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. 2009 Oct;2(5):428-35.
doi: 10.1161/CIRCGENETICS.109.858217. Epub 2009 Jun 3.

Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy

A Dénise den Haan  1 , Boon Yew Tan, Michelle N Zikusoka, Laura Ibañez Lladó, Rahul Jain, Amy Daly, Crystal Tichnell, Cynthia James, Nuria Amat-Alarcon, Theodore Abraham, Stuart D Russell, David A Bluemke, Hugh Calkins, Darshan Dalal, Daniel P Judge
Affiliations

Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy

A Dénise den Haan et al. Circ Cardiovasc Genet. 2009 Oct.

Abstract

Background: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited disorder typically caused by mutations in components of the cardiac desmosome. The prevalence and significance of desmosome mutations among patients with ARVD/C in North America have not been described previously. We report comprehensive desmosome genetic analysis for 100 North Americans with clinically confirmed or suspected ARVD/C.

Methods and results: In 82 individuals with ARVD/C and 18 people with suspected ARVD/C, DNA sequence analysis was performed on PKP2, DSG2, DSP, DSC2, and JUP. In those with ARVD/C, 52% harbored a desmosome mutation. A majority of these mutations occurred in PKP2. Notably, 3 of the individuals studied have a mutation in more than 1 gene. Patients with a desmosome mutation were more likely to have experienced ventricular tachycardia (73% versus 44%), and they presented at a younger age (33 versus 41 years) compared with those without a desmosome mutation. Men with ARVD/C were more likely than women to carry a desmosome mutation (63% versus 38%). A mutation was identified in 5 of 18 patients (28%) with suspected ARVD. In this smaller subgroup, there were no significant phenotypic differences identified between individuals with a desmosome mutation compared with those without a mutation.

Conclusions: Our study shows that in 52% of North Americans with ARVD/C a mutation in one of the cardiac desmosome genes can be identified. Compared with those without a desmosome gene mutation, individuals with a desmosome gene mutation had earlier-onset ARVD/C and were more likely to have ventricular tachycardia.

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Conflict of interest statement

Conflict of Interest Disclosures: HC receives honoraria from Boston Scientific, Medtronic, and St. Jude Medical, Inc and is a consultant for Medtronic. The authors have no other potential conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Conservation of the mutated amino acid in 4 novel missense mutations. Amino acids are represented by their standard abbreviations (I for isoleucine, T for threonine, L for leucine). * indicates site of mutation. Species are shown by their standard nomenclature.
Figure 2
Figure 2
Kaplan-Meier survival analysis demonstrating cumulative VT-free survival in the study population stratified by presence of a desmosome gene mutation and adjusted for gender
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