Encephalopathies with KCNC1 variants: genotype‐phenotype‐functional correlations

Abstract

Objective To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy‐causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype‐phenotype‐physiological correlations. Methods Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole‐exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the Kv3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two‐electrode voltage clamping were used. Results Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole‐cell current, but no dominant‐negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole‐cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance. Interpretation These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.

Progressive myoclonic epilepsy: myoclonic epilepsy and ataxia due to KCNC1 mutation (MEAK): a case report and review of the literature

“…In the pivotal paper, out of 84 clinically confirmed PME cases without clear genetic etiology, 16 who had MEAK were found to have a heterozygous missense mutation, c.959G>A (p.Arg320His), in KCNC1, 13 of whom were unrelated. Many other types of mutations have been described in KCNC1, resulting in different phenotypic N. Barot, et al expression, such as infantile-onset developmental epileptic encephalopathy (DEE) and dysmorphic features without epilepsy (Cameron et al, 2019;Poirier et al, 2017). A recent study found that a small molecular activator of Kv3 channel (RE01) can reverse the neurophysiologic changes from mutation and may guide us towards developing a therapeutic agent for MEAK (Munch et al, 2018).…”

Reanalysis of Genomic Sequencing Results in a Clinical Laboratory: Advantages and Limitations

“…The P3 variant in ITPR1, a gene encoding a calcium channel that modulates intracellular calcium signaling, was shown to decrease calcium ion release in the endoplasmic reticulum (21). The P13 variant in KCNC1, encoding a highly conserved subunit of a potassium ion channel, was demonstrated to decrease the amplitude of current (22). In the case of ALDH7A1 (P8), which is associated with the recessive disease pyridoxine-dependent epilepsy, two variants were identified near the intronic junction; these were not canonical splice variants but were reported as variants of uncertain significance owing to the lack of evidence.…”

Kv3.1 channelopathy: a novel loss-of-function variant and the mechanistic basis of its clinical phenotypes

“…KCNC1 p.R320H variant was found in patients with myoclonic epilepsy and ataxia due to potassium channel mutation (MEAK), which is a subtype of progressive myoclonic epilepsy (PME) with milder presentation and better prognosis (9,(16)(17)(18)(19). p.A421V was identified in patients with severe developmental and epileptic encephalopathy (DEE) (19)(20)(21). Subsequently, a wider spectrum of phenotypes designated as DE (developmental encephalopathy without seizures) has been reported to be associated with KCNC1.…”