title: Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases.
abstract: Sudden death of healthy young adults in the absence of any medical reason is generally categorised as autopsy-negative sudden unexplained death (SUD). Approximately 30 % of all SUD cases can be explained by lethal sequence variants in cardiac genes causing disturbed ion channel functions (channelopathies) or minimal structural heart abnormalities (cardiomyopathies). The aim of this study was to perform whole-exome sequencing (WES) in five young SUD cases in order to identify potentially disease-causing mutations with a focus on 184 genes associated with cardiac diseases or sudden death. WES analysis enabled the identification of damaging-predicted cardiac sequence alterations in three out of five SUD cases. Two SUD victims carried disease-causing variants in long QT syndrome (LQTS)-associated genes (KCNH2, SCN5A). In a third case, WES identified variants in two genes involved in mitral valve prolapse and thoracic aortic aneurism (DCHS1, TGFβ2). The genome of a fourth case carried several minor variants involved in arrhythmia pointing to a multigene influence that might have contributed to sudden death. Our results confirm that post-mortem genetic testing in SUD cases in addition to the conventional autopsy can help to identify familial cardiac diseases and can contribute to the identification of genetic risk factors for sudden death.
authors: Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057, Zurich, Switzerland. jacqueline.neubauer@irm.uzh.ch.
authors: Jacqueline
authors: J
authors: Neubauer
authors: Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057, Zurich, Switzerland.
authors: Cordula
authors: C
authors: Haas
authors: Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057, Zurich, Switzerland.
authors: Christine
authors: C
authors: Bartsch
authors: Department of Cardiology, Inselspital, University Hospital, Bern, Switzerland.
authors: Argelia
authors: A
authors: Medeiros-Domingo
authors: Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.|Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.|Neuroscience Center (ZNZ), University and ETH Zurich, Zurich, Switzerland.
authors: Wolfgang
authors: W
authors: Berger
mesh_terms: D000328:Adult; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D003645:Death, Sudden / Q000209:etiology*; D000072237:ERG1 Potassium Channel / Q000235:genetics*; D005260:Female; D053803:Forensic Genetics; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D011110:Polymorphism, Genetic; D053781:Transforming Growth Factor beta2 / Q000235:genetics*; D055815:Young Adult
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; D000072237:ERG1 Potassium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D053781:Transforming Growth Factor beta2; C442479:DCHS1 protein, human; C000606913:KCNH2 protein, human; C568320:SCN5A protein, human
keywords: Cardiac diseases; Molecular autopsy; Sudden unexplained death; Whole-exome sequencing