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Introduction: Sudden Unexpected Death in Epilepsy (SUDEP) is the leading epilepsy-related cause of death, affecting approximately 1 per 1,000 individuals with epilepsy per year. Genetic variants that affect autonomic function, such as genes associated with cardiac arrhythmias, may predispose people with epilepsy to greater risk of both sudden cardiac death and SUDEP. Advances in next generation sequencing allow for the exploration of gene variants as potential biomarkers. Methods: Genetic testing for the presence of cardiac arrhythmia and epilepsy gene variants was performed via genetic panels in 39 cases of SUDEP identified via autopsy by the Ontario Forensic Pathology Service. Variants were summarized by in-silico evidence for pathogenicity from 4 algorithms (SIFT, PolyPhen-2, PROVEAN, Mutation Taster) and allele frequencies in the general population (GnomAD). A maximum credible population allele frequency of 0.00004 was calculated based on epilepsy prevalence and SUDEP incidence to assess whether a variant was compatible with a pathogenic interpretation. Results: Median age at the time of death was 33.3years (range: 2, 60). Fifty-nine percent (n=23) were male. Gene panels detected 62 unique variants in 45 genes: 19 on the arrhythmia panel and 26 on the epilepsy panel. At least one variant was identified in 28 (72%) of decedents. Missense mutations comprised 57 (92%) of the observed variants. At least three in silico models predicted 12 (46%) cardiac arrhythmia panel missense variants and 20 (65%) epilepsy panel missense variants were pathogenic. Population allele frequencies were <0.00004 for 11 (42%) of the cardiac variants and 10 (32%) of the epilepsy variants. Together, these metrics identified 13 SUDEP variants of interest. Discussion: Nearly three-quarters of decedents in this SUDEP cohort carried variants in comprehensive epilepsy or cardiac arrhythmia gene panels, with more than a third having variants in both panels. The proportion of decedents with cardiac variants aligns with recent studies of the disproportionate cardiac burden the epilepsy community faces compared to the general population and suggests a possible cardiac contribution to epilepsy mortality. These results identified 13 priority targets for future functional studies of these genes potential role in sudden death and demonstrates the necessity for further exploration of potential genetic contributions to SUDEP. [ABSTRACT FROM AUTHOR]

Preclinical data report within subject modifiable ailments emerge weeks prior to SUDEP, including sleep disorders and cardiorespiratory changes; findings which support anecdotal clinical data. Here, we bridge preclinical findings with future clinical/preclinical studies, and survey whether caretakers or family members of victims noticed transient changes prior to SUDEP. The aim of this pilot study is to identify potential modifiable changes that may synergistically increase SUDEP risk for future research. A mobile electronic survey was posted on SUDEP community websites. The survey queried whether changes in seizures, sleep, physical well-being, emotional well-being, cognition, breathing, or heart rate were noticed before SUDEP. The most profound finding was that 85% of victims had multiple transient ailments prior to SUDEP. Changes in seizures (28/54), and sleep (30/58) occurred in more than 50% of the victims and represent the most influential changes identified. The second and third most influential changes were a reduction in physical well-being (25/57) and emotional well-being (26/56). Changes were observed within the last two months of life in approximately one third of the cases, and more than four months prior to SUDEP in approximately one third of cases, indicating a potential time frame for proactive preventative strategies. Respondents also noted changes in cognition (16/55), breathing (9/54) or heart rate (8/55). Data indicate these changes may be associated with increased SUDEP risk within subject. Study limitations include the responses were based on memory, there was a potential for data to be over reported, and caretakers were not prompted to observe changes a priori, thus some existing changes may have gone unnoticed. Data support the preclinical findings that transient, subclinical (i.e., not severe enough to require medical intervention), modifiable ailments may increase risk of SUDEP. This suggests that just as an epilepsy type can change over a lifetime and epilepsy type-specific treatments can reduce SUDEP risk, further personalization of SUDEP risk will improve our understanding as to whether variables contribute to risk differently across lifespan. Thus, with a dynamic capacity to change, differing factors may contribute to the distribution of risk probability within an individual at any given time. Understanding whether different combinations of transient changes are specific to epilepsy type, age, or sex needs to be determined to move the field forward in hopes of developing a personalized approach to preventative strategies. • Loved ones of victims were asked whether they noticed any changes before SUDEP. • 85% of SUDEP victims had multiple subclinical comorbidities prior to SUDEP. • Seizure worsening and sleep problems emerged in the months prior to SUDEP in more than half of the victims. • Changes in emotional and physical well-being were observed in more than 40% of SUDEP cases. • Whether changes are specific to epilepsy type needs to be determined to move towards personalized preventative strategies. [ABSTRACT FROM AUTHOR]