Functional analysis of a novel variant in a patient with seizures refractory to oxcarbazepine.

OBJECTIVE

We admitted a female patient with infantile onset epilepsy (<3-month-old). The use of oxcarbazepine exacerbated epileptic seizures in the patient. In the present study, we aimed to identify the genetic basis of the infantile onset epilepsy in the patient, and determine the correlations among genotype, phenotype, and clinical drug response.

METHODS

We described the clinical characteristics of an infant with refractory epilepsy. Whole exome sequencing (WES) was used to screen for the pathogenic variant. Whole-cell patch-clamp was performed to determine functional outcomes of the variant.

RESULTS

WES identified a novel variant (c.468 G > C, p.K156N) in the patient. In comparison with wildtype, electrophysiology revealed that -K156N variant in transfected cells demonstrated reduced sodium current density, delayed activation and accelerated inactivation process of Na channel, all of which suggested a loss-of-function (LOF) of Na1.2 channel.

CONCLUSION

We showed the importance of functional analysis for a variant with unknown significance to determine pathogenicity, drug reactions, and genotype-phenotype correlations. For patients suffering from early infantile epilepsies, the use of oxcarbazepine in some -related epilepsies requires vigilance to assess the possibility of epilepsy worsening.