A Novel KCNQ2 Gain‐of‐Function Variant I134N Causes Severe Developmental and Epileptic Encephalopathy

ABSTRACT Missense variants in the KCNQ2 gene can cause developmental and epileptic encephalopathy (DEE). While most KCNQ2‐DEE cases are attributed to loss‐of‐function (LOF) mutations, gain‐of‐function (GOF) mutations have also been implicated in the disorder. This study describes the clinical features of a DEE patient with a KCNQ2 mutation in the voltage‐sensing domain (VSD) and analyzes the variant's electrophysiological properties. Whole‐exome sequencing was performed to identify the genetic variant. Whole‐cell patch‐clamp electrophysiology was used to characterize the functional effects of the mutant channel, both alone and in combination with KCNQ3 subunits at a 1:1:2 ratio to mimic the patient's allele dosage. The effect of amitriptyline (AMI) on channel activity was also evaluated. A three‐year‐old female with early‐onset epileptic encephalopathy presented with intractable seizures, developmental regression, microcephaly, transient thyroid dysfunction, and a mixed EEG pattern of hypsarrhythmia and intermittent burst‐suppression. A de novo KCNQ2 variant (c.401T>A, p.Ile134Asn) located in the conserved S2 transmembrane domain was identified and classified as likely pathogenic. Electrophysiological analysis showed that the KCNQ2‐I134N mutation caused a hyperpolarizing shift in voltage‐dependent activation and significantly increased current density, indicating a GOF effect. This GOF phenotype persisted when the mutant subunit was co‐expressed with KCNQ3 and under a transfection ratio mimicking the patient's genotype. The hyperactivity of the mutant channel was effectively suppressed by amitriptyline. We report a novel GOF variant (I134N) in the KCNQ2 gene associated with DEE. The KCNQ blocker amitriptyline effectively suppressed mutant channel hyperactivity, suggesting its potential as a targeted therapeutic option for patients with this pathogenic variant.