Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.
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.
Fressart
Veronique
V
AP-HP, Hôpital Pitié-Salpêtrière, Service de Biochimie, Unité de Cardiogénétique et Myogénétique, Paris, France.
Duthoit
Guillaume
G
Donal
Erwan
E
Probst
Vincent
V
Deharo
Jean-Claude
JC
Chevalier
Philippe
P
Klug
Didier
D
Dubourg
Olivier
O
Delacretaz
Etienne
E
Cosnay
Pierre
P
Scanu
Patrice
P
Extramiana
Fabrice
F
Keller
Dagmar
D
Hidden-Lucet
Françoise
F
Simon
Françoise
F
Bessirard
Vanessa
V
Roux-Buisson
Nathalie
N
Hebert
Jean-Louis
JL
Azarine
Arshid
A
Casset-Senon
Daniele
D
Rouzet
François
F
Lecarpentier
Yves
Y
Fontaine
Guy
G
Coirault
Catherine
C
Frank
Robert
R
Hainque
Bernard
B
Charron
Philippe
P
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
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