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Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases

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Abstract

Sudden cardiac death (SCD) is responsible for a large proportion of sudden deaths in young individuals. In forensic medicine, many cases remain unexplained after routine postmortem autopsy and conventional investigations. These cases are called sudden unexplained deaths (SUD). Genetic testing has been suggested useful in forensic medicine, although in general with a significantly lower success rate compared to the clinical setting. The purpose of the study was to estimate the frequency of pathogenic variants in the genes most frequently associated with SCD in SUD cases and compare the frequency to that in patients with inherited cardiac channelopathies. Fifteen forensic SUD cases and 29 patients with channelopathies were investigated. DNA from 34 of the genes most frequently associated with SCD were captured using NimbleGen SeqCap EZ library build and were sequenced with next-generation sequencing (NGS) on an Illumina MiSeq. Likely pathogenic variants were identified in three out of 15 (20 %) forensic SUD cases compared to 12 out of 29 (41 %) patients with channelopathies. The difference was not statistically significant (p = 0.1). Additionally, two larger deletions of entire exons were identified in two of the patients (7 %). The frequency of likely pathogenic variants was >2-fold higher in the clinical setting as compared to SUD cases. However, the demonstration of likely pathogenic variants in three out of 15 forensic SUD cases indicates that NGS investigations will contribute to the clinical investigations. Hence, this has the potential to increase the diagnostic rate significantly in the forensic as well as in the clinical setting.

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Acknowledgments

This work was supported by Ellen and Aage Andersen’s foundation. The authors thank Francisc-Raul Kantor for the bioinformatics support.

Conflict of interest

The authors declare that they have no conflict of interest. AGH is an employee of Novo Nordisk A/S, Denmark.

Author information

Authors and Affiliations

  1. 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

    C. L. Hertz, S. L. Christiansen, L. Ferrero-Miliani, S. L. Fordyce, R. Frank-Hansen & N. Morling

  2. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark

    M. Dahl & H. Bundgaard

  3. The Unit for Inherited Cardiac Diseases, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    A. G. Holst

  4. Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    G. L. Ottesen

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  1. C. L. Hertz
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  2. S. L. Christiansen
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  3. L. Ferrero-Miliani
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  6. A. G. Holst
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  7. G. L. Ottesen
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  8. R. Frank-Hansen
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  9. H. Bundgaard
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Correspondence to C. L. Hertz.

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Hertz, C.L., Christiansen, S.L., Ferrero-Miliani, L. et al. Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases. Int J Legal Med 129, 793–800 (2015). https://doi.org/10.1007/s00414-014-1105-y

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  • DOI: https://doi.org/10.1007/s00414-014-1105-y

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