Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. We functionally characterized two novel presumed GoF KCNQ2 variants (Y141N and G239S), and described the associated phenotypic features. Furthermore, we evaluated the in vitro ability of the antidepressant drug amitriptyline to block channels carrying the Y141N or G239S variant, and describe the clinical response to amitriptyline treatment in one of the patients (G239S). Functional and pharmacological properties of variant subunits were analyzed in vitro by whole-cell patch-clamp in transiently transfected Chinese hamster ovary cells. We identified three patients carrying a de novo KCNQ2 Y141N (n = 1) or G239S variant (n = 2) respectively. All had a mild global DD, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. This showed a GoF effect of the two variants. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Amitriptyline was prescribed in one patient (G239S), and during the two-year-treatment period motor, verbal, social, sensory and adaptive behavior skills improved. KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures. Treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.