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

• DOI: 10.1093/europace/euq104
• Publication Date: 2010-04-17T00:13:02Z
• Authors: Veronique Fressart; Guillaume Duthoit; Erwan Donal; Vincent Probst; Jean-Claude Deharo; Philippe Chevalier; Didier Klug; Olivier Dubourg; Etienne Delacretaz; Pierre Cosnay; Patrice Scanu; Fabrice Extramiana; Dagmar Keller; Françoise Hidden-...; Françoise Simon; Vanessa Bessirard; Nathalie Roux-Bui...; Jean-Louis Hebert; Arshid Azarine; Daniele Casset-Senon; François Rouzet; Yves Lecarpentier; Guy Fontaine; Catherine Coirault; Robert Frank; Bernard Hainque; Philippe Charron
• Keywords: Male; MESH: Desmocollins; MESH: Plakophilins; DNA Mutational Analysis; Arrhythmogenic right ventricular dysplasia; Gene; MESH: Genotype; MESH: Arrhythmias; MESH: Desmoplakins; 0302 clinical medicine; MESH: Desmosomes; Diagnosis; MESH: DNA Mutational Analysis; Arrhythmogenic Right Ventricular Dysplasia; MESH: Middle Aged; Desmoglein 2; MESH: Genetic Testing; MESH: Genetic Predisposition to Disease; Desmosome; Desmosomes; Middle Aged; Prognosis; 3. Good health; MESH: Arrhythmias, Cardiac; MESH: Young Adult; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Female; Cardiac; Adult; Genotype; Cardiomyopathy; 610; MESH: Prognosis; Young Adult; 03 medical and health sciences; 616; Humans; Genetic Predisposition to Disease; [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Genetic Testing; MESH: Arrhythmogenic Right Ventricular Dysplasia; Desmocollins; MESH: Humans; MESH: Adult; Arrhythmias, Cardiac; MESH: Male; Desmoplakins; gamma Catenin; MESH: Female; Plakophilins; MESH: Desmoglein 2

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.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).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.