Abstract
Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy characterized by multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. Most patients with LGS do not respond well to drug treatment and show poor long-term prognosis. Approximately 30% of patients without brain abnormalities have unidentifiable causes. Therefore, accurate diagnosis and treatment of LGS remain challenging. To identify causative mutations of LGS, we analyzed the whole-exome sequencing data of 17 unrelated Korean families, including patients with LGS and LGS-like epilepsy without brain abnormalities, using the Genome Analysis Toolkit. We identified 14 mutations in 14 genes as causes of LGS or LGS-like epilepsy. 64 percent of the identified genes were reported as LGS or epilepsy-related genes. Many of these variations were novel and considered as pathogenic or likely pathogenic. Network analysis was performed to classify the identified genes into two network clusters: neuronal signal transmission or neuronal development. Additionally, knockdown of two candidate genes with insufficient evidence of neuronal functions, SLC25A39 and TBC1D8, decreased neurite outgrowth and the expression level of MAP2, a neuronal marker. These results expand the spectrum of genetic variations and may aid the diagnosis and management of individuals with LGS.
Highlights
Lennox-Gastaut syndrome (LGS) is a severe form of childhood-onset epilepsy with a heterogeneous etiology, and epileptiform abnormalities may contribute to progressive dysfunction (Lund et al, 2014; Asadi-Pooya, 2018)
We evaluated pathogenicity using criteria described in the American College of Medical Genetics and Association for Molecular Pathology guidelines, after which we selected genes with damaging, possibly damaging, pathogenic, or likely pathogenic mutations as candidate genes of LGS and LGS-like epilepsy (Richards et al, 2015)
We identified 14 candidate genes and genetic variations related to neuronal development or neurotransmission as biomarkers of LGS and LGS-like epilepsy with unknown causes
Summary
Lennox-Gastaut syndrome (LGS) is a severe form of childhood-onset epilepsy with a heterogeneous etiology, and epileptiform abnormalities may contribute to progressive dysfunction (Lund et al, 2014; Asadi-Pooya, 2018). Genetic Variations in Lennox-Gastaut Syndrome fast activity discharges on electroencephalography, and intellectual disabilities (Camfield, 2011; Asadi-Pooya, 2018). Thirty percent of LGS patients do not present abnormalities in brain imaging, and the cause of their condition is unclear (Asadi-Pooya, 2018). Functional magnetic resonance imaging studies showed that abnormal network connectivity in subcortical structures causes LGS (Pedersen et al, 2015). Several researchers have focused on screening genetic risk factors from patients with LGS without abnormalities by next-generation sequencing
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