The noncausal association between a loss-of-function CLCN2 variant and childhood absence epilepsy

Childhood absence epilepsy (CAE) is a subtype of idiopathic (genetic) generalized epilepsies (IGEs). In this study, four heterozygous variants in CLCN2 were found in 10 CAE patients using whole exome sequencing (WES). We used genetics, bioinformatics, molecular biology, and electrophysiology to study the four variants. Bioinformatics analysis showed that the four variants were probably damaging, and the c.1141C > G (p.Pro381Ala) and c.1885C > T (p.Arg629Cys) variants affected the tertiary structure of the ClC-2 chloride channel. Functional studies showed that the c.1141C > G (p.Pro381Ala) variant significantly reduced the expression of CLCN2 in the plasma membrane, and affected the Cl^- currents of ClC-2 chloride channel, indicating that the c.1141C > G (p.Pro381Ala) variant was a loss-of-function mutation. Furthermore, the minor allele frequency (MAF) of the variant was higher than the incidence of CAE. Therefore, we postulated that the c.1141C > G (p.Pro381Ala) variant was noncausal association with CAE. This study was valuable for further exploring the pathogenic variants of CAE.