Journal Article

Genetic etiologies with a large NGS panel in a monocentric cohort of 1000 patients with pediatric onset epilepsies

Barcia, Giulia, Hanein, Sylvain, Steffann, Julie, Sarda, Eugénie, Assouline, Zahra, Plante‐Bordeneuve, Pauline, Hully, Marie, Sareidaki, Doxa, Aubart, Mélodie, Barrois, Remi, Losito, Emma, Eisermann, Monika, Desguerre, Isabelle, Kaminska, Anna, Rio, Marlène, Fourrage, Cécile, Chemaly, Nicole, Nabbout, Rima, Gobin‐Limballe, Stéphanie, Barnerias, Christine, Zeitoun, Delphine Coste, Boddaert, Nathalie

2025

Overview

Objective Genetic testing is now included in the diagnostic assessment of childhood onset epilepsies. We evaluated the yield of a targeted next generation sequencing (TNGS) panel dedicated to pediatric epilepsies. Methods We tested by TNGS panel 1000 consecutive patients presenting with childhood onset epilepsies and including mainly patients with early onset epilepsies (under 2 years, 61%). Results Causal variants were identified in 31% of patients, spanning 78 different genes. Patients with benign familial neonatal/infantile epilepsy (BFN/IS) exhibited the highest rate of positive findings (82%). Developmental and epileptic encephalopathies (DEEs) had a global diagnostic yield of 37%, with epilepsy of infancy with migrating focal seizures (EIMFSI) and Dravet syndrome (DS) presenting the highest yield in this group (78%) and early infantile DEE (EIDEE) laying next with a yield of 43%. The lowest rates of genetic diagnosis were observed in infantile epileptic spasms syndrome (IESS, 17%), epilepsy with myoclonic‐atonic seizures (EMAtS, 19%), and DEE‐SWAS (14%). Patients with GEFS+ had a yield of 16%. Among patients with developmental encephalopathies and refractory seizures with onset after 2 years, TNGS yielded a 33% diagnostic rate. Atypical absences yielded 16%, focal epilepsy yielded 18%, and generalized epilepsies with refractory seizures yielded 13%. These groups exhibited a high genetic heterogeneity. Significance TNGS is an effective first‐step genetic screening in patients with high diagnostic yields (BFN/IS, EIMFS, DS, EIDEE) and for epilepsy syndromes associated with one or a few major genes (BFN/IS, EIMFS, DS, GEFS+, DEE‐SWAS). Whole exome or genome sequencing (WES/WGS) should be considered as a second step in these groups with a probably relevant Mendelian inheritance. WES/WGS could be proposed as first‐tier analysis in patients with IESS, EMAtS, generalized or focal epilepsies refractory to ASMs, and developmental encephalopathies with seizure onset after 2 years. However, the lower diagnostic yield obtained in these groups may suggest a complex inheritance. Plain Language Summary This study emphasizes the importance of accurately identifying different types of epilepsy and epilepsy syndromes to improve genetic testing strategies. We suggest that a targeted gene panel can be a good first step for some genetic conditions, such as benign familial neonatal/infantile epilepsy, Dravet syndrome, and epilepsy of infancy with migrating focal seizures.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adolescent / Age / Age of Onset / Child / Child, Preschool / Cohort Studies / Convulsions & seizures / developmental and epileptic encephalopathies / Dravet syndrome / Epilepsies, Myoclonic - genetics / Epilepsy / Epilepsy - diagnosis / Epilepsy - etiology / Epilepsy - genetics / epilepsy with migrating focal seizures of infancy / Female / Genetic counseling / Genetic Testing - methods / genetics / Genomes / High-Throughput Nucleotide Sequencing - methods / Humans / Infant / Infant, Newborn / Male / Mutation / next generation sequencing / Original / Patients / Pediatrics / Spasms, Infantile - genetics