Alexandre Janin1,2,3, Louis Januel1, Cécile Cazeneuve1, Antoine Delinière3,4, Philippe Chevalier3,4, Gilles Millat5,6,7. 1. Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron Cedex, 69677, Lyon, France. 2. Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France. 3. Université de Lyon, 69003, Lyon, France. 4. Hôpital Cardiologique Louis Pradel, Service de Rythmologie, Lyon, France. 5. Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron Cedex, 69677, Lyon, France. gilles.millat@chu-lyon.fr. 6. Institut NeuroMyoGène, CNRS UMR 5310, INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France. gilles.millat@chu-lyon.fr. 7. Université de Lyon, 69003, Lyon, France. gilles.millat@chu-lyon.fr.
Abstract
BACKGROUND AND OBJECTIVE: Molecular diagnosis in inherited cardiac diseases is challenging because of the significant genetic and clinical heterogeneity. We present a detailed molecular investigation of a cohort of 4185 patients with referrals for inherited cardiac diseases. METHODS: Patients suffering from cardiomyopathies (3235 probands), arrhythmia syndromes (760 probands), or unexplained sudden cardiac arrest (190 cases) were analyzed using a next-generation sequencing (NGS) workflow based on a panel of 105 genes involved in sudden cardiac death. RESULTS: (Likely) pathogenic variations were identified for approximately 30% of the cohort. Pathogenic copy number variations (CNVs) were detected in approximately 3.1% of patients for whom a (likely) pathogenic variation were identified. A (likely) pathogenic variation was also detected for 21.1% of patients who died from sudden cardiac death. Unexpected variants, including incidental findings, were present for 28 cases. Pathogenic variations were mainly observed in genes with definitive evidence of disease causation. CONCLUSIONS: Our study, which comprises over than 4000 probands, is one of most important cohorts reported in inherited cardiac diseases. The global mutation detection rate would be significantly increased by determining the putative pathogenicity of the large number of variants of uncertain significance. Identification of "unexpected" variants also showed the clinical utility of genetic testing in inherited cardiac diseases as they can redirect clinical management and medical resources toward a meaningful precision medicine. In cases with negative result, a WGS approach could be considered, but would probably have a limited impact on mutation detection rate as (likely) pathogenic variations were essentially clustered in genes with strong evidence of disease causation.
BACKGROUND AND OBJECTIVE: Molecular diagnosis in inherited cardiac diseases is challenging because of the significant genetic and clinical heterogeneity. We present a detailed molecular investigation of a cohort of 4185 patients with referrals for inherited cardiac diseases. METHODS: Patients suffering from cardiomyopathies (3235 probands), arrhythmia syndromes (760 probands), or unexplained sudden cardiac arrest (190 cases) were analyzed using a next-generation sequencing (NGS) workflow based on a panel of 105 genes involved in sudden cardiac death. RESULTS: (Likely) pathogenic variations were identified for approximately 30% of the cohort. Pathogenic copy number variations (CNVs) were detected in approximately 3.1% of patients for whom a (likely) pathogenic variation were identified. A (likely) pathogenic variation was also detected for 21.1% of patients who died from sudden cardiac death. Unexpected variants, including incidental findings, were present for 28 cases. Pathogenic variations were mainly observed in genes with definitive evidence of disease causation. CONCLUSIONS: Our study, which comprises over than 4000 probands, is one of most important cohorts reported in inherited cardiac diseases. The global mutation detection rate would be significantly increased by determining the putative pathogenicity of the large number of variants of uncertain significance. Identification of "unexpected" variants also showed the clinical utility of genetic testing in inherited cardiac diseases as they can redirect clinical management and medical resources toward a meaningful precision medicine. In cases with negative result, a WGS approach could be considered, but would probably have a limited impact on mutation detection rate as (likely) pathogenic variations were essentially clustered in genes with strong evidence of disease causation.
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Authors: Eimo Martens; Moritz F Sinner; Johannes Siebermair; Carsten Raufhake; Britt M Beckmann; Stefan Veith; Dieter Düvel; Gerhard Steinbeck; Stefan Kääb Journal: Europace Date: 2014-07-24 Impact factor: 5.214