Novel Mutation of SIK1 Gene Causing a Mild Form of Pediatric Epilepsy in a Chinese Family

Abstract Objective: Early infantile epileptic encephalopathy (EIEE) is a group of disorders affecting children at early stages of infancy, which is characterized by frequent seizures, epileptiform activity on EEG, and developmental retardation or regression. Salt-inducible kinases (SIKs) syndrome is a newly described EIEE, caused by heterozygous mutations in the salt-inducible kinase SIK1, which can present as early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Methods: In this study, we investigated a patient with early onset epilepsy. DNA sequencing of the whole coding region revealed a de novel heterozygous nucleotide substitution (c.880G>A) causing a missense mutation (p.A294T). This mutation was classified as variant of unknown significance (VUS) by American College of Medical Genetics and Genomics (ACMG). To further investigate the pathogenicity and pathogenesis of this mutation, we established a human neuroblastoma cell line (SH-SY5Y) stably-expressing wild type SIK1 and A294T mutant, and compared the transcriptome and metabolomics profiles. Results: We presented a pediatric patient suffering from infantile onset epilepsy. Early EEG showed a boundary dysfunction of activity and MRI scan of the brain was normal. The patient responded well to single anti-epileptic drug treatment. Whole-exome sequencing found a missense mutation of SIK1 gene (c.880G>A chr21: 43420326 p. A294T). Dysregulated transcriptome and metabolome in cell models expressing WT and MUT SIK1 confirmed the pathogenicity of the mutation. Specifically, we found MEF2C target genes, certain epilepsy causing genes and metabolites are dysregulated by SIK1 mutation.We found MEF2C target genes, certain epilepsy causing genes and metabolites are dysregulated by SIK1 mutation. Significance: Our finding further expanded the disease spectrum and provided novel mechanistic insights of SIK1 syndrome.