title: Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: AP-HP, Hôpital Pitié-Salpêtrière, Service de Biochimie, Unité de Cardiogénétique et Myogénétique, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Fressart
authors.forename: Guillaume
authors.initials: G
authors.lastname: Duthoit
authors.forename: Erwan
authors.initials: E
authors.lastname: Donal
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Deharo
authors.forename: Philippe
authors.initials: P
authors.lastname: Chevalier
authors.forename: Didier
authors.initials: D
authors.lastname: Klug
authors.forename: Olivier
authors.initials: O
authors.lastname: Dubourg
authors.forename: Etienne
authors.initials: E
authors.lastname: Delacretaz
authors.forename: Pierre
authors.initials: P
authors.lastname: Cosnay
authors.forename: Patrice
authors.initials: P
authors.lastname: Scanu
authors.forename: Fabrice
authors.initials: F
authors.lastname: Extramiana
authors.forename: Dagmar
authors.initials: D
authors.lastname: Keller
authors.forename: Françoise
authors.initials: F
authors.lastname: Hidden-Lucet
authors.forename: Françoise
authors.initials: F
authors.lastname: Simon
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bessirard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Roux-Buisson
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Hebert
authors.forename: Arshid
authors.initials: A
authors.lastname: Azarine
authors.forename: Daniele
authors.initials: D
authors.lastname: Casset-Senon
authors.forename: François
authors.initials: F
authors.lastname: Rouzet
authors.forename: Yves
authors.initials: Y
authors.lastname: Lecarpentier
authors.forename: Guy
authors.initials: G
authors.lastname: Fontaine
authors.forename: Catherine
authors.initials: C
authors.lastname: Coirault
authors.forename: Robert
authors.initials: R
authors.lastname: Frank
authors.forename: Bernard
authors.initials: B
authors.lastname: Hainque
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics*; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D051187:Desmocollins / Q000235:genetics; D051301:Desmoglein 2 / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics; D003896:Desmosomes / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D051191:Plakophilins / Q000235:genetics; D011379:Prognosis; D055815:Young Adult; D051185:gamma Catenin
chemical_list: C081561:DSC2 protein, human; C495314:DSG2 protein, human; C495294:DSP protein, human; D051187:Desmocollins; D051301:Desmoglein 2; D051180:Desmoplakins; C495292:JUP protein, human; C495337:PKP2 protein, human; D051191:Plakophilins; D051185:gamma Catenin