Quantitative analysis of PKP2 and neighbouring genes in a patient with arrhythmogenic right ventricular cardiomyopathy caused by heterozygous PKP2 deletion

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease mainly caused by desmosome gene mutations. The genetic culprit, however, remains elusive in similar to 50% of ARVC patients. One of the reasons for missing genetic abnormalities is the difficulty in detecting large deletions/duplications, which are called as copy number variation (CNV) by the Sanger sequencing method. This study aimed to identify CNVs in PKP2 and a part of other desmosome genes in ARVC patients. The study cohort consisted of 71 ARVC probands who were diagnosed as definite or borderline cases based on 2010 Task Force Criteria. Among them, 32 (45%) carried at least one mutation in desmosome genes detected by the Sanger method. Using the multiplex ligation-dependent probe amplification method, we identified a male proband (1.4%) with a complete deletion of all PKP2 coding exons. He was 31 years old and showed exercise-induced sustained ventricular tachycardia with superior axis and left bundle-branch block pattern. His cardiac magnetic resonance imaging and computed tomography showed right ventricular dilatation and reduced ejection fraction. His 12-lead electrocardiogram showed T-wave inversion in V1-V3, and late potentials were positive, indicating definite ARVC. To confirm the precise location of the deletion, we performed relative quantitative PCR. We found complete deletion of both SYT10 and ALG10 located in 3' of PKP2; the total deletion size was at least 1.23 Mb. Screening for CNVs in desmosome genes is useful to identify the genetic basis of disease in clinically suspected ARVC patients.