Identification of novel pathogenic genes of childhood epileptic encephalopathies

Abstract

AbstractBackgroundEpileptic encephalopathy is a devastating epilepsy with etiologies largely elusive, despite whole-gene/exon sequencing of large cohorts. This study targeted the genetic causes of childhood epileptic encephalopathy, typically Lennox-Gastaut syndrome (LGS) featured by age-dependent onset and characteristic clinical manifestations.MethodsTrio-based whole-exome sequencing was performed in 235 LGS cases with individualized analyses on each trio by explainable inheritance origin with stratified frequency filtration and on each gene in four aspects, and specified statistical analyses including that on compound heterozygous variants with controls of 1942 asymptomatic parents. Animal models were used to validate the roles of novel candidate genes.ResultsWe identified three novel causative genes, includingSBF1withde novo,CELSR2with recessive, andTENM1with X-linked recessive variants. Significantly higher excesses ofde novo SBF1variants and biallelicCELSR2variants, aggregated variant frequencies ofSBF1,CELSR2, andTENM1, and frequency of compound heterozygousCELSR2variants in the cases were detected. Phenotype severity/outcome was correlated with the genotype of the variants in these genes. InDrosophila, knockdown of these genes showed increased seizure-like behavior and increased firing of excitatory neurons.Sbf1knockout zebrafish showed seizure-like behavior, premature death, and increased firing of neurons.Celsr2knockout mice showed spontaneous seizures with epileptiform discharges. Additional 42 genes were identified as novel candidate pathogenic genes with evidence of the four genetic aspects/statistics.ConclusionsThis study suggestsSBF1,CELSR2, andTENM1are pathogenic genes of LGS and highlights the implications of phenotype subclassification and individualized analyses protocol in identifying genetic causes of human diseases.