Identification of novel causative genes of childhood epileptic encephalopathies

Abstract

Background and ObjectivesEpileptic encephalopathy is a devastating epilepsy with etiologies largely elusive, despite recent whole gene/exon sequencing on large cohorts. This study targeted on 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 241 unrelated cases from 21 epilepsy centers through China Epilepsy Gene 1.0 Project with individualized analyses on each trio by explainable inheritance origin with stratified frequency filtration, on each gene in four aspects that include gene expression in the brain, previously reported phenotypes, pLI/pRec/Z-missense index, and genetic knockout/knockdown phenotypes, followed by multiple/specific statistical analyses depending on the inheritance pattern of variants, including the establishment of controls for analysis of compound heterozygous variants. ResultsThree genes presented highly repetitive variants with statistical significances, including SBF1 with de novo, CELSR2 with recessive, and TENM1 with X-linked recessive variants. The frequency of compound heterozygous/homozygous CELSR2 variants in the cases was significantly higher than that in 1942 asymptomatic parent controls. The variants located at functional domains in SBF1 and TENM1, and homozygous/compound heterozygous variants with one of the paired variants located in functional domains in CELSR2, were associated with more frequent and refractory seizures. Six genes were suggested to be potential causative genes with evidence of gene profile and statistical significance. Additional 41 genes were considered as potential candidate genes with evidence of gene profile/statistical significance. DiscussionThis study suggests that SBF1, CELSR2, and TENM1 are causative genes of LGS and highlights the implication of individualized analysis protocol, i.e., individualization on phenotype, individualization on each case, and individualization on each gene, in identifying genetic causes of human diseases.