Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia.
BACKGROUND
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses.


OBJECTIVE
This study sought to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers.


METHODS
Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing.


RESULTS
Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers.


CONCLUSIONS
Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.
Department of Cardiac-Thoracic and Vascular Sciences, University of Padua Medical School, Padua, Italy.
Barbara
B
Bauce
Andrea
A
Nava
Giorgia
G
Beffagna
Cristina
C
Basso
Alessandra
A
Lorenzon
Gessica
G
Smaniotto
Marzia
M
De Bortoli
Ilaria
I
Rigato
Elisa
E
Mazzotti
Alexandros
A
Steriotis
Martina Perazzolo
MP
Marra
Jeffry A
JA
Towbin
Gaetano
G
Thiene
Gian Antonio
GA
Danieli
Alessandra
A
Rampazzo
D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D051187:Desmocollins / Q000235:genetics*; D051301:Desmoglein 2 / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics; D003896:Desmosomes / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D051191:Plakophilins / Q000235:genetics; D018570:Risk Assessment; D055815:Young Adult; D051185:gamma Catenin
D003598:Cytoskeletal Proteins; 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