Abstract
Sudden cardiac death in people between the ages of 1–40 years is a devastating event and is frequently caused by several heritable cardiac disorders. These disorders include cardiac ion channelopathies, such as long QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome and cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. Through careful molecular genetic evaluation of DNA from sudden death victims, the causative gene mutation can be uncovered, and the rest of the family can be screened and preventative measures implemented in at-risk individuals. The current screening approach in most diagnostic laboratories uses Sanger-based sequencing; however, this method is time consuming and labour intensive. The development of massively parallel sequencing has made it possible to produce millions of sequence reads simultaneously and is potentially an ideal approach to screen for mutations in genes that are associated with sudden cardiac death. This approach offers mutation screening at reduced cost and turnaround time. Here, we will review the current commercially available enrichment kits, massively parallel sequencing (MPS) platforms, downstream data analysis and its application to sudden cardiac death in a diagnostic environment.
Highlights
Sudden cardiac death (SCD) in people between the ages of 1–40 years is common [1] and is a devastating event in any family
Several larger diagnostic laboratories already offer the screening of large gene panels for cardiac/SCD patients [6,7]; smaller laboratories are challenged in offering a similar service, due to limitations in accessing relevant technology and fewer referrals compared to larger laboratories
Whole exome sequencing (WES) involves enriching for the entire coding region of an individual’s genome and is a good method for discovering new genes that are associated with diseases [13], as well as offering diagnostic outcomes, at a greater cost compared to a gene list-focused enrichment
Summary
Sudden cardiac death (SCD) in people between the ages of 1–40 years is common [1] and is a devastating event in any family. The most common are hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). These have typical morphological and histological features, they may be subtle or even absent, in the very young. The current molecular genetic screening system in most diagnostic laboratories use a Sanger-based sequencing approach, which is the prevailing gold standard for sequence-based testing of Mendelian disease. This method involves a one-by-one approach, where only a single sequence is interrogated at a time, which makes screening disorders with more than a handful of genes inefficient and costly. Several larger diagnostic laboratories already offer the screening of large gene panels for cardiac/SCD patients [6,7]; smaller laboratories are challenged in offering a similar service, due to limitations in accessing relevant technology and fewer referrals compared to larger laboratories
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