Key result
Severe loss-of-function KCNQ2 variants are linked to ~1-point higher non-seizure severity scores vs loss-of-function.
Why the study?
Variants in KCNQ2 are associated with developmental and epileptic encephalopathy of varying severity, prompting examination of how KCNQ2 variant dysfunction relates to the neurodevelopmental phenotype.
Cross-Sectional (n=48)
The modest correlation between KV7.2 channel dysfunction and overall non-seizure phenotype severity suggests that factors beyond channel dysfunction contribute to the variable clinical severity in KCNQ2-DEE.
Severe loss-of-function KCNQ2 variants may modestly elevate non-seizure severity; leaves open whether channel dysfunction alone drives KCNQ2-DEE outcomes.
Objective Variants in KCNQ2 encoding the voltage‐gated potassium channel K V 7.2 are associated with developmental and epileptic encephalopathy (DEE) of varying severity. This study examined the relationship of KCNQ2 variant dysfunction with the neurodevelopmental phenotype of individuals with KCNQ2 ‐DEE. Methods A parent‐reported survey gathered clinical and genetic data for individuals with KCNQ2 ‐DEE. Several clinical features were analyzed separately and as a composite non‐seizure phenotype severity score (PSS) for six features (mobility, communication, hand use, eating, scoliosis, cerebral visual impairment). The effect of variants on K V 7.2 channel function was determined by voltage‐clamp recording in heterologous cells co‐expressing K V 7.3. Functional effects were classified as severe loss of function (SLOF), loss of function (LOF), wild‐type‐like (WTL), and gain of function (GOF). Results The study included 48 individuals each heterozygous for one of 38 unique variants. Median seizure‐onset age was 1 day. Complete or significant seizure reduction was reported in 7/13 with carbamazepine, 13/17 with oxcarbazepine, 10/13 with phenytoin, and 3/4 with retigabine. The median PSS was 1 (interquartile range 1–3). On the participant level, 29 had SLOF variants, 13 had LOF variants, and the remaining participants had variants with GOF (3) or exhibited WTL (2) function. There were no significant associations of variant function with individual phenotypes in the PSS; however, the PSS itself was higher in those with SLOF versus LOF variants ( p = 0.02). Among individuals with SLOF or LOF variants, there was an intriguing lower prevalence of epileptic spasms among individuals with dominant‐negative variants. Significance Multiple and severe neurodevelopmental impairments are common in KCNQ2 ‐DEE. There was a modest correlation between K V 7.2 channel dysfunction and overall non‐seizure phenotype severity in this cohort. These findings suggest that factors other than differences in channel dysfunction contribute to variable clinical severity in KCNQ2 ‐DEE. Plain Language Summary We examined how changes in the KCNQ2 gene, which affect the function of a brain potassium channel, relate to developmental and seizure features in children with KCNQ2 ‐related epilepsy. Using parent surveys and lab studies of gene variants, we found that variants causing the channel to lose most of its function were linked to slightly worse overall development. Our results suggest that while channel dysfunction plays a role, other biological or environmental factors likely influence how severely children are affected.
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Bidwell et al. (2025) conducted a cross-sectional in KCNQ2 developmental and epileptic encephalopathy (n=48). Severe loss-of-function (SLOF) KCNQ2 variants vs. Loss-of-function (LOF) KCNQ2 variants was evaluated on Composite non-seizure phenotype severity score (PSS) (p=0.02). Severe loss-of-function KCNQ2 variants were associated with a modestly higher non-seizure phenotype severity score compared to loss-of-function variants (median 2 vs 1, p=0.02).
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