Abstract
Sudden cardiac death (SCD) in the young (<40 years) occurs in the setting of a variety of rare inherited cardiac disorders and is a disastrous event for family members. Establishing the cause of SCD is important as it permits the pre-symptomatic identification of relatives at risk of SCD. Sudden arrhythmic death syndrome (SADS) is defined as SCD in the setting of negative autopsy findings and toxicological analysis. In such cases, reaching a diagnosis is even more challenging and post-mortem genetic testing can crucially contribute to the identification of the underlying cause of death. In this review, we will discuss the current achievements of “the molecular autopsy” in young SADS cases and provide an overview of key challenges in assessing pathogenicity (i.e., causality) of genetic variants identified through next-generation sequencing.
Highlights
Each year, thousands of individuals die suddenly before the age of 35
We will discuss the current achievements of the molecular autopsy in young Sudden arrhythmic death syndrome (SADS) cases and provide an overview of key challenges in assessing pathogenicity of genetic variants identified through next-generation sequencing (NGS)
Next-generation sequencing (NGS) has made it possible to screen large gene panels, spanning the channelopathy genes and the cardiomyopathy genes, in search for the cause of Sudden cardiac death (SCD). While these panels have made it possible to broadly screen for genetic variation, it comes with the challenge of interpreting any identified VUS
Summary
Thousands of individuals die suddenly before the age of 35. Sudden cardiac death (SCD) in this age category has an estimated incidence of 0.005–0.2 per 1000 individuals per year, which is lower than in the general adult population [1]. Sudden arrhythmic death syndrome (SADS) is defined as SCD in the setting of a negative autopsy and toxicological analysis [4, 5] In these cases, reaching a diagnosis is challenging and post-mortem genetic testing, the so-called molecular autopsy, can crucially contribute to the identification of the underlying (genetic) cause of death [6]. The recent advances in sequencing technologies (next-generation sequencing) have made it possible to screen in detail large proportions of the human genome at relatively low cost Despite these significant developments, distinguishing true disease-causing genetic variants from the bulk of genetic variation that is not directly associated with the SCD phenotype is of major importance [8]. We will discuss the current achievements of the molecular autopsy in young SADS cases and provide an overview of key challenges in assessing pathogenicity (i.e., causality) of genetic variants identified through next-generation sequencing (NGS)
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