De Novo ACTB Variant Associated With Juvenile-Onset Temporal Lobe Epilepsy With Favorable Outcomes

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Genetic factors are implicated in approximately 80% of epilepsy cases.
• Limited genetic associations (only four genes) have been reported for temporal lobe epilepsy (TLE).
• The genetic underpinnings of TLE require further investigation to identify novel causative genes.

Purpose of the Study:

• To investigate the potential association between the ACTB gene and temporal lobe epilepsy (TLE).
• To identify and characterize novel genetic variants contributing to TLE pathogenesis.

Main Methods:

• Trio-based exome sequencing was employed to analyze genetic variations in a patient with TLE and their parents.
• In silico tools and American College of Medical Genetics and Genomics (ACMG) guidelines were used to assess the pathogenicity of the identified ACTB variant.
• Protein modeling was performed to evaluate the structural and stability impacts of the variant.

Main Results:

• A de novo ACTB variant was identified in a patient presenting with juvenile-onset TLE, adult seizure remission, memory decline, irritability, and bilateral hippocampal sclerosis.
• The identified ACTB variant was predicted to be damaging, with high conservation and a missense tolerance ratio of 0%, leading to its classification as likely pathogenic.
• Protein modeling revealed structural alterations, and the spatiotemporal expression pattern of ACTB aligned with the patient's TLE phenotype.

Conclusions:

• ACTB is proposed as a novel candidate gene associated with the development of temporal lobe epilepsy (TLE).
• The identified variant's pathogenicity is supported by multiple lines of evidence, including in silico predictions and protein structural analysis.
• The correlation between ACTB expression patterns and TLE phenotypes offers a new avenue for understanding disease mechanisms and prognosis.