Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice

Abstract

Epilepsy is one of the most common neurological disorders with diverse phenotypic characteristics and high genetic heterogeneity. Epilepsy often occurs in childhood, so timely diagnosis and adequate therapy are crucial for preserving quality of life and unhindered development of a child. Next-generation-sequencing (NGS)-based tools have shown potential in increasing diagnostic yield. The primary objective of this study was to evaluate the impact of genetic testing and to investigate the diagnostic utility of targeted gene panel sequencing. This retrospective cohort study included 277 patients aged 6 months to 17 years undergoing NGS with an epilepsy panel covering 142 genes. Of 118 variants detected, 38 (32.2%) were not described in the literature. We identified 64 pathogenic or likely pathogenic variants with an overall diagnostic yield of 23.1%. We showed a significantly higher diagnostic yield in patients with developmental delay (28.9%). Furthermore, we showed that patients with variants reported as pathogenic presented with seizures at a younger age, which led to the conclusion that such children should be included in genomic diagnostic procedures as soon as possible to achieve a correct diagnosis in a timely manner, potentially leading to better treatment and avoidance of unnecessary procedures. Describing and discovering the genetic background of the disease not only leads to a better understanding of the mechanisms of the disorder but also opens the possibility of more precise and individualized treatment based on stratified medicine.

Evaluating Clinical Presentation and Long-Term Outcomes in Individuals with Genetic and Non-Genetic Epilepsy Treated with Epilepsy Surgery: A Single-Center Study

“…Indeed, developmental delay of different severity is a feature of numerous genetic disorders associated with epilepsy. The yield of genetic testing in individuals with epilepsy increases if concurrent developmental delay is present 33,34 , making this combination of clinical features an important triaging factor for genetic testing. 35 We thus suggest that the presence of developmental delay in individuals assessed for epilepsy surgery prompts consideration of genetic testing.…”

“…We matched individuals with non-genetic epilepsy separately to individuals with mTORopathies and other genetic epilepsy etiologies using 1:1 nearest-neighbor matching on propensity scores. Propensity scores were derived by running a generalized linear regression model where the dependent variable was the genetic status, and predictors included clinical variables known to be associated with postsurgical outcomes 33,34 : sex, age at seizure onset and surgery, presence of MRI lesion, presence of developmental delay, preoperative seizure frequency, EEG findings at presurgical evaluation, and side and extent of intervention. Individuals with mTORopathies were matched with individuals with non-genetic epilepsies first.…”

In vitro human cell culture models in a bench‐to‐bedside approach to epilepsy

“…dermal fibroblasts, peripheral blood cells, buccal cells, exfoliated cells in the urine, and other cell types 74 , 75 , 76 ). Even though of nonneural origin, these cells are commonly utilized for detecting pathogenic variants of epilepsy‐related genes 77 , 78 , 79 , 80 and as source cells for reprogramming into iPSCs. 21 Furthermore, basic genomic and proteomic analyses, transcription profiling, biomarker analysis, drug screening, and metabolic analyses of the patient‐derived somatic nonneural cells are performed (Refs.…”

Rare heterozygous genetic variants of NRXN and NLGN gene families involved in synaptic function and their association with neurodevelopmental disorders

“…Homozygous variants of NRXN1 cause Pitt Hopkins-like syndrome 2 (PTHSL2, OMIM no 614325). Among the genes directly involved in synaptic function, the NRXN1 gene has been the most implicated gene in previous reports of neurodevelopmental disorders and neuropsychiatric conditions (Blazekovic et al, 2022;Fromer et al, 2014;Satterstrom et al, 2020;Takata et al, 2018;Taşkıran et al, 2021;Truty et al, 2019;Wang et al, 2020).…”