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International Journal of Legal Medicine

, Volume 130, Issue 1, pp 91–102 | Cite as

Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death with structural abnormalities of the heart

  • C. L. HertzEmail author
  • S. L. Christiansen
  • L. Ferrero-Miliani
  • M. Dahl
  • P. E. Weeke
  • LuCamp
  • G. L. Ottesen
  • R. Frank-Hansen
  • H. Bundgaard
  • N. Morling
Original Article

Abstract

Background

In sudden, unexpected, non-traumatic death in young individuals, structural abnormalities of the heart are frequently identified at autopsy. However, the findings may be unspecific and cause of death may remain unclear. A significant proportion of these cases are most likely caused by inherited cardiac diseases, and the cases are categorized as sudden cardiac death (SCD). The purpose of this study was to explore the added diagnostic value of genetic testing by next-generation sequencing (NGS) of a broad gene panel, as a supplement to the traditional forensic investigation in cases with non-diagnostic structural abnormalities of the heart.

Methods and results

We screened 72 suspected SCD cases (<50 years) using the HaloPlex Target Enrichment System (Agilent) and NGS (Illumina MiSeq) for 100 genes previously associated with inherited cardiomyopathies and channelopathies. Fifty-two cases had non-diagnostic structural cardiac abnormalities and 20 cases, diagnosed with a cardiomyopathy post-mortem (ARVC = 14, HCM = 6), served as comparators. Fifteen (29 %) of the deceased individuals with non-diagnostic findings had variants with likely functional effects based on conservation, computational prediction, allele-frequency and supportive literature. The corresponding frequency in deceased individuals with cardiomyopathies was 35 % (p = 0.8).

Conclusion

The broad genetic screening revealed variants with likely functional effects at similar high rates, i.e. in 29 and 35 % of the suspected SCD cases with non-diagnostic and diagnostic cardiac abnormalities, respectively. Although the interpretation of broad NGS screening is challenging, it can support the forensic investigation and help the cardiologist’s decision to offer counselling and clinical evaluation to relatives of young SCD victims.

Keywords

Cardiomyopathy Sudden death Sudden cardiac death Genetics Pathology Next-generation sequencing 

Notes

Acknowledgments

The authors thank Francisc-Raul Kantor for bioinformatics support. For the screening of variants among Danish controls, we thank LuCamp, The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention, and Care (www.lucamp.org), and the Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent Research Center at the University of Copenhagen partially supported by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk).

Funding sources

This work was supported by Ellen and Aage Andersen’s foundation and The A.P. Møller Foundation.

Conflic of interest

The authors declare that they have no competing interests.

Supplementary material

414_2015_1261_MOESM1_ESM.pdf (480 kb)
ESM 1 (PDF 479 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • C. L. Hertz
    • 1
    Email author
  • S. L. Christiansen
    • 1
  • L. Ferrero-Miliani
    • 1
  • M. Dahl
    • 2
  • P. E. Weeke
    • 3
  • LuCamp
    • 4
  • G. L. Ottesen
    • 5
  • R. Frank-Hansen
    • 1
  • H. Bundgaard
    • 6
  • N. Morling
    • 1
  1. 1.The Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  2. 2.The Department of Clinical BiochemistryKøge University HospitalKøgeDenmark
  3. 3.The Department of Cardiology, Laboratory of Molecular CardiologyCopenhagen University Hospital RigshospitaletCopenhagenDenmark
  4. 4.The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and CareCopenhagenDenmark
  5. 5.The Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  6. 6.The Unit for Inherited Cardiac Diseases, The Heart Centre, RigshospitaletCopenhagen University HospitalCopenhagenDenmark

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