Sudden cardiac death and epilepsy: Is there a role of genetics?

The main cause of premature death in people with epilepsy (pwE) is sudden unexpected death in epilepsy (SUDEP), that could be misconcepted as sudden cardiac death (SCD). Several factors contribute to an increased likelihood of SUDEP, with the most significant risks associated with the seizure type, epilepsy severity, cumulative number of seizures, gender, associated symptoms, and therapy. The direct role of genetic risk factors for SUDEP is linked to the mechanisms of death, such as cardiac arrhythmias, respiratory dysfunction, and autonomic dysregulation. The highest genetic risk is associated with pathogenic variants in genes linked to arrhythmias, such as long QT and Brugada syndrome, as well as epilepsy, like Dravet syndrome. Some variants identified by employing arrhythmogenic and epilepsy gene panels, although predicted to be deleterious or absent in the general population, did not meet the criteria for the pathogenicity and were therefore classified as VUS. Additionally, some identified variants were classified as benign or likely benign. However, SUDEP risk could also result from a polygenic effect. Considering that SUDEP is the most frequent cause of premature death in pwE, genetic testing should become an essential part of epilepsy care, particularly for patients with drug-resistant epilepsy or unexplained cardiac symptoms.