Published Online
on June 3, 2009

A more recent version of this article appeared on October 1, 2009

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Original Article

Comprehensive Desmosome Mutation Analysis in North Americans with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

A. Dénise den Haan¹; Boon Yew Tan²; Michelle N. Zikusoka²; Laura Ibañez Lladó²; Rahul Jain²; Amy Daly²; Crystal Tichnell²; Cynthia James²; Nuria Amat–Alarcon²; Theodore Abraham²; Stuart D. Russell²; David A. Bluemke³; Hugh Calkins²; Darshan Dalal² and Daniel P. Judge^2,4

¹ Johns Hopkins Univ., Baltimore, MD & Univ. Medical Center Utrecht, Utrecht, The Netherlands;
² Johns Hopkins University, Baltimore, MD;
³ National Institutes of Health, Bethesda, MD

⁴ E-mail: djudge{at}jhmi.edu

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 ARVD/C patients in North America has not previously been described. 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 one 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 to those without a desmosome mutation. Males with ARVD/C were more likely to carry a desmosome mutation than females (63% versus 38%). A mutation was identified in 5/18 (28%) patients with suspected ARVD. In this smaller subgroup there were no significant phenotypic differences identified between individuals with a desmosome mutation compared to 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 to 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.

Key Words: arrhythmia • cardiomyopathy • death, sudden (if surviving, use heart arrest) • genetics • ARVD/C • ventricular tachycardia • desmosome

Related Article

Desmosome Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy: Important Insight but Only Part of the Picture

Jeffrey E. Saffitz
Circ Cardiovasc Genet 2009 2: 415-417. [Extract] [Full Text] [PDF]