Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy.
BACKGROUND
Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC.


RESULTS
The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years [22-52]) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively.


CONCLUSIONS
Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.
Departments of Cardiac, Thoracic, and Vascular Sciences, and Biology, University of Padua, Padova, Italy.
Ilaria
I
Rigato
Barbara
B
Bauce
Alessandra
A
Rampazzo
Alessandro
A
Zorzi
Kalliopi
K
Pilichou
Elisa
E
Mazzotti
Federico
F
Migliore
Martina Perazzolo
MP
Marra
Alessandra
A
Lorenzon
Marzia
M
De Bortoli
Martina
M
Calore
Andrea
A
Nava
Luciano
L
Daliento
Dario
D
Gregori
Sabino
S
Iliceto
Gaetano
G
Thiene
Cristina
C
Basso
Domenico
D
Corrado
D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000503:physiopathology; D016757:Death, Sudden, Cardiac; D051187:Desmocollins / Q000235:genetics; D051301:Desmoglein 2 / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics; D003896:Desmosomes / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051191:Plakophilins / Q000235:genetics; D011379:Prognosis; D012307:Risk Factors; D012737:Sex Factors; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000503:physiopathology; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult
C081561:DSC2 protein, human; D051187:Desmocollins; D051301:Desmoglein 2; D051180:Desmoplakins; D051191:Plakophilins
cardiomyopathies; death, sudden, cardiac; genetics