Epilepsies are a group of neurological disorders characterized by the recurrent occurrence of epileptic seizures due to abnormal electrical activity in the brain. Although for many years their cause was attributed primarily to acquired factors such as trauma, infections, tumors, or structural lesions, we now know that a significant proportion of epilepsies have a genetic component. This knowledge has transformed our understanding of the disease and is profoundly changing the way patients are diagnosed and treated.
Genetic epilepsies can manifest at any stage of life, although they are particularly common in childhood and adolescence. In many cases, the mechanism that triggers seizures is a mutation in genes that regulate ion channels, neuronal synapses, or brain development processes. Variants in genes such as SCN1A, KCNQ2, STXBP1, CDKL5, or PCDH19 have been identified as direct causes of specific epileptic syndromes. Some of these alterations cause severe, early-onset epilepsies, while others result in milder forms or those that respond well to treatment. For clinicians, distinguishing between these possibilities is essential, and genetics offers a precise tool to achieve this.
“We now know that a significant proportion of epilepsy cases have a genetic component.”
The use of genetic testing in epilepsy has become particularly important thanks to the development of next-generation sequencing (NGS). This technology allows for the simultaneous analysis of hundreds or thousands of genes with high sensitivity and in a short amount of time. Among these techniques, two main approaches stand out: targeted exome sequencing and whole-exome sequencing. Although both are based on the sequencing of coding regions of DNA, they serve complementary roles in the diagnostic process.
Targeted exome sequencing and whole exome sequencing
Targeted exome sequencing involves analyzing a panel of genes specifically selected for their known association with epilepsy. These panels include dozens or hundreds of genes whose involvement has been extensively demonstrated in various epileptic syndromes. Their main advantage is efficiency: by focusing on genes of high clinical relevance, they provide rapid results with less interpretive complexity and at a lower cost. Furthermore, they are often the first-line investigation when genetic epilepsy with well-defined clinical features is suspected. However, their main limitation is that they only analyze what is already known; if the cause lies in genes not included in the panel, it may go unnoticed.
To overcome this limitation, whole-exome sequencing has become an invaluable tool, especially in complex cases, early-onset epilepsy syndromes, or patients with multiple comorbidities. Whole-exome sequencing analyzes virtually all coding genes in the human genome, making it possible to identify rare or unexpected variants that would not have been considered initially. Thanks to this comprehensive view, whole-exome sequencing contributes both to clinical diagnosis and to the discovery of new genes associated with epilepsy, continuously expanding scientific knowledge about the disease. Furthermore, one of its most significant advantages is the ability to reanalyze the data in the future, as research progresses and new evidence emerges.
Reaching an accurate and early genetic diagnosis has critical implications for the treatment of epilepsy. First, it allows for the selection of more appropriate therapies. Some mutations respond better to certain drugs, while others make the use of specific medications inadvisable. For example, in epilepsies associated with SCN1A variants, certain antiepileptic drugs can worsen seizures, so it is essential to identify this subtype as soon as possible. Second, genetic diagnosis helps predict clinical progression, plan follow-up, and anticipate potential comorbidities. It also allows for guiding families through genetic counseling, providing reliable information on recurrence risks and reproductive possibilities.
Genetics is transforming the way we understand and treat epilepsy. The combined use of targeted panels and whole-exome sequencing offers a robust and flexible approach to achieving accurate diagnoses, particularly for complex neurological disorders. As these technologies continue to evolve, their application will enable progress toward more personalized, effective care tailored to each patient’s specific characteristics.
BIBLIOGRAPHY
- Krygier, J., et al. Next-generation sequencing testing in children with epilepsy reveals novel clinical, diagnostic, and therapeutic implications. Frontiers in Genetics (2023).
- Miao, Q. et al. Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice. Genes 13 (2022): 1466
- Wu et al. Genome sequencing of 320 Chinese children with epilepsy: a clinical and molecular study. Brain 144 (2021): 3623–3637.
