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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

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An Erratum to this article was published on 10 March 2016

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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Acknowledgments

This project was supported by the Swiss National Science Foundation (SNF, project-Nr. 320030_149456). Special thanks to Luzy Bähr and Silke Feil for technical support, to Barbara Fliss for the colour images of the histological sections, and to Claudine Rieubland for additional information regarding the family history of case V.

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Authors and Affiliations

  1. Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057, Zurich, Switzerland

    Jacqueline Neubauer, Cordula Haas & Christine Bartsch

  2. Department of Cardiology, Inselspital, University Hospital, Bern, Switzerland

    Argelia Medeiros-Domingo

  3. Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland

    Wolfgang Berger

  4. Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

    Wolfgang Berger

  5. Neuroscience Center (ZNZ), University and ETH Zurich, Zurich, Switzerland

    Wolfgang Berger

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  1. Jacqueline Neubauer
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Correspondence to Jacqueline Neubauer.

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Neubauer, J., Haas, C., Bartsch, C. et al. Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases. Int J Legal Med 130, 1011–1021 (2016). https://doi.org/10.1007/s00414-016-1317-4

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