De novo KCNB1 mutations in epileptic encephalopathy

Abstract

Background Numerous studies have demonstrated increased load of de novo copy number variants (CNVs) or single nucleotide variants (SNVs) in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability and autism. Methods We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high coverage whole exome sequencing (WES) and lower coverage whole genome sequencing (WGS). Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system. Results We identified a de novo missense mutation in KCNB1 that encodes the KV2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified two additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV2.1 dysfunction. Interpretation Our genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology.

When Inhibiting Repetitive Firing is Pro-Epileptic

“…Seizures were refractory to therapy. On EEG, patients showed high-amplitude diffuse spike-and-wave discharges, which was also a common feature in previously reported patients (1,3,4). This finding provided further evidence that infantile onset seizures with spike-and-wave discharges are a key feature of KCNB1-associated epilepsy.…”

“…Of interest, the reported KCNB1 mutations were all clustered within the pore domain of the channel. Functional characterization of the mutant channels in Chinese hamster ovary (CHO) K1 cells demonstrated a loss of ion selectivity and voltage-dependence for three of the mutations (S347R, T374I, G379R) (1) and loss of ion selectivity (V378A) (3). Additionally, the V378A mutation showed disruption of channel trafficking to the cell surface in COS-7 cells (3).…”

Clinical application of whole-exome sequencing across clinical indications

“…Utilizing the power of our large data set, we were able to identify novel candidate genes in which multiple patients with similar phenotypes had rare variants predicted to result in loss of function, many of which were de novo. Access to this large number of cases has proven extremely valu- [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] As a result of our experience, we believe that candidate genes should be reported from WES analysis and shared in databases, such as GeneMatcher, so that clinicians, researchers, and clinical laboratories can be connected to facilitate more rapid dissemination of information and validation of novel disease genes. Our series is larger than previously reported clinical diagnostic series and has the power to begin to address the yield of WES for a large number of clinical indications.…”

Functional antagonism of voltage-gated K+ channel α-subunits in the developing brain ventricular system

“…By extension, other negative regulators of K v 2.1 channel activity represent a reserve pool of factors that could similarly contribute to hydrocephalus. In contrast, deficiency of K v 2.1 has been linked with epileptic encephalopathy (Torkamani et al, 2014). It is rather remarkable that the two proteins involved in the same developmental mechanism underlying formation of the BVS, could be linked to two different hereditary diseases.…”