Functional evidence for SCN8A splice-donor variant c.4419+1 A > G causing loss of function

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Severe developmental and epileptic encephalopathies are debilitating neurological disorders.
• SCN8A gene variants are increasingly recognized as a cause of these conditions.
• Interpreting the pathogenicity of novel SCN8A variants can be challenging.

Purpose of the Study:

• To investigate the pathogenicity of a rare SCN8A splice-site variant found in a child with severe developmental and epileptic encephalopathy.
• To determine the functional impact of the identified SCN8A variant.
• To emphasize the utility of splicing assays in variant interpretation.

Main Methods:

• Clinical data analysis of a pediatric patient.
• Genetic sequencing to identify the SCN8A variant.
• Minigene assay to assess the splicing defect caused by the variant.

Main Results:

• A rare SCN8A splice-site variant was identified in the affected child.
• The minigene assay demonstrated aberrant splicing, confirming a loss-of-function mechanism.
• Integrated evidence classified the SCN8A variant as pathogenic.

Conclusions:

• The SCN8A splice-site variant is pathogenic and contributes to severe developmental and epileptic encephalopathy.
• Splicing assays are crucial tools for elucidating the functional consequences of rare SCN8A variants.
• This case highlights the importance of functional studies in diagnosing genetic epilepsy syndromes.