Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

Vincenzo Castiglione; Martina Modena; Alberto Aimo; Enrica Chiti; Nicoletta Botto; Simona Vittorini; Benedetta Guidi; Giuseppe Vergaro; Andrea Barison; Andrea Rossi; Claudio Passino; Alberto Giannoni; Marco Di Paolo; Michele Emdin

doi:10.3390/diagnostics11081378

July 30, 2021DiagnosticsOpen Access

Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

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Key Points

To review the technological evolution, clinical utility, and interpretive challenges of molecular autopsy in investigating sudden unexplained cardiac death.
Evaluation of molecular autopsy workflows used when traditional autopsy yields negative or non-diagnostic findings in sudden unexplained death cases.
Comparison between low-throughput Sanger sequencing of focused gene panels and high-throughput next-generation sequencing covering exomes and genomes.
Next-generation sequencing enhances pathogenic variant detection across the exome and genome and facilitates the identification of novel genotype-phenotype associations compared to Sanger sequencing.
Expanded genomic profiling creates substantial interpretive difficulty due to the high volume of variants of unknown significance identified in each decedent.

Structured PICO

P

Population

Cases of sudden unexplained deaths (SUDs), often due to an underlying inherited arrhythmogenic cardiac disease

I

Intervention

Molecular autopsy using next-generation sequencing (NGS)

C

Comparator

Traditional autopsy or Sanger sequencing

O

Outcome

Detection of pathogenic variants and discovery of genotype-phenotype associations

The transition to next-generation sequencing in molecular autopsy improves the detection of pathogenic variants in sudden unexplained death but introduces challenges in interpreting variants of unknown significance.

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Implication

NGS may support expanded molecular autopsy in sudden death; leaves open standardized VUS interpretation before routine clinical use.

Abstract

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.

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Cite This Study

Castiglione et al. (2021) studied this question.

synapsesocial.com/papers/69f14b762811130d0cde2193 https://doi.org/10.3390/diagnostics11081378

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Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

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Key Points

Structured PICO

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

Figures

Key Points

Structured PICO

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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