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01-01-2016 | Original Article

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

Authors: C. L. Hertz, S. L. Christiansen, L. Ferrero-Miliani, M. Dahl, P. E. Weeke, G. L. Ottesen, R. Frank-Hansen, H. Bundgaard, N. Morling, LuCamp

Published in: International Journal of Legal Medicine | Issue 1/2016

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.

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Hertz CL, Christiansen SL, Larsen MK, Dahl M, Ferrero-Miliani L, Weeke PE, Pedersen O, Hansen T, Grarup N, Ottesen GL, Frank-Hansen R, Banner J, Morling N (2015) Genetic investigations of sudden unexpected deaths in infancy using next-generation sequencing of 100 genes associated with cardiac diseases. Eur J Human Genet Accept. In press

Title: Next-generation sequencing of 100 candidate genes in young victims of suspected sudden cardiac death with structural abnormalities of the heart
Authors: C. L. Hertz
S. L. Christiansen
L. Ferrero-Miliani
M. Dahl
P. E. Weeke
G. L. Ottesen
R. Frank-Hansen
H. Bundgaard
N. Morling
LuCamp
Publication date: 01-01-2016
Publisher: Springer Berlin Heidelberg
Published in: International Journal of Legal Medicine / Issue 1/2016
Print ISSN: 0937-9827
Electronic ISSN: 1437-1596
DOI: https://doi.org/10.1007/s00414-015-1261-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods and results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods and results

Conclusion

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