Next Generation Sequencing in Pediatric Epilepsy Using Customized Panels: Size Matters.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Next-generation sequencing (NGS) with customized gene panels is crucial for diagnosing monogenic epilepsy syndromes.
• The size of customized epilepsy gene panels can vary considerably, impacting diagnostic efficiency.

Purpose of the Study:

• To compare the diagnostic yield of small (<25 kb) versus large (>25 kb) customized epilepsy gene panels.
• To analyze diagnostic yield differences based on epilepsy severity, specifically developmental and epileptic encephalopathy (DEE) versus non-DEE.

Main Methods:

• Retrospective cohort study of 190 pediatric patients (≤18 years) with epilepsy of unknown etiology.
• NGS using customized gene panels was performed, comparing small and large panels for variant classification (benign, likely benign, pathogenic, likely pathogenic, unclear significance).

Main Results:

• Large panels showed a significantly higher diagnostic yield (29%) compared to small panels (13%) (p=0.0198).
• In non-DEE patients, large panels yielded significantly more diagnoses (35%) than small panels (13%) (p=0.0378).
• This significant increase in diagnostic yield for large panels was not observed in DEE patients.

Conclusions:

• Large customized epilepsy panels (>25 kb) offer superior diagnostic yield for pediatric epilepsy patients, particularly those without DEE.
• For DEE patients, smaller panels (≤10 genes) may be adequate.
• Increased panel size correlates with a higher proportion of variants of unclear significance.