Abstract
BACKGROUND AND OBJECTIVES: The aim of this study was to characterize clinical features, genetic architecture, treatment responses, and neurodevelopmental outcomes in neonatal epilepsy associated with KCNQ2 variants and to delineate genotype-phenotype correlations. METHODS: We conducted a retrospective, two-center study of 30 neonates from 2019 to 2024. All patients underwent whole-exome sequencing with Sanger confirmation and, at last follow-up, were classified, according to International League Against Epilepsy criteria as having self-limited (familial) neonatal epilepsy (SeL[F]NE) or developmental and epileptic encephalopathy (DEE). Primary outcomes were seizure freedom by 6 months and milestone-based three-level neurodevelopment (normal/mild/severe). Clinical/EEG/MRI features and variant class/topology were compared across phenotypes. RESULTS: Most infants presented in the first week of life (median 3 days), typically with focal tonic seizures. EEG abnormalities were common (90%); burst-suppression/profound discontinuity consistently signaled adverse neurodevelopment. MRI was often normal (53%) or nonspecific. We identified 29 distinct variants (32 occurrences) across 30 patients. Twenty-eight carried a single heterozygous variant, and 2 carried 2 heterozygous variants (phase not determined); missense variants predominated (21/30, 70%). Clear topology-phenotype patterns emerged: transmembrane missense variants-especially S5-pore-S6-were enriched in DEE, whereas C-terminal/nontransmembrane variants were associated with SeL(F)NE and benign outcomes. At the last follow-up, SeL(F)NE accounted for 63% and DEE 37%. Seizure freedom reached 93%. Oxcarbazepine was often associated with seizure control after phenobarbital nonresponse, but this observational signal should not be interpreted as causal. Neurodevelopment was normal in 63%; delays occurred only within the DEE cohort. All 5 single-allele truncating/NMD lesions (CNV deletion, canonical splice-site, 2 nonsense, 1 frameshift) aligned with SeL(F)NE, whereas the 2 individuals with 2 heterozygous variants were classified as DEE with marked impairment; however, phase was not determined and 1 recurrent variant (p.E515D) was classified as likely benign, precluding inference of 2 pathogenic alleles. DISCUSSION: KCNQ2-related neonatal epilepsy shows robust, topology-dependent genotype-phenotype correlations with prognostic utility: early EEG patterns flag risk; transmembrane missense variants are associated with DEE, whereas single-allele truncating/NMD variants are associated with SeL(F)NE. Apparent benefits of oxcarbazepine reflect associations in an observational cohort and should not be interpreted as causal; prospective, phenotype-stratified studies are warranted. Long-term developmental surveillance remains essential, particularly for individuals with DEE and those with severe early EEG patterns or variants in transmembrane/pore regions.