Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting

Abstract

In forensic medicine, one-third of the sudden deaths remain unexplained after medico-legal autopsy. A major proportion of these sudden unexplained deaths (SUD) are considered to be caused by inherited cardiac diseases. Sudden cardiac death (SCD) may be the first manifestation of these diseases. The purpose of this study was to explore the yield of next-generation sequencing of genes associated with SCD in a cohort of SUD victims. We investigated 100 genes associated with cardiac diseases in 61 young (1-50 years) SUD cases. DNA was captured with the Haloplex target enrichment system and sequenced using an Illumina MiSeq. The identified genetic variants were evaluated and classified as likely, unknown or unlikely to have a functional effect. The criteria for this classification were based on the literature, databases, conservation and prediction of the effect of the variant. We found that 21 (34%) individuals carried variants with a likely functional effect. Ten (40%) of these variants were located in genes associated with cardiomyopathies and 15 (60%) of the variants in genes associated with cardiac channelopathies. Nineteen individuals carried variants with unknown functional effect. Our findings indicate that broad genetic investigation of SUD victims increases the diagnostic outcome, and the investigation should comprise genes involved in both cardiomyopathies and cardiac channelopathies.

Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two‐year prospective study in a large medical examiner’s office with an in‐house molecular genetics laboratory and genetic counseling services

“…Cardiac channelopathy and cardiomyopathy have been widely recognized as causes of deaths in individuals who died suddenly in a natural manner (Fernandez-Falgueras, Sarquella-Brugada, Brugada, Brugada, & Campuzano, 2017;Magi, Lariccia, Maiolino, Amoroso, & Gratteri, 2017). Studies have shown that 13%-41% of the time, a pathogenic or likely pathogenic genetic change can be identified through postmortem genetic testing in SD, which is consistent with a NAME position statement that suggests this number could be up to 40% (Campuzano et al, 2014;Christiansen et al, 2016;Lahrouchi et al, 2017;Middleton et al, 2013;Stattin et al, 2016;Tester, Medeiros-Domingo, Will, Haglund, & Ackerman, 2012). Two separate studies found that a clinical diagnosis was established in family members of a decedent with a pathogenic variant in a cardiac gene approximately 12%-13% of the time (Bagnall et al, 2016;Lahrouchi et al, 2017).…”

“…The yield, or percentage of positive cases, of 10.6% is markedly lower than other cohorts which have described yields upwards of 40% (Campuzano et al, 2014;Christiansen et al, 2016;Lahrouchi et al, 2017;Middleton et al, 2013;Stattin et al, 2016;Tester et al, 2012). This could be due to the inclusion of genes associated with both channelopathies and cardiomyopathies, for all SD cases deemed necessary for testing by medical examiners, versus stringent inclusion criteria and more targeted panels.…”

Sudden arrhythmia death syndrome in young victims: a five-year retrospective review and two-year prospective molecular autopsy study by next-generation sequencing and clinical evaluation of their first-degree relatives

“…Post-mortem genetic studies have shown that SCD in these victims can be caused by fatal arrhythmias secondary to a group of inheritable cardiac electrical disorders collectively known as sudden arrhythmia death syndrome (SADS). [10][11][12][13][14] These include Brugada syndrome (BrS), long QT syndrome (LQTS), short QT syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), and other cardiomyopathies.…”

Current approaches to the investigation and protection methods of sudden cardiac deaths

“…Bu da bu vakalarda yaştan bağımsız bir şekilde ayrıntılı genetik incelemenin yapılmasını tanısal bilgimizin artması perspektifinden destekler niteliktedir. (9) 10318 hastanın katıldığı bir meta-analizde 261 tesadüfi AKÖ vakası değerlendirilmiş (ortalama takip süresi 9,1 yıl) ve yüksek serbest T4 seviyelerinin tiroid fonksiyonu normal olsa bile artmış AKÖ riski ile ilişkili olduğu gösterilmiştir. Yaş, cinsiyet ve duyarlılık analizlerinde yapılan düzeltmelerle de riskte anlamlı bir değişim olmamıştır.…”