TY - JOUR

T1 - Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases

AU - Hertz, Christin Løth

AU - Christiansen, Sofie Lindgren

AU - Ferrero-Miliani, Laura

AU - Fordyce, Sarah Louise

AU - Dahl, Morten

AU - Holst, Anders Gaarsdal

AU - Ottesen, Gyda Lolk

AU - Frank-Hansen, Rune

AU - Bundgaard, Henning

AU - Morling, Niels

PY - 2015/7

Y1 - 2015/7

N2 - 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.

AB - 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.

U2 - 10.1007/s00414-014-1105-y

DO - 10.1007/s00414-014-1105-y

M3 - Journal article

C2 - 25467552

VL - 129

SP - 793

EP - 800

JO - International Journal of Legal Medicine

JF - International Journal of Legal Medicine

SN - 0937-9827

IS - 4

ER -