Greater use of genome sequencing (GS) and exome sequencing (ES) in children and adults with epilepsy should identify specific gene variants that cause seizures in a significant population of patients. In addition, genetic testing can result in treatment changes that improve patient outcomes.[8] Although much has been learned about the etiologies of individual epilepsy types, it seems that genetic testing holds the key to better care.[5,8,9]
Epilepsy may be diagnosed at any point during the human life cycle, from infants younger than six months to adults older than 60 years.[1] The types of epilepsy and their causes are different in younger patients and older patients. Diagnostic delays, which may be measured in years, continues to be an issue for patients with seizures. Reducing these delays can be critical to instituting treatment appropriate to the individual patient, in the hope of optimizing outcomes.[2] Once the diagnosis of epilepsy is made, the underlying cause can be evaluated, further enhancing the opportunity for targeted treatment and genetic counseling.[2,9]
THE INCIDENCE OF EPILEPSY
A 2017 study of pediatric epilepsy found an incidence of 144 per 100,000 person-years from birth to age 1 year, declining to 58 per 100,000 person-years for those between 1 and 10 years of age, and with a cumulative incidence of 0.66% by age 10.[10] According to the Centers for Disease Control and Prevention, approximately 456,000 US children (ages, ≤ 17 yr) have active epilepsy.[11]
The incidence of epilepsy in adults seems to rise from age 50 years to 55/100,000 person-years by age 69 and then to more than 110/100,000 person-years by age 79, with a prevalence of 1.5%, or double that of younger adults.[12] Researchers estimate that up to one-half of elderly patients with epilepsy or unprovoked seizures were found to be idiopathic or unexplained.[12]
PATHOGENIC CAUSES OF EPILEPSY
Although estimates vary, partly because of new genetic-related associations with epilepsy, it is estimated that genetic etiologies are responsible for seizures in up to 40% of cases of pediatric-onset and 23% of adult-onset epilepsy.[9,13]
The use of next-generation sequencing (NGS) has resulted in the discovery of many previously unknown pathogenic variants in epilepsy.[6] Genetic variants found to play a direct role in the development of seizures cause a variety of conditions that can be broadly classified into syndromic disorders (i.e., single-gene variants or chromosomal abnormalities), metabolic disorders, brain malformations, and abnormal cellular signaling.[6]
As of March 2025, the number of genes involved in epilepsy is thought to exceed 1,000.[14,15] In individuals with a pathogenic cause for their epilepsy and seizures, symptoms may be the result of interactions of several genes or from a single genetic variant.[4] Additionally, gene variants that have been associated with epilepsy and its manifestations have also been linked to neurologic conditions, such as intellectual disability, developmental delay, cerebral palsy, and autism.[2,13,16]
The pathogenic variants involved in epilepsy may be inherited or spontaneously appearing (de novo). For example, in patients with focal epilepsy (or seizures localized to one part of the brain), some commonly implicated genes include DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19.[7] Other examples of identified variants include ALDH7A1, KCNA2, KCNQ2, PNPO, SCN2A, TSC1, TSC2, all associated with different epilepsy syndromes.[5,17]
Patients with generalized seizures (abnormal neuronal activity emanating from both sides of the brain) are associated with variants in a variety of different genes and interaction among them.[1] It now seems that in most monogenic epilepsies, the genetic variant(s) affects the opening and closing of ion channels or neurotransmitter receptor operation.[5]
Seizures are not universally caused by genetic factors; they can also be caused by other medical issues, such as febrile illness, stroke, brain tumors, head trauma, brain infection, hyper- or hypoglycemia, chemical imbalances, eclampsia, or dysfunction of the liver or kidneys.[1]
With the evolution of genetic testing, it is possible to identify seizure-causing variants. In a 2020 study, researchers using NGS in 116 patients with early-onset epilepsy detected 40 disease-causing variants (19 pathogenic, 21 likely pathogenic).[17]
A study by McKnight and colleagues[9] found that in 418 patients with epilepsy who received a genetic diagnosis, the finding altered clinical management in 208 (50%). Based on follow-up of 167 patients, the treatment changes instituted improved outcomes in three quarters of the cohort. The most common improvement was the elimination or reduction of seizures (in 65%). A subset of patients attained a 90% reduction in seizure frequency.[8]
A genetic diagnosis can help guide a more tailored management approach and treatment changes, even into the seventh decade of life and after many decades of drug-resistant seizures and treatment with contraindicated medications. This can result not only in improvements in seizure frequency, but in cognition, language and communication, and quality of life.[18,19]
GENETIC TESTING PATHWAYS
Genetic testing for patients with epilepsy has evolved to include several clinically available options, including genome-wide comparative genomic hybridization/chromosomal microarray (CGH/CMA), multigene panel (MGP), ES, and GS to assay for copy number and sequence variants involving genes associated with epilepsy.[8] In exome sequencing, only the exons (protein-coding regions) of the genome are analyzed. This comprises up to 2% of the total genome. In genome sequencing, the entire DNA sequence is analyzed, which may detect a broader range of variants.[20] Chromosomal microarray testing detects disorders on a chromosomal level (minimum resolution ≥ 30,000 base pairs) rather than a base-pair level as with ES and GS (minimum resolution ≥ 1 base pair).[21]
A systematic review of 154 articles in the literature revealed that GS identified epilepsy-associated genetic variants in 48% of cases, ES identified variants in 24%, followed by MGP (19%), and CGH/CMA (9%).[8] Genome sequencing and ES were found to have even higher diagnostic yields in subpopulations with developmental disabilities.
Importantly, most seizure-related genes identified through ES were not included on commercially available panels, with 57% missing from six leading panels.[22]
FROM GENETIC CAUSE TO TREATMENT PLAN
A realistic goal for precision medicine in this disease state is to offer customized treatment for a single epileptic syndrome based on the involved gene or molecular anomaly.[5] For example, for patients with GRIN2A or GRIN2B variants, who have focal epilepsy, researching the effectiveness of targeted therapies with NMDA-receptor antagonists like memantine or dextromethorphan may be potentially fruitful.[5]
Furthermore, inborn errors of metabolism, which raise the risk of epilepsy, when promptly diagnosed, can result in early, preventive treatment. An example might be the use of a ketogenic diet in patients with a SLC2A1 variant (which results in glucose transporter deficiency). [23,24] The Table below represents examples of the impact of variant type, gain-of-function and loss-of-function, on potential therapeutic approaches for SCN1A and SCN2A-related disorders.[25]
TABLE. EPILEPSY SYNDROMES ASSOCIATED WITH SCN1A AND SCN2A VARIANTS
| Epilepsy Syndrome | Gene Involved (Loss/Gain of Function) | Potential Therapeutic Approach |
|---|---|---|
| Dravet Syndrome GEFS+ EIMFS Developmental and Epileptic Encephalopathy | SCN1A (LOF) | Stiripentol (+valproate+clobazam) Fenfluramine Cannabidiol Avoidance of Sodium-Channel Blockers |
| Benign Familial Neonatal Infantile Epilepsy GEFS+ EIMFS Epileptic Spasms Syndrome Ohtahara Syndrome Developmental and Epileptic Encephalopathy | SCN2A (GOF) | Sodium-Channel Blockers |
| Benign Familial Neonatal Infantile Epilepsy GEFS+ EIMFS Epileptic Spasms Syndrome Ohtahara Syndrome Developmental and Epileptic Encephalopathy | SCN2A (LOF) | Avoid Sodium-Channel blockers |
| EIMFS = Early infantile focal migrating seizure; GEFS+ = genetic epilepsy with febrile seizures plus; GOF = gain of function; LOF = loss of function. Adapted from Bayat et al.[25] |
||
With increasing use of highly specific genetic testing, precision-based treatment in patients with epilepsy seems a realistic goal for patients, parents, and providers.
EPILEPSY TYPES AND CLASSIFICATIONS
The International League Against Epilepsy most recently modified its classification of seizures in 2017. It is based on whether the seizure onset is focal, generalized, or an unknown source.
In a focal-onset seizure, the patient can be awake and aware of the seizure, or they may have impaired awareness. An initially focal-onset seizure may spread to both hemispheres of the brain, resulting in uncoordinated muscle movements like rhythmical jerking and stiffening of large muscle groups (tonic-clonic seizures).
A patient experiencing a tonic-clonic seizure may initially have a visual disturbance called an aura, characterized by flashes of bright lights, blurriness, or vision loss; this seizure may also result in the patient losing consciousness. Those tonic-clonic seizures lasting more than five minutes are referred to as status epilepticus, and require medical assistance with rescue medications.[26]
On the other hand, focal-onset epilepsy may feature non-motor seizures, or absence seizures, which have few muscular signs other than localized twitches or stiffness of the face or limbs. Focal-onset epilepsy may be characterized by moments of staring blankly without focus and a general lack of awareness.
In a generalized-onset seizure, the patient initially experiences effects on both sides of the brain and typically has impaired awareness. Tonic-clonic seizures may result, as well as other motor complications. Furthermore, non-motor involvement also may occur with generalized-onset seizures. For more information on seizure classification and epilepsy types, see https://www.epilepsy.com/what-is-epilepsy/seizure-types.[26]
THE CAUSES OF ADULT-ONSET EPILEPSY
Compared with epilepsy that first appears in children, adult-onset epilepsy is less likely to have an identifiable genetic etiology. Perhaps 10% of those with adult-onset neurologic disorders may have an identifiable pathogenic cause.[27]
Next-generation sequencing may best be applied in adult-onset epilepsy for those with refractory epilepsy or accompanying dysmorphism, and/or developmental delay/cognitive regression/intellectual disability.[5] Johannesen and colleagues[13] found that in adult-onset epilepsy, patients with comorbid intellectual disability were more likely to have a genetic cause for their seizures. Of 200 patients referred for diagnostic gene panel testing at a Danish center, 23% had a genetic variant identified (most commonly SCN1A, KCNT1, and STCXBP1). Ninety-one percent of the total cohort had intellectual disability.
Furthermore, a significant proportion of individuals with adult-onset epilepsy, particularly those presenting with generalized seizures, have an unidentified idiopathic etiology.[12,29] There is optimism that further genetic study may someday reveal a pathogenic cause, leading to the potential for precision medicine for a portion of this subgroup with adult-onset epilepsy.[2] In addition, for many adult patients first diagnosed with epilepsy as children, the root cause of their seizures has not yet been ascertained. These patients, especially if they have developmental and epileptic encephalopathies, may also benefit from identification of a genetic variant and subsequent changes in treatment.[18]
EMERGING RESEARCH LINKING GENETIC FINDINGS IN EPILEPSY AND COMORBID CONDITIONS
The field of genomic and exome testing in patients with epilepsy continues to expand, and the list of new pathogenic or likely pathogenic variants is growing. With this expansion, our understanding of the mechanisms leading to patients’ seizures has also broadened. For example, the discovery of mutations in ion channels (related to SCN1A and SCN2A function), neurotransmitter receptors (related to GABRA1), and synaptic proteins (associated with SYNGAP1 and KCNQ2 activity), have provided vital information about the mechanisms for epilepsy susceptibility and pathogenesis.[28]
Additional research has revealed that certain gain-of-function variants are associated with neonatal symptoms, as well as certain loss-of-function variants are associated with concurrent autism spectrum disorders, developmental delays, and epileptic encephalopathies.[2] In a systematic review of studies in neurologic disorders, researchers found that targeted gene panel sequencing or exome sequencing resulted in pathogenetic identifications in 28% of patients with epilepsy and intellectual delay.[29] As stated earlier, a separate systematic evidence review found that the presence of neurodevelopmental comorbidities was significantly associated with greater diagnostic yield for GS and ES, compared with CMA.[8]
Once the genetic variant(s) is targeted, it may be possible to reevaluate existing pharmaceuticals or test new medicines to compensate for the resulting dysfunctional enzyme or protein production. Memantine is one such example, as it may be useful to compensate for a gain-in-function variant in GRIN2A. Another example is quinidine, which has been shown to decrease seizure frequency in patients with KCNT1-related epilepsy.[2] In a cohort of patients with developmental disabilities associated with epilepsy, greater than 90% reduction of seizures was obtained with a ketogenic diet.[8]
Another logical avenue of exploration involves directly correcting the variant, through gene editing or adenovirus vector transport. Antisense oligonucleotides, which are single-stranded nucleic acid sequences that bind to messenger RNA and alter their function, may in the future effect changes in the mRNA to compensate for either gain-of-function or loss-of-function variants.[2]
CLINICAL IMPLICATIONS OF GENE TESTING IN PATIENTS WITH EPILEPSY
The increasing utilization of gene and exome sequencing in children and adults with epilepsy has the potential to bolster the evidence base identifying specific gene variants that cause seizures. In addition, genetic testing can support clinical decision making and help inform insurance coverage policies for patients with epilepsy.[8]
For patients with unexplained epilepsies, genetic testing is strongly recommended by the National Society of Genetic Counselors “without limitation of age, with exome/genome sequencing and/or a multi-gene panel (>25 genes) as first-tier testing followed by chromosomal microarray, with exome/genome sequencing conditionally recommended over multi-gene panel” in concert with genetic counseling.[31] This position is also endorsed by the American Epilepsy Society.[32]
Genetic testing for epilepsy is critical in helping to identify the underlying cause of a patient’s disease, which may lead to a more definitive diagnosis, better medical management of one’s overall condition, and improved treatment of associated seizures.
REFERENCES
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20. What are whole exome sequencing and whole genome sequencing? National Institutes of Health July 28, 2021. https://medlineplus.gov/genetics/understanding/testing/sequencing/.
21. Genomic microarray and whole exome sequencing: Final evidence report. Washington State Health Care Authority December 19, 2017. https://www.hca.wa.gov/assets/program/micro-array-wes-final-rpt-20171221.pdf#:~:text=This%20report%20discusses%20chromosomal%20microarray%20(CMA)%20and,as%20small%20as%20a%20single%20base%20pair.
22. Butler L, Tuttle A, Havens Dyer L, et al. Exome-based testing for patients with seizures: Advantages over panel-based testing. Poster presented at American Epilepsy Society Annual Meeting; December 2, 2023; Orlando, FL.
23. Daci A, Bozalija A, Jashari F, et al. Individualizing treatment approaches for epileptic patients with glucose transporter type 1 (GLUT-1) deficiency. Int J Mol Sci. 2018;19:122. doi:10.3390/ijms19010122.
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29. Kaur S, Garg R, Aggarwal S, et al. Adult-onset seizures: Clinical, etiological, and radiological profile. J Family Med Prim Care. 2018;7:191-197. doi: 10.4103/jfmpc.jfmpc_322_16.
30. Stefanski A, Calle-Lopez Y, Leu C, et al. Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability: A systematic review and meta-analysis. Epilepsia. 2021;62:143–151. doi: 10.1111/epi.16755.
31. Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: An evidence-based practice guideline of the National Society of Genetic Counselors. J Genet Couns. 2023;32:266–280. doi: 10.1002/jgc4.1646.
32. Melendez-Zaidi A, Angione K, Williams J, et al. Genetic testing in epilepsy: Practical considerations for clinical use. American Epilepsy Society June 2025. https://aesnet.org/clinical-care/running-your-practice/genetic-testing-epilepsy-practical-considerations-for-clinical-use.
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