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Post-mortem whole-exome sequencing(WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death(SUD) cases


Neubauer, Jacqueline; Haas, Cordula; Bartsch, Christine; Medeiros-Domingo, Argelia; Berger, Wolfgang (2016). Post-mortem whole-exome sequencing(WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death(SUD) cases. International journal of legal medicine, 130(4):1011-1021.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Neuroscience Center Zurich
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > Institute of Legal Medicine
04 Faculty of Medicine > Institute of Medical Molecular Genetics
Dewey Decimal Classification:340 Law
610 Medicine & health
Uncontrolled Keywords:Cardiac diseases; Molecular autopsy; Sudden unexplained death; Whole-exome sequencing
Language:English
Date:2016
Deposited On:06 May 2016 16:24
Last Modified:31 Aug 2016 07:39
Publisher:Springer
ISSN:0937-9827
Additional Information:The final publication is available at Springer via http://dx.doi.org/10.1007/s00414-016-1317-4
Publisher DOI:https://doi.org/10.1007/s00414-016-1317-4
PubMed ID:26846766

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Embargo till: 2017-02-04

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