Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy

• Published in: European journal of human genetics : EJHG Vol. 21; no. 11; pp. 1226 - 1231
• Main Authors: Li Mura, Ilena Egle Astrid, Bauce, Barbara, Nava, Andrea, Fanciulli, Manuela, Vazza, Giovanni, Mazzotti, Elisa, Rigato, Ilaria, De Bortoli, Marzia, Beffagna, Giorgia, Lorenzon, Alessandra, Calore, Martina, Dazzo, Emanuela, Nobile, Carlo, Mostacciuolo, Maria Luisa, Corrado, Domenico, Basso, Cristina, Daliento, Luciano, Thiene, Gaetano, Rampazzo, Alessandra
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2013
• Subjects: Adult; Aged; Aged, 80 and over; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia - diagnostic imaging; Arrhythmogenic Right Ventricular Dysplasia - genetics; Bioinformatics; Cardiac arrhythmia; Cardiac muscle; Cardiomyopathy; Chromosome 12; Chromosome deletion; Chromosomes, Human, Pair 12 - genetics; Clonal deletion; Copy number; Coronary heart disease; DNA Copy Number Variations; Electrocardiography; Family; Female; Gene Deletion; Gene Dosage - genetics; Gene expression; Genetic Linkage; Genetics; Genomes; Heart; Heart diseases; Humans; Long QT syndrome; Male; Males; Middle Aged; Mutation; Pedigree; Phenotypes; Plakophilins - genetics; Real-Time Polymerase Chain Reaction; Single-nucleotide polymorphism; Task forces; Ultrasonic imaging; Ultrasonography; Ventricle; Young Adult; Italy
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2013.39

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary heart muscle disease characterized by progressive myocardial loss, with fibro-fatty replacement, and high frequency of ventricular arrhythmias that can lead to sudden cardiac death. ARVC is a genetically determined disorder, usually caused by point mutations in components of the cardiac desmosome. Conventional mutation screening of ARVC genes fails to detect causative mutations in about 50% of index cases, suggesting a further genetic heterogeneity. We performed a genome-wide linkage study and a copy number variations (CNVs) analysis, using high-density SNP arrays, in an ARVC family showing no mutations in any of the desmosomal genes. The CNVs analysis identified a heterozygous deletion of about 122 kb on chromosome 12p11.21, including the entire plakophilin-2 gene and shared by all affected family members. It was not listed on any of available public CNVs databases and was confirmed by quantitative real-time PCR. This is the first SNP array-based genome-wide study leading to the identification of a CNV segregating with the disease phenotype in an ARVC family. This result underscores the importance of performing additional analysis for possible genomic deletions/duplications in ARVC patients without point mutations in known disease genes.