Unveiling a sudden unexplained death case by whole exome sequencing and bioinformatic analysis

Modena, Martina; Castiglione, Vincenzo; Aretini, Paolo; Mazzanti, Chiara Maria; Chiti, Enrica; Giannoni, Alberto; Emdin, Michele; Paolo, Marco Di

doi:10.1002/mgg3.1182

Cited by 7 publications

(5 citation statements)

References 25 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, combined heterozygous rare variants were found in 3 of the 25 cases, and 2 subjects carried 3 or more variants [39]. These data support the notion that the paradigm of "one gene-one disease" may not apply to all SUD cases, which may sometimes result from the interaction of multiple mutations, as also postulated in a case report by our group [40].…”

Section: Next-generation Sequencing In Sudden Cardiac Deathsupporting

confidence: 84%

Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

et al. 2021

Self Cite

View full text Add to dashboard Cite

Molecular autopsy is the process of investigating sudden death through genetic analysis. It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. The final goal of molecular autopsy in SUD cases is to aid medico-legal inquiries and to guide cascade genetic screening of the victim’s relatives. Early attempts of molecular autopsy relied on Sanger sequencing, which, despite being accurate and easy to use, has a low throughput and can only be employed to analyse a small panel of genes. Conversely, the recent adoption of next-generation sequencing (NGS) technologies has allowed exome/genome wide examination, providing an increase in detection of pathogenic variants and the discovery of newer genotype-phenotype associations. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the clinical interpretation of the large number of variants of unknown significance detected in each individual.

show abstract

Section: Next-generation Sequencing In Sudden Cardiac Deathsupporting

confidence: 84%

Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…For genetic diagnosis, only panels have been used regularly to date. In the last few years, hospitals and centers of genetic diagnosis use WES approach, but the final report is only performed focused on a list of concrete genes associated with the suspected or diagnosed IAS; the main reason is the similar economic cost and potential use of genetic data in diagnosis, as well as for research purposes (68)(69)(70)(71)(72)(73)(74)(75)(76)(77). However, ethical issues should be considered and patient consent should include all data concerning genetic analysis that will be performed, as well as potential clinical implications.…”

Section: Genetic Analysis/interpretationmentioning

confidence: 99%

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

et al. 2023

View full text Add to dashboard Cite

In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim’s relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.

show abstract

“…Both WES and WGS approaches are used mainly for research proposes. It is important to remark that some hospitals and centres of genetic diagnosis use WES approach but a final report is only performed focused on a list of genes associated with the suspected or diagnosed disease, in the same way that occurs using a panel [35][36][37][38][39][40][41] .…”

Section: Genetic Analysismentioning

confidence: 99%

Molecular autopsy in sudden cardiac death

Campuzano

Sarquella‐Brugada

2023

gcsp

View full text Add to dashboard Cite

A post-mortem genetic analysis in the process of investigating a sudden death episode is known as ‘molecular autopsy’. It is usually performed in cases without a conclusive cause of death and after a comprehensive medico-legal autopsy. In these sudden unexplained death cases, an underlying inherited arrhythmogenic cardiac disease is the main suspected cause of death. The objective is to unravel a genetic diagnosis of the victim, but it also enables cascade genetic screening of the victim’s relatives. Early identification of a deleterious genetic alteration associated with an inherited arrhythmogenic disease may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death. It is important to remark that the first symptom of an inherited arrhythmogenic cardiac disease may the malignant arrhythmia and even sudden death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis. Close interaction between the forensic scientist, pathologist, cardiologist, pediatric cardiologist and geneticist has allowed a progressive increase of genetic yield in recent years, identifying the pathogenic genetic alteration. However, large numbers of rare genetic alterations remain classified as having an ambiguous role, impeding a proper genetic interpretation and useful translation into both forensic and cardiological arena.

show abstract

Unveiling a sudden unexplained death case by whole exome sequencing and bioinformatic analysis

Cited by 7 publications

References 25 publications

Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death

Molecular autopsy in sudden cardiac death

Contact Info

Product

Resources

About