Post-mortem genetic analysis in juvenile cases of sudden cardiac death

Abstract

Background: The reason behind a sudden death of a young individual remains unknown in up to 50% of postmortem cases. Pathogenic mutations in genes encoding heart proteins are known to cause sudden cardiac death. Objective: The aim of our study was to ascertain whether genetic alterations could provide an explanation for sudden cardiac death in a juvenile cohort with no-conclusive cause of death after comprehensive autopsy. Methods: Twenty-nine cases <15 years showing no-conclusive cause of death after a complete autopsy were studied. Genetic analysis of 7 main genes associated with sudden cardiac death was performed using Sanger technology in low quality DNA cases, while in good quality cases the analysis of 55 genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Results: Thirty-five genetic variants were identified in 12 cases (41.37%). Ten genetic/variants in genes encoding cardiac ion channels were identified in 8 cases (27.58%). We also identified 9 cases (31.03%) carrying 25 genetic variants in genes encoding structural cardiac proteins. Nine cases carried more than one genetic variation, 5 of them combining structural and non-structural genes. Conclusions: Our study supports the inclusion of molecular autopsy in forensic routine protocols when no conclusive cause of death is identified. Around 40% of sudden cardiac death young cases carry a genetic variant that could provide an explanation for the cause of death. Because relatives could be at risk of sudden cardiac death, our data reinforce their need of clinical assessment and, if indicated, of genetic analysi

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

“…Post-mortem genetic testing by using specific gene panels or whole-exome sequencing (WES) represents an efficient tool to elucidate potential disease-causing mechanisms, which remained undetected during autopsy [8,12,13]. The exome represents approximately 1-2% of 4 the human genome, but it accounts for over 85% of all mutations that have been identified in Mendelian disorders [14].…”

Targeted next generation sequencing application in cardiac channelopathies: Analysis of a cohort of autopsy-negative sudden unexplained deaths

“…His medical history was unremarkable. The variant c.3457C > T (p.His1153Tyr) was previously reported in Table 4 List of all putatively pathogenic variants identified in the cohort within the 23 LQTS patients by Napolitano et al [30] and is reported in the Human Gene Mutation Database [31]. Case 5: Missense variants c.6007G > A (p.Asp2003Asn) in the SCN5A gene, previously undescribed, and c.5509G > A (p.Glu1837Lys) in the ANK2 gene, described by Mohler et al [32], were identified in a 20-year-old female who collapsed during psychiatric hospitalization, 2 weeks after her admission.…”

“…Until now, to our knowledge, only three studies have performed genetic testing using NGS technology on post-mortem samples of SUD. The study of Brion et al [21] used the SOLID TM system and the studies of Hertz et al [22] and Campuzano et al [23] used the MiSeq Illumina sequencer.…”

Negative Autopsy in Infant and Juvenile Population: Role of Cardiac Arrhythmias

“…Genetic analysis in post-mortem patients (also called molecular autopsy) may identify the genetic alteration responsible for an arrhythmogenic cardiac disease [5]. Current guidelines recommend performing the molecular autopsy in all these cases as a part of the comprehensive medico-legal investigation in SCD cases [6] but post-mortem genetic testing of the proband was reported in a low percentage of SCD cases with no structural alterations patients [7][8][9], mainly because forensic centers do not have the economic resources to perform genetic testing or do not collect samples due to currently legal restrictions involved with the sampling and storage of DNA [10].…”