LAUSR

Aim: Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy with multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. However, LGS-related genes are largely unknown. To identify causative genes related to LGS, we collected and analyzed data from a three-generation Korean family in which one member had LGS and two had intellectual disability. Methods: Genomic DNAs were extracted from blood samples of all participants and used in whole-exome sequencing (WES). Genetic variants were detected by the Genome Analysis Toolkit and confirmed by Sanger sequencing. Variant pathogenicity was evaluated by prediction programs and the American College of Medical Genetics criteria. The LGS patient had generalized slow spike-and-wave discharges, multiple types of seizures, and developmental delay. Results: Analyses of WES data from the family revealed a novel variant (c.1048G>A, p.Ala350Thr) in IQ motif and Sec7 domain 2 (IQSEC2). This variant is within a highly evolutionarily conserved IQ-like motif, indicating a decrease in the calmodulin-binding capacity or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid transmission. The hemizygous variant in the male with LGS was a maternally inherited X-linked variant from the heterozygous maternal grandmother and mother with intellectual disability. Conclusion: These findings indicate that the variant of IQSEC2 triggered both LGS and intellectual disability dependent on sex and variant types in this family. We report a novel X-linked inherited IQSEC2 variant for LGS and intellectual disability, which enhances the spectrum of variants in the IQ-like motif of IQSEC2.