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

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.

Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases

“…In addition, QTc interval prolongation is described in patients taking amphetamine-type stimulants [35], also detected in therapeutic concentration in this 31-year-old man. 15 Genetic testing in case IV identified one variant in KCNH2 (p.Lys897Thr) and several borderline variants in arrhythmia-associated genes (DSP: p.Ille2869Val; KCNQ1:…”

“…Loporcaro et al recently published a first proof-of-principle case report of a WES-based comprehensive molecular autopsy of an otherwise healthy 16-year-old SUDY (SUD in the young) victim, where they identified a pathogenic MYH7 mutation, previously described in familial HCM, sudden death, and impaired MHC-β actin-translocating and actin-activated ATPase activity [12]. Further studies described the detection of eight ultra-rare variants in seven of 14 Caucasian SUDY victims by focusing on 117 sudden deathsusceptibility genes and the identification of likely pathogenic variants in 34 genes in 20% of forensic SUD cases [8,15]. Post-mortem genetic analysis of SUD victims may not only enable an accurate determination of cause and manner of death, but may also have significant impact for affected living first-degree family members in whom death-predisposing disorders had remained unrecognized so far [16,17].…”

Role of risk stratification and genetics in sudden cardiac death

“…Channelopathy due to mutations is an important etiology of SCD and post-mortem genetic testing (Anderson et al 2016;Cann et al 2016), molecular screening (Kauferstein et al 2013), and next-generation sequencing (Campuzano et al 2014;Hertz et al 2015;Millet et al 2014). Whole exome sequencing may be a promising, time-and cost-effective technique for discovering the genetic basis of SCD in at-risk families and patients (Bagnall et al 2014;Hajj et al 2014;Narula et al 2015).…”

Next generation sequencing (NGS): a golden tool in forensic toolkit

“…Sudden cardiac death in young is often caused by cardiomyopathies and channelopathies [35]. Despite the progress in knowledge of SCD, it is a public-health problem [36].…”

“…Nagła śmierć sercowa u młodych osób jest często skutkiem kardiomiopatii i kanałopatii [35]. Niezależnie od rozwoju wiedzy na temat SCD, zjawisko nadal stanowi istotny problem dla zdrowia publicznego [36].…”