Key result
Desmosome gene copy number screening identifies complete PKP2 deletions in ~1.4% of ARVC probands.
Why the study?
The genetic cause remains unidentified in approximately 50% of ARVC patients due to difficulty detecting large deletions or duplications by Sanger sequencing.
Observational (n=71)
Screening for copy number variations in desmosome genes using MLPA is useful for identifying the genetic basis of disease in clinically suspected ARVC patients who lack mutations on standard sequencing.
May support CNV screening in Sanger-negative ARVC; leaves open prevalence and impact pending larger studies.
AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease mainly caused by desmosome gene mutations. The genetic culprit, however, remains elusive in ∼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. METHODS AND RESULTS: 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. CONCLUSION: Screening for CNVs in desmosome genes is useful to identify the genetic basis of disease in clinically suspected ARVC patients.
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Sonoda et al. (2016) conducted an observational in Arrhythmogenic right ventricular cardiomyopathy (ARVC) (n=71). Screening for copy number variations (CNVs) in desmosome genes was evaluated on Identification of complete deletion of all PKP2 coding exons. Screening for copy number variations in desmosome genes identified a complete deletion of all PKP2 coding exons in 1.4% of ARVC probands.
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