title: A fast and cost-effective molecular diagnostic tool for genetic diseases involved in sudden cardiac death.
abstract: BACKGROUND
  Cardiomyopathies and arrhythmia syndromes are common genetic cardiac diseases that account for a significant number of sudden cardiac death (SCD) cases.
  
  
  METHODS
  NGS workflow based on a panel of 95 genes was developed on Illumina NextSeq500™ sequencer for sequencing prevalent SCD-causing genes. A cohort of 90 patients (56 genotype-positive, 27 genotype-negative and 7 new cases) was screened to evaluate this strategy in terms of sensitivity, specificity, practicability and cost. In silico analysis were performed using a pipeline based on NextGENe® software and a personalized Sophia Genetics pipeline.
  
  
  RESULTS
  Using our panel custom, 100% of targeted sequences were efficiently covered and all previously identified genetic variants were readily detected. Applied to 27 genotype-negative patients, this molecular strategy allowed the identification of pathogenic or likely pathogenic variants into 12 cases. It confirmed the involvement of HCN4 mutations in the combined bradycardia–myocardial non-compaction phenotype, and also suggested, for the first time, the involvement of PKP2, usually associated with arrhythmogenic right ventricular dysplasia, in ventricular non-compaction.
  
  
  CONCLUSIONS
  This NGS approach is a fast, cheap, sensitive and high-throughput mutation detection method that is ready to be deployed in clinical laboratories and would provide new insights on physiopathology of SCD, more particularly of cardiomyopathies and arrhythmia syndromes.
authors.affiliation: Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France; NGS Sequencing Platform for Molecular Diagnosis, Hospices Civils de Lyon, Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Chanavat
authors.affiliation: Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France; Université de Lyon, Lyon F-69003, France; Université Lyon 1, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Janin
authors.affiliation: Laboratoire de Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Lyon, France; NGS Sequencing Platform for Molecular Diagnosis, Hospices Civils de Lyon, Lyon, France; Université de Lyon, Lyon F-69003, France; Université Lyon 1, Lyon, France. Electronic address: gilles.millat@chu-lyon.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Millat
mesh_terms: D003362:Cost-Benefit Analysis; D016757:Death, Sudden, Cardiac; D005091:Exons / Q000235:genetics; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D025202:Molecular Diagnostic Techniques / Q000191:economics*; D013997:Time Factors
keywords: Arrhythmia syndromes; Cardiomyopathies; Molecular diagnosis; Mutations; NGS sequencing; Sudden cardiac death