Unravelling the Mystery of Sudden Cardiac Death Through Genetic Approaches

The sudden unexplained death syndrome is a tragic and distressing event, which may arise due to an underlying fatal cardiac arrhythmia, which may be associated with a defective ion channel. These electrical abnormalities of the heart do not present with gross structural changes, rendering it a challenging task to the forensic pathologist in ascertaining the cause of death during autopsies. The attempts to identify genetic variations in the key ion channels known to cause arrhythmias have only been able to reveal the presence of putative mutations in a small percentage of the cases. It is thus imperative to look beyond the discovery of single-nucleotide polymorphisms to other forms of genetic variations (such as copy number variations and structural rearrangements), as well as alternative mechanisms that may underlie the molecular pathogenesis of arrhythmias and electrocardiographic abnormalities causing sudden death. Additionally, the various technological platforms for genetic analysis are also described in this article. Key Concepts: Sudden unexplained death syndrome is an important clinical problem. Sudden death may be the result of a fatal cardiac arrhythmia. Arrhythmias are associated with genetic mutations in ion channel genes. Genetic mutations often exhibit incomplete penetrance. Genetic mutations may have functional impact on the ion channel. Single-nucleotide polymorphisms only account for a fraction of the cases. Copy number variations and chromosomal aberrations may play a role in sudden death pathology. The role of alternative mechanisms such as epigenetics in arrhythmias/sudden death remains to be ascertained. The technology for identifying genetic variations is advancing rapidly. Genome-wide sequencing is expected to become increasingly feasible. Keywords: sudden unexplained death syndrome; arrhythmias; genetic variants; ion channels; genome-wide association studies; candidate gene sequencing; next-generation sequencing