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While most KCNQ2\u2010DEE cases are attributed to loss\u2010of\u2010function (LOF) mutations, gain\u2010of\u2010function (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\u2010sensing domain (VSD) and analyzes the variant's electrophysiological properties. Whole\u2010exome sequencing was performed to identify the genetic variant. Whole\u2010cell patch\u2010clamp 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\u2010year\u2010old female with early\u2010onset epileptic encephalopathy presented with intractable seizures, developmental regression, microcephaly, transient thyroid dysfunction, and a mixed EEG pattern of hypsarrhythmia and intermittent burst\u2010suppression. A de novo KCNQ2 variant (c.401T&gt;A, p.Ile134Asn) located in the conserved S2 transmembrane domain was identified and classified as likely pathogenic. Electrophysiological analysis showed that the KCNQ2\u2010I134N mutation caused a hyperpolarizing shift in voltage\u2010dependent activation and significantly increased current density, indicating a GOF effect. This GOF phenotype persisted when the mutant subunit was co\u2010expressed 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.<\/jats:p>","DOI":"10.1002\/ajmga.70044","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T12:03:00Z","timestamp":1767700980000},"page":"1109-1116","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Novel KCNQ2 Gain\u2010of\u2010Function Variant\n                    <scp>I134N<\/scp>\n                    Causes Severe Developmental and Epileptic Encephalopathy"],"prefix":"10.1002","volume":"200","author":[{"given":"Fengmei","family":"Zeng","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Southern Medical University  Guangzhou China"},{"name":"Zhongshan Institute for Drug Discovery Shanghai Institute of Materia Medica, Chinese Academy of Sciences  Zhongshan 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