Neurodevelopmental features in KCNQ2 developmental and epileptic encephalopathy may have limited associations with...

Variants in KCNQ2 encoding the voltage-gated potassium channel K_V7.2 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.

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_V7.2 channel function was determined by voltage-clamp recording in heterologous cells co-expressing K_V7.3. Functional effects were classified as severe loss of function (SLOF), loss of function (LOF), wild-type-like (WTL), and gain of function (GOF).

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.

Multiple and severe neurodevelopmental impairments are common in KCNQ2-DEE. There was a modest correlation between K_V7.2 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.

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.