Abstract
Objective: The genetic aetiology of epileptic encephalopathy (EE) is growing rapidly based on next generation sequencing (NGS) results. In this single-centre study, we aimed to investigate a cohort of Chinese children with early infantile epileptic encephalopathy (EIEE).Methods: NGS was performed on 50 children with unexplained EIEE. The clinical profiles of children with pathogenic variants were characterised and analysed in detail. Conservation analysis and homology modelling were performed to predict the impact of STXBP1 variant on the protein structure.Results: Pathogenic variants were identified in 17 (34%) of 50 children. Sixteen variants including STXBP1 (n = 2), CDKL5 (n = 2), PAFAH1B1, SCN1A (n = 9), SCN2A, and KCNQ2 were de novo, and one (PIGN) was a compound heterozygous variant. The phenotypes of the identified genes were broadened. PIGN phenotypic spectrum may include EIEE. The STXBP1 variants were predicted to affect protein stability.Significance: NGS is a useful diagnostic tool for EIEE and contributes to expanding the EIEE-associated genotypes. Early diagnosis may lead to precise therapeutic interventions and can improve the developmental outcome.
Highlights
Epileptic encephalopathy (EE) describes a group of severe intractable seizures and neurological disorders in which epileptic activity itself may contribute to severe neurologic and cognitive impairment, beyond the damage that would be expected from the underlying pathology alone, and these effects can worsen over time [1]
Pathogenic variants of 17 genes were identified in 50 patients (34%) and pathogenic Copy number variations (CNVs) were not detected
Multiple sequence alignments and comparative protein structures of two STXBP1 missense variants are shown in Supplementary Figures 1, 2
Summary
Epileptic encephalopathy (EE) describes a group of severe intractable seizures and neurological disorders in which epileptic activity itself may contribute to severe neurologic and cognitive impairment, beyond the damage that would be expected from the underlying pathology alone, and these effects can worsen over time [1]. Infantile epileptic encephalopathies (EIEEs) occur during infancy and comprise a spectrum of syndromes such as Ohtahara syndrome (OS), West syndrome (WS), epilepsy of infancy with migrating focal seizures, and Dravet syndrome (DS) [2]. EIEEs exhibit overlap and pleiotropy, which makes it challenging to establish genotype-phenotype correlations. Gene and Phenotype of EIEE sequencing (NGS) have provided a significant advancement in the diagnosis of epileptic patients [4]. NGS was performed in a cohort of Chinese children with unexplained EIEEs. We analysed genotype-phenotype correlations and elucidated therapeutic effects and adjustments.
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