Variants inSBF1, CELSR2,andTENM1cause childhood epileptic encephalopathies

medRxiv (Cold Spring Harbor Laboratory)(2023)

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Abstract Epileptic encephalopathy is a devastating epilepsy with etiologies that remain largely elusive, despite recent whole-gene/exon sequencing of large cohorts. This study targeted childhood epileptic encephalopathy, typically Lennox-Gastaut syndrome, which is characterized by age-dependent onset and characteristic clinical manifestations. Trio-based whole-exome sequencing was performed in 235 unrelated cases with individualized analysis by explainable inheritance origin with stratified frequency filtration and specified statistical analysis, including setting controls for compound heterozygous variants. We identified three novel causative genes, including SBF1 with de novo variants in three cases, CELSR2 with recessive variants in eight cases, and TENM1 with X-linked recessive variants in six cases. Significantly higher excesses of de novo variants in SBF1 and biallelic variants in CELSR2 and aggregated frequencies of variants in SBF1 , CELSR2 , and TENM1 were detected. The frequency of compound heterozygous/homozygous CELSR2 variants in the cases was significantly higher than that in 1942 asymptomatic parent controls. In Drosophila , knockdown of the three genes showed increased seizure-like behavior and increased firing of excitatory neurons. Sbf1 knockout zebrafish showed seizure-like behavior, premature death, and increased firing of excitatory neurons. Celsr2 knockout mice showed spontaneous seizures with epileptiform discharges. These results indicate that SBF1 , CELSR2 , and TENM1 are pathogenic genes of Lennox-Gastaut syndrome.
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