WHOLE-EXOME SEQUENCING IDENTIFIES A POTENTIALLY PATHOGENIC VARIANT IN A HIGH PROPORTION OF IDIOPATHIC VENTRICULAR FIBRILLATION PROBANDS FROM THE CASPER REGISTRY
R. Tadros, A.D. Krahn, K.S. Lo, N. Chami, J.S. Healey, V.S. Chauhan, D.H. Birnie, J. Champagne, S. Sanatani, P. Angaran, R.M. Gow, S. Chakrabarti, B. Gerull, L. Sterns, R. Yee, L.J. Gula, G.J. Klein, M.H. Gollob, M. Gardner, C.S. Simpson, M. Talajic, G. Lettre
Department of Medicine, Montreal Heart Institute and Université de Montréal, Canada Whole-exome sequencing identifies a potentially pathogenic variant in a high proportion of idiopathic ventricular fibrillation probands from the CASPER registry
Introduction: The genetics of idiopathic ventricular fibrillation (IVF) remains largely elusive. We assessed the yield of whole-exome sequencing (WES) in identifying pathogenic variants in IVF probands from the CASPER registry.
Methods: Patients with a history of ventricular fibrillation without a specific etiology despite extensive workup underwent WES using NimbleGen SeqCap and Illumina HiSeq2000. Only rare variants ( < 0.1% in exome aggregation consortium) predicted to be damaging (PolyPhen2 or SIFT) were considered.
Results: WES performed in 23 IVF probands yielded a mean coverage of 105X (93% at >20X). There was no enrichment of variants in any single gene compared to data from the Exome Sequencing Project. We identified 15 rare, predicted damaging variants in known arrhythmia/cardiomyopathy genes in 11 patients (48%). Among these variants, 5 are novel while 3 were previously reported in patients with arrhythmogenic cardiomyopathy or long QT syndrome.
Conclusions: Whole-exome sequencing identifies rare potentially pathogenic variants in arrhythmia and cardiomyopathy genes in nearly half of this IVF cohort. Functional and segregation analyses are required to assess pathogenicity. Our data support the heterogenic genetic nature of IVF.
