KCNQ2 Variants in Neonatal Epilepsy: Clinical Characteristics and Neurodevelopmental Outcomes in 30 Patients

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.

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.

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.

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.