Holistic Exome-Based Genetic Testing in Adults With Epilepsy.

Area of Science:

• Genetics
• Neurology
• Epilepsy Research

Background:

• Exome sequencing (ES) is established for pediatric epilepsy diagnosis.
• The diagnostic utility of ES in adult epilepsy remains less defined.
• This study investigates a comprehensive exome-based approach for adult epilepsy.

Purpose of the Study:

• To evaluate the diagnostic outcomes of holistic exome sequencing in adults with epilepsy.
• To compare the diagnostic yield of ES with comprehensive gene panels.
• To identify novel genetic etiologies and expand known epilepsy gene phenotypes.

Main Methods:

• 106 adults with epilepsy and presumed genetic etiology underwent diagnostic exome sequencing.
• Analyses included copy number variation (CNV) and mitochondrial DNA.
• Outcomes were compared against three simulated comprehensive gene panels.

Main Results:

• A 30.2% diagnostic yield was achieved, exceeding all simulated gene panels.
• Developmental and epileptic encephalopathy phenotypes were associated with genetic diagnoses.
• Twenty-seven distinct molecular etiologies were identified, including pathogenic CNVs and mitochondrial DNA variants. Clinical implications led to treatment changes in 15.6% of solved cases. Phenotype expansions for three genes and a potential new candidate gene (CLASP1) were reported.

Conclusions:

• Holistic exome sequencing, including CNV and mitochondrial analyses, is strongly supported for adult epilepsy diagnosis.
• Genetic findings can inform clinical management, similar to pediatric cases.
• This approach facilitates phenotype expansion and candidate gene discovery in adult epilepsy.