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Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.

Veronique Fressart 1 Guillaume Duthoit 2 Erwan Donal 3, 4 Vincent Probst 5 Jean-Claude Deharo 6 Philippe Chevalier 7 Didier Klug 8 Olivier Dubourg 9 Etienne Delacretaz 10 Pierre Cosnay 11 Patrice Scanu 12 Fabrice Extramiana 13 Dagmar Keller 14 Françoise Hidden-Lucet 2 Françoise Simon 1 Vanessa Bessirard 15 Nathalie Roux-Buisson 16 Jean-Louis Hebert 17 Arshid Azarine 18 Daniele Casset-Senon 19 François Rouzet 20 yves Lecarpentier 17 Guy Fontaine 2 Catherine Coirault 21 Robert Frank 2 Bernard Hainque 1 Philippe Charron 2, 15, * 
Abstract : AIMS: Five desmosomal genes have been recently implicated in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) but the clinical impact of genetics remains poorly understood. We wanted to address the potential impact of genotyping. METHODS AND RESULTS: Direct sequencing of the five genes (JUP, DSP, PKP2, DSG2, and DSC2) was performed in 135 unrelated patients with ARVD/C. We identified 41 different disease-causing mutations, including 28 novel ones, in 62 patients (46%). In addition, a genetic variant of unknown significance was identified in nine additional patients (7%). Distribution of genes was 31% (PKP2), 10% (DSG2), 4.5% (DSP), 1.5% (DSC2), and 0% (JUP). The presence of desmosomal mutations was not associated with familial context but was associated with young age, symptoms, electrical substrate, and extensive structural damage. When compared with other genes, DSG2 mutations were associated with more frequent left ventricular involvement (P = 0.006). Finally, complex genetic status with multiple mutations was identified in 4% of patients and was associated with more frequent sudden death (P = 0.047). CONCLUSION: This study supports the use of genetic testing as a new diagnostic tool in ARVC/D and also suggests a prognostic impact, as the severity of the disease appears different according to the underlying gene or the presence of multiple mutations.
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Submitted on : Wednesday, July 13, 2011 - 1:19:52 PM
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Veronique Fressart, Guillaume Duthoit, Erwan Donal, Vincent Probst, Jean-Claude Deharo, et al.. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 2010, 12 (6), pp.861-8. ⟨10.1093/europace/euq104⟩. ⟨inserm-00588266⟩



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