A Novel KCNA1 Variant in a Patient With Tremor and Autism Spectrum Disorder Causes Mixed LOF/GOF Defects of Kv1.1 Channels.

Abstract

Variants in KCNA1, encoding the Kv1.1 potassium channel, cause neurological disorders including episodic ataxia and developmental and epileptic encephalopathy. We identified a novel KCNA1 variant (A401T) in a 16-year-old patient with autism spectrum disorder, borderline intellectual disability, and tremor, without episodic ataxia or epilepsy. Functional analysis in HEK293 cells showed that A401T markedly reduced potassium currents, slowed activation, and accelerated C-type inactivation, consistent with loss-of-function (LOF), while shifting channel activation to more negative potentials, indicating gain-of-function (GOF). Overall, our findings expand both the clinical and functional spectrum of KCNA1-related disorders by identifying autism spectrum disorder and tremor associated with a mixed LOF/GOF KCNA1 variant.