Expanding the genotype-phenotype spectrum in SCN8A-related disorders

Abstract

Background: SCN8A-related disorders are a group of variable conditions caused by pathogenic variations in SCN8A. Online Mendelian Inheritance in Man (OMIM) terms them as developmental and epileptic encephalopathy 13, benign familial infantile seizures 5 or cognitive impairment with or without cerebellar ataxia.

Methods: In this study, we describe clinical and genetic results on eight individuals from six families with SCN8A pathogenic variants identified via exome sequencing.

Results: Clinical findings ranged from normal development with well-controlled epilepsy to significant developmental delay with treatment-resistant epilepsy. Three novel and three reported variants were observed in SCN8A. Electrophysiological analysis in transfected cells revealed a loss-of-function variant in Patient 4.

Conclusions: This work expands the clinical and genotypic spectrum of SCN8A-related disorders and provides electrophysiological results on a novel loss-of-function SCN8A variant.

Keywords: Developmental and Epileptic Encephalopathy; Electrophysiological study; Epilepsy; Exome sequencing; Gain-of-function; Loss-of-function; SCN8A; Seizure; Variant of Uncertain Significance.

Figure 1

A. Simplified diagram of NaV1.6 channel showing the locations of the variants identified in our cohort (novel mutations are in red font). B. HEK-293 cells were transiently transfected with hNaV1.6 WT, hNaV1.6 C324Y, plasmid vector with no channel construct to look for functional effects of C324Y variant. C324Y current levels were significantly different from WT but not from Vector control.