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

Publication Number: 3561.580

Xiaowei Sun, Department of Neonatology, Qilu Hospital of Shandong University, jinan, Shandong, China (People's Republic); Yang Li, Department of Neonatology, Qilu Hospital of Shandong University, Jinan, Shandong, China (People's Republic); Jing'e Li, Department of Neonatology, Qilu Hospital of Shandong University, Jinan, Shanghai, China (People's Republic); Lili Li, Department of Neurology, Children’s Hospital Affiliated to Shandong University, Jinan, Shandong, China (People's Republic); Hongwei Zhang, Department of Neurology, Children’s Hospital Affiliated to Shandong University, Jinan, Shandong, China (People's Republic)

Background: Pathogenic KCNQ2 variants are a major cause of neonatal-onset epilepsy. However, comprehensive data integrating clinical, electrophysiologic, and genetic features remain limited, and predictors of long-term neurodevelopmental outcome are not well established.

Objective: To systematically characterize the clinical spectrum, genetic architecture, treatment responses, and neurodevelopmental outcomes of KCNQ2-related neonatal epilepsy, and to delineate genotype-phenotype correlations.

Design/Methods: Two-center retrospective cohort of 30 neonates (2019-2024). Whole-exome sequencing with Sanger confirmation; phenotypes (SeL(F)NE vs DEE) assigned at last follow-up (ILAE usage). Primary outcomes: 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. Twenty-nine unique variants were identified; missense predominated (21/30, 70%). Clear topology-phenotype patterns emerged: transmembrane missense-especially S5-pore-S6-was enriched in DEE, whereas C-terminal/non-transmembrane variants tracked with SeL(F)NE and benign outcomes. At last follow-up, SeL(F)NE 63% and DEE 37%. Seizure freedom reached 93%. OXC use was frequently associated with seizure control after phenobarbital nonresponse, but-given the observational design with possible confounding and variable co-treatments-these findings should be interpreted as associations rather than causal effects. Neurodevelopment was normal in 63%. All five single-allele truncating/NMD lesions (CNV deletion, canonical splice-site, two nonsense, one frameshift) aligned with SeL(F)NE, whereas two biallelic cases clustered in DEE with marked impairment.

Conclusion(s): KCNQ2-related neonatal epilepsy shows robust, topology-dependent genotype-phenotype correlations with prognostic utility: early EEG patterns flag risk; transmembrane missense is 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 DEE or biallelic genotypes.

KCNQ2 transmembrane topology and distribution of variants with developmental outcomes.
The schematic shows the intracellular amino (N) and carboxyl (C) termini, six transmembrane segments (S1-S6), and the S5-S6 pore loop. Variants are mapped at approximate residue positions (not to scale). Only single-variant-type, single-allele cases are displayed (n = 25: missense, nonsense, frameshift, or in-frame deletion); compound heterozygotes (Cases 20, 29), copy-number deletion (Case 3), and splice-site/region variants (Cases 14, 24) are not depicted. Cases 10 and 13 are siblings with the same variant (p.R395S) and are indicated as "(2 cases)". Symbols: triangle = nonsense, circle = missense, square = frameshift, star = in-frame deletion. Colors: green = normal development, yellow = mild delay, red = significant delay (status at last follow-up).

Table 1. Baseline clinical features, early EEG/MRI, treatment, and seizure outcomes in 30 neonates with KCNQ2-related epilepsy.
Age at onset is reported in postnatal days (day 0 = birth). Initial antiseizure medication(s) [ASM(s)] = regimen started during the index admission; Final ASM(s) = regimen at last follow-up. Seizure types: FT = focal tonic; FMC = focal motor with tonic-clonic features; FM = focal myoclonic. EEG: Multi = multifocal discharges; Focal = focal-onset discharges; BS = burst-suppression; N = normal; Other = nonspecific paroxysmal delta-theta activity with intermixed sharp waves. MRI: N = normal; EAS widen = widened extra-axial spaces; GP abn = globus pallidus signal abnormality; SDH = subdural hematoma. Drugs: PB = phenobarbital; LEV = levetiracetam; OXC = oxcarbazepine; VPA = valproate; LCM = lacosamide; TPM = topiramate. Outcomes: SF = seizure-free; AS = active seizures; mo = months; y = years; wk = weekly; SF (X mo/y) = seizure freedom since age X months/years and maintained through last follow-up; AS, n/mo = n per month (e.g., AS, 2-3/mo); AS, wk = weekly.

Table 2. KCNQ2 variants and genotype-phenotype summary in 30 neonates.
HGVS-compliant cDNA/protein nomenclature is based on KCNQ2 RefSeq NM_172107.2 (protein NP_736633.2); genomic build and coordinates are provided in the Supplement. Type: MIS = missense; NS = nonsense; FS = frameshift; IFD = in-frame deletion; SSM = canonical splice-site mutation; SRV = splice-region variant; LCND = large copy-number deletion; Truncating (Y/N): Y indicates NS, FS, SSM, or exon-level deletions under LCND. Origin: DN = de novo; IH = inherited; UNK = unknown; IH (bi) = inherited from both parents (biallelic); IH+DN = co-occurrence of inherited and de novo variants in the same individual. ClinVar column: "Reported" indicates an entry in dbSNP/ClinVar and/or prior literature; "Novel" indicates no record in dbSNP/ClinVar and no prior publication at the time of analysis (accessed October 2025). Details for Reported entries (by case no.): 4 rs118192194; 6 rs796052653; 8 rs886041262; 11 rs796052645; 14 rs1057516104; 15 rs1057518492; 21 ClinVar RCV005135626.1; 25 rs796052650; 26 rs118192212. Phenotype: SeL(F)NE = self-limited (familial) neonatal epilepsy; DEE = developmental and epileptic encephalopathy.