title: Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death with structural abnormalities of the heart.
abstract: BACKGROUND
  In sudden, unexpected, non-traumatic death in young individuals, structural abnormalities of the heart are frequently identified at autopsy. However, the findings may be unspecific and cause of death may remain unclear. A significant proportion of these cases are most likely caused by inherited cardiac diseases, and the cases are categorized as sudden cardiac death (SCD). The purpose of this study was to explore the added diagnostic value of genetic testing by next-generation sequencing (NGS) of a broad gene panel, as a supplement to the traditional forensic investigation in cases with non-diagnostic structural abnormalities of the heart.
  
  
  RESULTS
  We screened 72 suspected SCD cases (<50 years) using the HaloPlex Target Enrichment System (Agilent) and NGS (Illumina MiSeq) for 100 genes previously associated with inherited cardiomyopathies and channelopathies. Fifty-two cases had non-diagnostic structural cardiac abnormalities and 20 cases, diagnosed with a cardiomyopathy post-mortem (ARVC = 14, HCM = 6), served as comparators. Fifteen (29%) of the deceased individuals with non-diagnostic findings had variants with likely functional effects based on conservation, computational prediction, allele-frequency and supportive literature. The corresponding frequency in deceased individuals with cardiomyopathies was 35% (p = 0.8).
  
  
  CONCLUSIONS
  The broad genetic screening revealed variants with likely functional effects at similar high rates, i.e. in 29 and 35% of the suspected SCD cases with non-diagnostic and diagnostic cardiac abnormalities, respectively. Although the interpretation of broad NGS screening is challenging, it can support the forensic investigation and help the cardiologist's decision to offer counselling and clinical evaluation to relatives of young SCD victims.
authors.affiliation: The Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 11 Frederik V's Vej, 2100, Copenhagen, Denmark. christin.hertz@sund.ku.dk.
authors.forename: C L
authors.initials: CL
authors.lastname: Hertz
authors.affiliation: The Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 11 Frederik V's Vej, 2100, Copenhagen, Denmark.
authors.forename: S L
authors.initials: SL
authors.lastname: Christiansen
authors.affiliation: The Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 11 Frederik V's Vej, 2100, Copenhagen, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Ferrero-Miliani
authors.affiliation: The Department of Clinical Biochemistry, Køge University Hospital, Køge, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Dahl
authors.affiliation: The Department of Cardiology, Laboratory of Molecular Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: P E
authors.initials: PE
authors.lastname: Weeke
authors.affiliation: The Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: G L
authors.initials: GL
authors.lastname: Ottesen
authors.affiliation: The Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 11 Frederik V's Vej, 2100, Copenhagen, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Frank-Hansen
authors.affiliation: The Unit for Inherited Cardiac Diseases, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: H
authors.initials: H
authors.lastname: Bundgaard
authors.affiliation: The Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 11 Frederik V's Vej, 2100, Copenhagen, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Morling
mesh_terms: D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D005355:Fibrosis; D053803:Forensic Genetics; D049429:Forensic Pathology; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D055815:Young Adult
keywords: Cardiomyopathy; Genetics; Next-generation sequencing; Pathology; Sudden cardiac death; Sudden death