Epilepsy – therapy-relevant panel

Within the wider spectrum of epilepsies, monogenic forms with increased therapeutic relevance present predominantly in the neonatal period or early childhood, with many therapeutically actionable entities manifesting within the first year of life. Clinical presentations span isolated recurrent unprovoked seizures, developmental and epileptic encephalopathies (DEEs), and epilepsies
embedded in broader neurometabolic or neurocutaneous phenotypes; seizure semiology, electroencephalographic features, and developmental trajectory vary substantially with the underlying entity. The classical syndromic / nonsyndromic dichotomy is of limited clinical utility within this group, where clinically meaningful categorisation rests on therapeutic actionability rather than on syndrome phenotype. Early aetiological clarification is therefore particularly relevant for neonatal-onset and infantile-onset presentations, in which the highest concentration of identifiable monogenic causes is observed and in which timely modification of anti-seizure medication or initiation of substrate-substitution therapy can materially influence the clinical course.

Due to insufficient data, no reliable statement on prevalence can currently be made. The overall diagnostic yield of epilepsy gene panels ranges 15-48%, reaching approximately 57% in neonatal-onset epileptic encephalopathies; a paediatric cohort using a 142-gene panel reported 23.1% yield.

A large number of genes have been associated with epilepsy. The genetic forms can be grouped into channelopathies, vitamin- and metabolism-responsive epilepsies, and mTOR-pathway disorders. Frequently identified causes include (SCN1A; sodium-channel blockers contraindicated), (ALDH7A1; pyridoxine substitution therapy available), and (TSC1, TSC2; mTOR inhibitor therapy indicated). In paediatric cohorts, SCN1A is most frequently implicated.

The genetic conditions associated with this group of epilepsies follow heterogeneous inheritance patterns. Autosomal dominant inheritance, frequently arising from de novo variants, predominates among developmental and epileptic encephalopathy genes; autosomal recessive inheritance applies to several vitamin- and metabolism-responsive forms; X-linked inheritance occurs with selected encephalopathy genes; and mitochondrial inheritance is encountered in mitochondrial-DNA-encoded encephalopathies.

• Where epilepsy is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Blazekovic A, Gotovac Jercic K, Meglaj S, Duranovic V, Prpic I, Lozic B, et al. Genetics of pediatric epilepsy: next-generation sequencing in clinical practice. Genes (Basel). 2022;13(8):1466. PMID: .
• Bayat A, Bayat M, Rubboli G, Møller RS. Epilepsy syndromes in the first year of life and usefulness of genetic testing for precision therapy. Genes (Basel). 2021;12(7):1051. PMID: .
• Nabbout R, Kuchenbuch M. Embracing the future: neonatal screening for epileptic syndromes. Epilepsia. 2025;66(6):1843-1853. PMID: .