title: Postmortem genetic analysis of sudden unexplained death syndrome under 50 years of age: A next-generation sequencing study.
abstract: Recent studies on the genetic analysis of victims of sudden unexplained death syndrome (SUDS) have shown diagnostic potential. Previously, such analyses mainly targeted the major channelopathy-associated genes.
  
  
  
  The purpose of this study was to evaluate the utility of next-generation sequencing (NGS) in the postmortem diagnosis of SUDS.
  
  
  
  Our data are derived from 25 cases of SUDS (21 men and 4 women; age 19-50 years). A total of 70 genes were examined by NGS, and the pathogenicity of any detected rare variants with minor allele frequencies of <0.5% was evaluated using a widely used database and eight in silico algorithms.
  
  
  
  Five known and 15 potentially pathogenic variants with a high in silico score were identified in 14 cases. In all, 6 channelopathy-related variants were identified in 5 cases, including 2 cases with history of arrhythmia; 11 cases had cardiomyopathy- or cardiac transcription factor-related variants. Three cases with desmosomal gene- or other cardiomyopathy-related variants showed possibly related pathologic changes. Three cases with RYR2 or TBX5 variants showed possible pathogenic fibrosis of the cardiac conduction system. Only 12 variants showed moderate or strong possible pathogenicity in SUDS cases compared with qualifying controls.
  
  
  
  Hereditary heart diseases other than channelopathy may also be a significant cause of SUDS, even if clinical and pathologic findings do not show advanced disease. A combination of gene analysis using NGS and some predictive methods for detecting variants and careful pathologic evaluation may provide a reliable diagnosis of hereditary heart disease for potential SUDS cases.
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hata
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Kinoshita
authors.affiliation: Clinical Research and Ethics Center, University of Toyama, Toyoma, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Mizumaki
authors.affiliation: Second Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyoma, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hirono
authors.affiliation: Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyoma, Japan.
authors.forename: Fukiko
authors.initials: F
authors.lastname: Ichida
authors.affiliation: Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyoma, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Takasaki
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyoma, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Legal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. Electronic address: nishida@med.u-toyama.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishida
mesh_terms: D000328:Adult; D017487:Ankyrins / Q000235:genetics; D001344:Autopsy; D003645:Death, Sudden / Q000209:etiology / Q000473:pathology; D003933:Diagnosis; D005260:Female; D006331:Heart Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D020825:T-Box Domain Proteins / Q000235:genetics
chemical_list: C498994:ANK2 protein, human; D017487:Ankyrins; C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5
keywords: Arrhythmogenic right ventricular cardiomyopathy; Autopsy; Cardiomyopathy; Channelopathy; Next-generation sequencing; Pathology; Sudden unexplained death syndrome