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

Abstract

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.

Keywords: Dravet syndrome; developmental and epileptic encephalopathies; epilepsy with migrating focal seizures of infancy; genetics; next generation sequencing.

FIGURE 1

Description of the 1000 included patients and their NGS results. (A) NGS results obtained in this cohort and study design, (B) NGS results in patients with developmental epileptic encephalopathies, and (C) NGS result in patients with other epilepsy syndromes according to ILAE classification. (D) Genetic results in different DEE according to the ILAE classification (Adapted from Wirrel et al. ⁴ ). (E) Proposed algorithm for genetic testing in patients with pediatric epilepsy. DEE‐SWAS, developmental and epileptic encephalopathy with spike–wave activity in sleep; DS, Dravet syndrome; EIDEE, Early‐infantile developmental and epileptic encephalopathy syndrome; EIMFS, epilepsy of infancy with migrating focal seizures; EMAtS, epilepsy with myoclonic‐atonic seizures; GEFS+, generalized epilepsy with febrile seizures plus; HHE, hemiconvulsion hemiplegia epilepsy syndrome; IESS, infantile epileptic spasms syndrome; LGS, Lennox–Gastaut syndrome.

FIGURE 2

Genetic results obtained in this cohort in patients with developmental epileptic encephalopathies and other epilepsy syndromes according to ILAE classification. (A) The graphs show the percentage of molecular diagnosis obtained in each epilepsy syndrome that are presented from left to right following the age at onset (Adapted from Wirrel et al. ⁴ ). We shaded in red the percentage of patients with a pathogenic variant on one major gene (indicated by an arrow). We shaded in blue the percentage of patients with pathogenic variants in heterogeneous genes. In gray, we indicate the percentage of patients with a negative panel result. In the center, we present the percentage of patients with a confirmed genetic etiology. (B) The graphs show the percentage of molecular diagnosis obtained in syndromes other than DEEs. We shaded in green the percentage of patients with a pathogenic variant in one major gene (indicated by arrows). We shaded in orange the percentage of patients with pathogenic variants in more heterogeneous genes. In gray, we indicate the percentage of patients with a negative panel result. In the center, we present the percentage of patients with a confirmed genetic etiology. DEE‐SWAS, developmental and epileptic encephalopathy with spike–wave activity in sleep; DS, Dravet syndrome; EIDEE, Early‐infantile developmental and epileptic encephalopathy syndrome; EIMFS, epilepsy of infancy with migrating focal seizures; EMAtS, epilepsy with myoclonic‐atonic seizures; GEFS+, generalized epilepsy with febrile seizures plus; IESS, infantile epileptic spasms syndrome.