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- Title
Contribution of exome sequencing for genetic diagnostic in arrhythmogenic right ventricular cardiomyopathy/dysplasia.
- Authors
Fedida, Joel; Fressart, Veronique; Charron, Philippe; Surget, Elodie; Hery, Tiphaine; Richard, Pascale; Donal, Erwan; Keren, Boris; Duthoit, Guillaume; Hidden-Lucet, Françoise; Villard, Eric; Gandjbakhch, Estelle
- Abstract
Background: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing. Methods: WES was performed in 22 patients, all without a mutation identified in desmosomal genes. Putative pathogenic variants were screened in 96 candidate genes associated with other cardiomyopathies/channelopathies. The sequencing coverage depth of PKP2, DSP, DSG2, DSC2, JUP and TMEM43 exons was compared to the mean coverage distribution to detect large insertions/deletions. All suspected deletions were verified by real-time qPCR, Multiplex-Ligation-dependent-Probe-Amplification (MLPA) and cGH-Array. MLPA was performed in 50 additional gene-negative probands. Results: Coverage-depth analysis from the 22 WES data identified two large heterozygous PKP2 deletions: one from exon 1 to 14 and one restricted to exon 4, confirmed by qPCR and MLPA. MLPA identified 2 additional PKP2 deletions (exon 1–7 and exon 1–14) in 50 additional probands confirming a significant frequency of large PKP2 deletions (5.7%) in gene-negative ARVC/D. Putative pathogenic heterozygous variants in EYA4, RBM20, PSEN1, and COX15 were identified in 4 unrelated probands. Conclusion: A rather high frequency (5.7%) of large PKP2 deletions, undetectable by Sanger sequencing, was detected as the cause of ARVC/D. Coverage-depth analysis through next-generation sequencing appears accurate to detect large deletions at the same time than conventional putative mutations in desmosomal and cardiomyopathy-associated genes.
- Subjects
DYSPLASIA; GENETIC mutation; CARDIOMYOPATHIES; GENETIC testing; DIAGNOSIS; DISEASE risk factors
- Publication
PLoS ONE, 2017, Vol 12, Issue 8, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0181840