua, Italy.

PII: S1547-5271(09)01145-X

doi:10.1016/j.hrthm.2009.09.070

5 of 28