2017 - Characterization of a KCNB1 variant associated with autism, intellectual disability, and epilepsy
SyncroPatch 768PE publication in Neurology Genetics (2017)
Calhoun, J.D., Vanoye, C.G., Kok, F., George, A.L., Kearney, J.A.
Neurology Genetics (2017) 3(6):e198
Objective: To perform functional characterization of a potentially pathogenic KCNB1 variant identified by clinical exome sequencing of a proband with a neurodevelopmental disorder that included epilepsy and centrotemporal spikes on EEG.
Methods: Whole-exome sequencing identified the KCNB1 variant c.595A.T (p.Ile199Phe). Biochemical and electrophysiologic experiments were performed to determine whether this variant affected protein expression, trafficking, and channel functional properties.
Results: Biochemical characterization of the variant suggested normal protein expression and trafficking. Functional characterization revealed biophysical channel defects in assembled homotetrameric and heterotetrameric channels.
Conclusions: The identification of the KCNB1 variant c.595A.T (p.Ile199Phe) in a neurodevelopmental disorder that included epilepsy with centrotemporal spikes expands the phenotypic spectrum of epilepsies associated with KCNB1 variants. The KCNB1-I199F variant exhibited partial loss of function relative to the wild-type channel. This defect is arguably less severe than previously reported KCNB1 variants, suggesting the possibility that the degree of KCNB1 protein dysfunction may influence disease severity.