The impact of next generation sequencing in the diagnostic work-up of pediatric epilepsies: a single centre observational cohort study

Background Next generation sequencing techniques (targeted gene panels, whole exome sequencing and whole genome sequencing) allowed an increase of molecular diagnosis of genetic epilepsies, an expansion of the phenotypic spectrum of several epileptic syndromes and an optimization of the correlated diagnostic work-up. Aim of the study: To characterize the epilepsy phenotypes that could be associated with a better detection rate of targeted next generation sequencing for pathogenic/likely pathogenic variants. Patients and methods: A retrospective cohort analysis was performed on 58 patients (28 males and 30 females; mean age=9,06 ± 6,97 years) who underwent targeted next generation sequencing gene for epilepsy between 2015 and 2018. Data about demographic features, seizures semiology and evolution during follow-up, associated neurological and non-neurological features, EEG and MRI characteristics were collected. These variables were evaluated and compared in: - patients with epileptic encephalopathies (seizures causing developmental impairment- A group); -patients with developmental encephalopathies including epilepsy (developmental impairment preceding epilepsy- B group); - patients with isolated idiopathic epilepsy without signs of encephalopathy (no developmental impairment- C group). Results: Pathogenic or likely pathogenic variants were assessed in 18/58 patients (13/18 were de novo) with a detection rate of 31,03% in the whole sample (51,6% in the B group; 11,1% in group C and 0% in the A group). Genes with pathogenic/likely pathogenic mutations were represented by: SCN1A (in 3 patients), IQSEC2 (in 2 patients), PRICKLE1, GABRB3, SLC2A1, MFF, SCN1B, KCTD7, CDKL5; FOXG1, SYNGAP1, ATP1A3, GRIN2A, PRRT2 and CACNA1A (one affected patients for each one of these genes). Atypical phenotypes were associated with variants involving SCN1A, KCTD7, PRICKLE1 and PRRT2. Molecular diagnosis addressed positively therapeutic choices in 13/18 patients with an optimization of seizures control. Conclusions: Patients with developmental encephalopathies including epilepsy should undergo targeted next generation sequencing since the first stages of diagnostic work-up.