Expanding the genotype-phenotype spectrum in SCN8A-related disorders

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• SCN8A-related disorders encompass a range of conditions including developmental and epileptic encephalopathy 13, benign infantile seizures 5, and cognitive impairment.
• These disorders arise from pathogenic variations within the SCN8A gene.

Purpose of the Study:

• To characterize the clinical and genetic findings in individuals with SCN8A pathogenic variants.
• To expand the known genotypic and phenotypic spectrum of SCN8A-related disorders.

Main Methods:

• Exome sequencing was employed to identify SCN8A pathogenic variants in eight individuals from six families.
• Electrophysiological analysis was performed on transfected cells to assess variant function.

Main Results:

• Clinical presentations varied from normal development with controlled epilepsy to severe developmental delay with intractable epilepsy.
• Six SCN8A variants were identified, including three novel and three previously reported.
• Electrophysiological studies confirmed a loss-of-function effect for a novel variant in Patient 4.

Conclusions:

• This study broadens the understanding of SCN8A-related disorders by detailing a wider range of clinical manifestations and genetic variations.
• Novel insights into the functional consequences of an SCN8A loss-of-function variant were provided.