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. 2024 Jan 17;24(1):31.
doi: 10.1186/s12883-023-03478-y.

Expanding the genotype-phenotype spectrum in SCN8A-related disorders

Malavika Hebbar  1 , Nawaf Al-Taweel  1 , Inderpal Gill  1 , Cyrus Boelman  1 , Richard A Dean  2 , Samuel J Goodchild  2 , Janette Mezeyova  2 , Noah Gregory Shuart  2 , J P Johnson Jr  2 , James Lee  1 , Aspasia Michoulas  1 , Linda L Huh  1 , Linlea Armstrong  3 , Mary B Connolly  1 , Michelle K Demos  4
Affiliations

Expanding the genotype-phenotype spectrum in SCN8A-related disorders

Malavika Hebbar et al. BMC Neurol. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 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 peak current density (pA/pF) levels were significantly different from WT but not from Vector control
See this image and copyright information in PMC

Update of

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