Abstract
Sudden unexpected death in epilepsy is an unpredicted condition in patients with a diagnosis of epilepsy, and autopsy does not conclusively identify cause of death. Although the pathophysiological mechanisms that underlie this entity remain unknown, the fact that epilepsy can affect cardiac function is not surprising. The genetic factors involving ion channels co-expressed in the heart and brain and other candidate genes have been previously described. In the present study, 20 epilepsy patients with personal or family history of heart rhythm disturbance/cardiac arrhythmias/sudden death were sequenced using a custom re-sequencing panel. Twenty-six relatives were genetically analysed to ascertain the family segregation in ten individuals. Four subjects revealed variants with positive genotype-phenotype segregation: four missense variants in the CDKL5, CNTNAP2, GRIN2A and ADGRV1 genes and one copy number variant in KCNQ1. The potential pathogenic role of variants in new candidate genes will need further studies in larger cohorts, and the evaluation of the potential pathogenic role in the cardio-cerebral mechanisms requires in vivo/in vitro studies. In addition to family segregation, evaluation of the potential pathogenic roles of these variants in cardio-cerebral mechanisms by in vivo/in vitro studies should also be performed. The potential pathogenic role of variants in new candidate genes will need further studies in larger cohorts.
Highlights
Only four variants, i.e., KCNQ1, KCNE1, SCN1A, and CACNA1C, were previously associated with Sudden unexpected death (SUDEP) or other disorders associated with sudden cardiac death (SCD)
Rare genetic alterations in genes encoding brain/heart ion channels are responsible for epilepsy associated with cardiac conduction disorder/SUDEP
We identified 5 rare genetic variants that segregated within the pedigree and explain the cardiac conduction disorder/SUDEP
Summary
The present study is a follow-up study in patients with clinical and EEG features consistent with a diagnosis of non-lesional (MRI-negative) focal or generalized epilepsy and a personal or family history of heart rhythm disturbances/cardiac arrhythmias/sudden death (Table 2). DNA samples of relatives were obtained when available to ascertain the segregation of each genetic variant. Vague histories of heart rhythm disturbances in family members not clearly known by the proband or with any available clinical/instrumental data were excluded. Each proband was genetically evaluated by target re-sequencing of exonic and intron-exon boundary regions. Clinical data and DNA from available relatives were obtained for testing in segregation studies of the rare genetic variants. The four SUDEP cases included in this cohort were genetically negative in a previous published SUDEP study [9]
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