Whole-Exome Sequencing Utility and Drug Resistance in a Real-World Epilepsy Cohort from Southern Kazakhstan

Whole-exome sequencing in pediatric drug-resistant epilepsy: diagnostic yield and clinical impact in a resource-limited setting

Genetic landscape of pediatric seizures in Southeast China: identification of a novel GLI3 frameshift variant through whole-exome sequencing

Pediatric seizure disorders are clinically and genetically heterogeneous. Whole-exome sequencing has improved the detection of rare genetic variants in childhood epilepsy; however, data from pediatric populations in Southeast China remain limited. This study aimed to characterize the genetic landscape of pediatric seizure disorders in Southeast China and to evaluate the clinical diagnostic yield of whole-exome sequencing. This retrospective observational study included 21 pediatric patients with seizure disorders who were recruited at the Fifth Hospital of Xiamen, Fujian, China, between January 2021 and June 2024. Clinical data were extracted from medical records. Whole-exome sequencing was performed on DNA extracted from peripheral blood. Sequence variants were annotated, filtered, and classified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Copy-number variants were evaluated using exome-based algorithms. Descriptive statistics were used because of the limited sample size. WES identified three clinically relevant, likely pathogenic findings in 3 of 21 patients, corresponding to a provisional diagnostic yield of 14.3%. The remaining 62 of 65 variants were of uncertain significance (VUS). The three retained variants included a GLI3 frameshift variant (exon 2: c.90_91insCAGATGTGAGC; p.Glu31Glnfs*3) and two copy-number variants (16p13.12-16p13.11 duplication and Xp22.31 deletion) with established clinical significance. Functional analysis of all 65 variants revealed that ion channel genes and neurodevelopmental genes were the most frequently affected categories. Whole-exome sequencing identified clinically relevant genetic findings in a subset of Southeast Chinese children with seizure disorders. The novel GLI3 frameshift variant may suggest an expansion of the GLI3-associated phenotypic spectrum, but further segregation, functional validation, and larger cohort studies are needed. The high proportion of variants of uncertain significance highlights the ongoing challenges of genetic interpretation in pediatric seizure disorders.

Clinical heterogeneity and diagnostic challenges in CASK-related neurodevelopmental disorders: a longitudinal observational study

CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.

From targeted SCN1A analysis to whole exome sequencing: clinical utility and novel genetic findings in a Hungarian paediatric epilepsy cohort

Epilepsy represents a highly prevalent neurological disorder with a significant genetic component, particularly implicating ion channel genes, including SCN1A. In this study, 431 individuals with heterogeneous paediatric-onset epilepsy phenotypes were assessed at the Department of Medical Genetics, University of Pécs between 2018 and 2024. Genetic investigations employed Sanger sequencing, targeted epilepsy gene panels, whole exome sequencing, and multiplex ligation-dependent probe amplification for SCN1A copy number analysis. Thirty-six pathogenic or likely pathogenic SCN1A variants were identified, including 15 variants which have not been reported previously. Furthermore, 9 novel variants were detected in 12 additional epilepsy-associated genes. Diagnostic yield was proportional to the breadth of genomic interrogation. WES analysis revealed 6 novel variants in 19 genes. These findings underscore the considerable genetic heterogeneity of epilepsy and demonstrate the clinical utility of gene panels and WES, particularly in complex phenotypes. The identification of novel variants enhances molecular understanding and facilitates more precise genotype-phenotype correlations, reinforcing the value of comprehensive genomic diagnostics in epilepsy management.

Clinical phenotype spectrum and prognostic analysis of DNM1L-related disorders: a single-center cohort study of 18 patients

“hemiconvulsion-hemiplegia-epilepsy syndrome” is identified as a distinct feature and potential prognostic indicator for middle domain variants in DNM1L variants, which are predominantly missense, with the middle domain as a hotspot.

Genetic Insights into Overcoming Drug Resistance in Paediatric Epilepsy: The Role of SCN1A and ABCB1 Polymorphisms