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. 2013 Nov;21(11):1226-31.
doi: 10.1038/ejhg.2013.39. Epub 2013 Mar 13.

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

Ilena Egle Astrid Li Mura  1 , Barbara Bauce, Andrea Nava, Manuela Fanciulli, Giovanni Vazza, Elisa Mazzotti, Ilaria Rigato, Marzia De Bortoli, Giorgia Beffagna, Alessandra Lorenzon, Martina Calore, Emanuela Dazzo, Carlo Nobile, Maria Luisa Mostacciuolo, Domenico Corrado, Cristina Basso, Luciano Daliento, Gaetano Thiene, Alessandra Rampazzo
Affiliations

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

Ilena Egle Astrid Li Mura et al. Eur J Hum Genet. 2013 Nov.

Abstract

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.

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Figures

Figure 1
Figure 1
Pedigree of the ARVC family. Proband is indicated by the arrow. Circles denote females; squares denote males. Black and white symbols represent clinically affected and unaffected individuals, respectively; gray symbol indicates the subject with minor signs of the disease. Asterisks denote subjects carrying the heterozygous PKP2 deletion; traits indicate a normal gene copy number.
Figure 2
Figure 2
Results of CNVs analysis on chromosome 12p11.21 showing the PKP2 gene deletion. Log R Ratios (top) and B allele frequencies (bottom) are plotted against chromosome 12 position (32 822 606–33 184 590 bp). Red dots denote SNPs included in the deleted region, blue dots indicate markers outside the deletion. The length of the deleted region is displayed as distance between the two gray vertical lines and included 26 SNPs. Hemizygosity appears as a drop in log R Ratio (red dots below 0.0) and as a missing in heterozygote SNP calls (lack of dots at 0.5).
Figure 3
Figure 3
PKP2 gene dosage by quantitative real-time PCR in a control individual (CP) and family members. The target gene copy number was normalized to the reference gene TATA-binding protein (TBP). Each experiment was done in triplicate. Error bars represent SD of replicates. Similar results (not showed) were obtained using β-actin (ACTB) as internal reference gene.
Figure 4
Figure 4
Instrumental findings of patient III-6 at the time of diagnosis. (a) 12-lead ECG showing sinus rhythm, negative T waves in V1–V2 and biphasic in V3; (b) 2D-echocardiogram (parasternal long axis view) with evidence of a dilated right ventricle (RVOT: 19,2 mm/m2); (c) sustained VT tachycardia with LBBB morphology and right axis deviation.
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