KCNQ2 Variants in Neonatal Epilepsy: Clinical Characteristics and Neurodevelopmental Outcomes in 30 Patients
June 2026 | Neurology: Genetics
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.
© 2026 Wolters Kluwer. All right reserved.