Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

Abstract

ObjectiveSudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy-related mortality in young adults. It has been suggested that SUDEP may kill over 20 000 people with epilepsy in China yearly. The aetiology of SUDEP is unclear. Little is known about candidate genes for SUDEP in people of Chinese origin as most studies have ascertained this in Caucasians. No candidate genes for SUDEP in Chinese people have been identified.MethodsWe performed whole exome sequencing (WES) in DNA samples collected from five incident cases of SUDEP identified in a large epilepsy cohort in rural China. We filtered rare variants identified from these cases as well as screened for SUDEP, epilepsy, heart disease or respiratory disease-related genes from previous published reports and compared them with publicly available data, living epilepsy controls and ethnicity-match non-epilepsy controls, to identify potential candidate genes for SUDEP.ResultsAfter the filtering process, the five cases carried 168 qualified mutations in 167 genes. Among these genetic anomalies, we identified rare variants in SCN5A (1/5:20% in our cases), KIF6 (1/5:20% in our cases) and TBX18 (1/5:20% in our cases) which were absent in 330 living epilepsy control alleles from the same original cohort and 320 ethnicity-match non-epilepsy control alleles.ConclusionsThese three genes were previously related to heart disease, providing support to the hypothesis that underlying heart disorder may be a driver of SUDEP risk.

Low tolerance for transcriptional variation at cohesin genes is accompanied by functional links to disease-relevant pathways

“…Of particular relevance to the cohesinopathies, in which affected individuals present with cognitive defects, a mutation in human KIF6 caused neurodevelopmental defects and intellectual disability. 29 Variation in KIF6 expression has been associated with epilepsy, 30 another notable cohesinopathy phenotype. 31 It has also been proposed that KIF6 is a conserved regulator of neurological development.…”

Dysregulated long noncoding RNAs in the brainstem of the DBA/1 mouse model of SUDEP

“…Recently, increased awareness has been given to SUDEP-related genes, which have mostly been identified as neurocardiac genes (i.e., KCNA1, SCN1A, SCN8A, KCNQ1) [ 12 , 27 ]. However, although some SUDEP cases have a genetic background, a large proportion of cases have not carried clear genetic mutations [ 28 ]. This suggests that SUDEP is a highly heterogenic disease in genetics and requires further study in different aspects.…”

Identification of Functional Genetic Variants Associated With Alcohol Dependence and Related Phenotypes Using a High‐Throughput Assay

“…It plays a role in ciliogenesis in vertebrate ependymal cell (specialized glial cells that forms the epithelial lining of the ventricular walls of the brain and spinal canal), and a frameshift mutation in KIF6 was found in a child who displayed neurodevelopmental defects and intellectual disability (Konjikusic et al, 2018). A rare variant in KIF6 was reported to play a role in some sudden unexpected deaths in people with epilepsy (Ge et al, 2020). ADD2 (adducin 2) encodes a cytoskeleton associated protein involved in synaptic plasticity; alcohol exposure at early neurulation alters the expression of ADD2 (Zhou et al, 2011).…”