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Next-generation sequencing in pediatric-onset epilepsies: Analysis with target panels and personalized therapeutic
Barbara Castellotti1, Francesca Ragona2, Elena Freri2
1Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Insights
Genetic analysis identified pathogenic variants in 24% of pediatric epilepsy patients, with 33% potentially eligible for precision medicine. This highlights the utility of next-generation sequencing (NGS) for targeted treatments in epilepsy.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Pediatric-onset epilepsies represent a significant clinical challenge with diverse etiologies.
- Identifying the genetic basis of epilepsy is crucial for understanding disease mechanisms and guiding treatment.
- Precision medicine offers a promising avenue for tailored therapeutic strategies in epilepsy management.
Purpose of the Study:
- To conduct genetic analysis in a large cohort of patients with pediatric-onset epilepsies.
- To identify patients who could benefit from precision medicine treatments based on genetic findings.
- To evaluate the diagnostic yield of next-generation sequencing (NGS) panels in this population.
Main Methods:
- Retrospective observational study of 562 patients with pediatric-onset epilepsy over 7 years.
- Exclusion of structural and metabolic causes followed by NGS panel screening for suspected genetic etiologies.
- Analysis of clinical data and genetic variants (classes IV and V) to identify associations and treatment eligibility.
Main Results:
- Likely pathogenic or pathogenic variants were detected in 24% of patients undergoing genetic testing.
- Early onset epilepsy, neurological deficits, psychomotor delay, and brain MRI abnormalities were associated with pathogenic variants.
- Next-generation sequencing (NGS) showed higher diagnostic yield for specific epilepsy types like Progressive Myoclonic Epilepsy (PME) and early-onset Developmental and Epileptic Encephalopathies (DEE).
- Up to 33% of patients with pathogenic variants were potentially eligible for precision medicine treatments.
Conclusions:
- Large-scale application of NGS multigene panels is effective for molecular diagnosis in pediatric-onset epilepsies.
- Genetic findings facilitate the identification of patients suitable for personalized therapeutic approaches.
- Understanding genetic mechanisms can guide the selection and optimization of treatments for pediatric epilepsy.
Objective:
The objective of this study is to report the results of the genetic analysis in a large and well-characterized population with pediatric-onset epilepsies and to identify those who could benefit from precision medicine treatments.
Methods:
In this retrospective observational study, we consecutively recruited patients with pediatric-onset epilepsy observed at a tertiary neurological center over a time span of 7 years, collecting clinical and laboratory findings. Following in-depth diagnostic process to exclude possible structural and metabolic causes of the disease, patients with a suspected genetically determined etiology underwent next-generation sequencing (NGS) screening with panels for the analysis of target genes causative of epilepsy.
Results:
We detected likely pathogenic or pathogenic variants (classes IV and V) in 24% of the 562 patients who underwent genetic investigations. By the evaluation of patients' data, we observed that some features (onset of epilepsy before one year old, presence of neurological deficits, psychomotor delay/cognitive disability, and malformative aspects at brain MRI) were significantly associated with class IV or V variants. Moreover, statistical analysis showed that the diagnostic yield resulted higher for patients affected by Progressive Myoclonic Epilepsy (PME) and with early onset developmental and epileptic encephalopathies (DEE), compared with focal epilepsies, genetic generalized epilepsies, DEE with onset at/after 1 y.o., and unclassified epileptic syndromes. According to the results of the genetic screening, up to 33% of patients carrying class IV or V variants resulted potentially eligible for precision medicine treatments.
Significance:
The large-scale application of NGS multigene panels of analysis is a useful tool for the molecular diagnosis of patients with pediatric-onset epilepsies, allowing the identification of those who could benefit from a personalized therapeutic approach.
Plain Language Summary:
The analysis of patients with pediatric-onset epilepsy using advanced technologies for the screening of all the implicated genes allows the identification of the cause of diseases in an ever-increasing number of cases. Understanding the pathogenic mechanisms could, in some cases, guide the selection and optimization of appropriate treatment approaches for patients.
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