Abstract / Summary
Abstract Background Epileptic and/or developmental encephalopathies (DEEs) represent a particularly severe subgroup of early-onset epilepsies, with an identifiable genetic aetiology in 30–50% of cases. Mutations in the SCN1A , SCN2A , and SCN8A genes, encoding the α-subunits of the voltage-gated sodium channels Nav1.1, Nav1.2, and Nav1.6, respectively, are frequent causes of drug-resistant epilepsy with genotype-specific therapeutic implications. Objectives To evaluate the diagnostic utility and clinical impact of salivary genetic testing in paediatric patients with suspected drug-resistant epilepsy, defined according to the 2010 ILAE criteria as failure of adequate trials of two tolerated and appropriately chosen antiepileptic drug schedules, whether as monotherapy or in combination, to achieve sustained seizure freedom, analysing genotype–phenotype correlations in SCN1A , SCN2A , and SCN8A mutations. Methods Seventy-four patients (44 males, 59.5%; 30 females, 40.5%) referred to the Paediatric Neurology Unit of Policlinico Umberto I, Rome, with suspected drug-resistant epilepsy, were enrolled. Genomic DNA was extracted from salivary samples and analysed by next-generation sequencing (NGS) with integrated Copy Number Variant (CNV) detection, using the Flex Comprehensive Epilepsy Panel Plus (Blueprint Genetics, version 1, January 2023; 668 nuclear and 37 mitochondrial genes). Results At least one genetic variant of interest was identified in 70/74 patients (94.6%); however, this figure includes pathogenic, likely pathogenic, and variants of uncertain significance (VUS) according to ACMG/AMP criteria and should not be interpreted as reflecting exclusively clinically actionable diagnoses. Mutations in SCN1A , SCN2A , and SCN8A enabled syndromic confirmation and genotype-guided therapeutic orientation. Conclusions Salivary genetic testing demonstrates potential as a non-invasive and clinically relevant diagnostic tool in DEEs. Given the retrospective design, limited cohort size, and absence of direct comparison with blood-derived DNA testing, these findings should be interpreted cautiously. Further prospective, comparative studies are needed before recommending systematic integration of salivary genetic testing into standard diagnostic protocols.