Genetics and SUDEP: Challenges and Future Directions.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related deaths in children and adults with epilepsy. The incidence of SUDEP in children and adults is equal, approximately 1.2 per 1000-person years. Although inroads have been made in our understanding of SUDEP, its pathophysiology remains unknown. The most important risk factor for SUDEP is the presence of tonic-clonic seizures. Recently there has been growing interest in the contribution of genetic risk factors to SUDEP deaths. Pathogenic variants in epilepsy-related and cardiac genes have been found in some cases of SUDEP post-mortem. Pleiotropy may occur in which a single gene when altered may cause multiple phenotypes (i.e., epilepsy and cardiac arrhythmia). Recently it has been shown that some developmental and epileptic encephalopathies (DEEs) may also be at heightened risk of SUDEP. In addition, polygenic risk has been postulated to effect SUDEP risk with current models evaluating the additive effect of variants in multiple genes. However, the mechanisms underpinning polygenic risk in SUDEP are likely more complex than this. Some preliminary studies also highlight the feasibility of detecting genetic variants in brain tissue post-mortem. Despite the advances in the field of SUDEP genetics, the use of molecular autopsy remains underutilized in SUDEP cases. Several challenges exist concerning genetic testing post-mortem in SUDEP cases, such as interpretation, cost of testing, and availability. In this focused review, we highlight the current landscape of genetic testing in SUDEP cases, its challenges, and future directions.