Clinical and genetic spectrum of a large cohort of children with epilepsy in China

Abstract

Purpose: Genetic diagnosis for children suffering from epilepsy has important implications for treatment, prognosis, and development of precision medicine strategies.

Methods: We performed exome sequencing (ES) or targeted sequencing on 733 children with epilepsy onset within the first year of life. We subgrouped our patients based on the onset age of seizure into neonatal and before 1 year (1-12 months), to compare the clinical and genetic features.

Results: The subgroups with different onset age of seizure showed different pathogenic variant spectrum, and the 1-year age group was more likely to have developmental delays than the neonate group (p = 0.000614). The diagnostic rate was 26.7% for targeted sequencing using a 2742-gene panel, and 42% for ES. We identified 12 genes, which covered 48.7% of diagnostic cases. Our data revealed that 41.9% of patients in the neonate group and 49.7% patients in the 1-year group had treatment options based on molecular diagnosis.

Conclusion: The 12 most commonly implicated genes in this cohort and the genes with treatment options should be considered as part of the essential panel for early diagnosis of epilepsy onset, if large medical exome analyses or ES are not feasible as first-tier analysis. Genetic results are beginning to improve therapy by antiepileptic medication selections and precision medicine approaches.

Keywords: Children; Epilepsy; Genetics; Pathogenic variant spectrum; Seizures.

Fig. 1. Genetic disorder spectrum in the subgroups with different onset ages.

a Gene distribution in subgroup with different onset age; the two groups were patients with neonatal seizures and patients with seizures or epilepsy onset within the first year of life. Patients with development delay are denoted by red; patients with normal intellectual are denoted by dark blue; unable to assess the development or lost follow-up are denoted by yellow. b Bar plot for the number of genes observed in each onset age (neonatal and less than 1 year). Each bar in each subfigure represents the counts for the genes labeled above. c Pie chart for the count of the recurrent corresponding gene (SCN1A, KCNQ2) in the two onset ages. The radius of each pie is proportional to the total observation number for each gene

Fig. 2. Treatment in patients with SCN1A, KCNQ2, and TSC2 gene pathogenic variation.

a Treatment in patients with SCN1A gene pathogenic variation. b Treatment in patients with KCNQ2 gene pathogenic variation. c Treatment in patients with TSC2 gene pathogenic variation. The horizontal coordinate represents specific drugs. The ordinate represents the percentage of the number of cases. LEV levetiracetam, VPA valproate, BDZ benzodiazepines, TPM topiramate, LTG lamotrigine, OXC oxcarbazepine, KD ketogenic diet, PB phenobarbital, VGB vigabatrin