Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations

Area of Science:

• Neurogenetics
• Channelopathies
• Epilepsy Genetics

Background:

• KCNC1 gene encodes the K_v3.1 potassium channel, crucial for neuronal excitability.
• Mutations in KCNC1 have been linked to Progressive Myoclonus Epilepsy (PME).
• The full spectrum of KCNC1-associated neurodevelopmental disorders remains incompletely understood.

Purpose of the Study:

• To investigate clinical phenotypes associated with KCNC1 variants beyond the known PME-causing mutation.
• To determine the functional electrophysiological impact of identified KCNC1 variants.
• To explore correlations between genotype, phenotype, and physiological function.

Main Methods:

• Analysis of clinical data from ten patients with putative pathogenic KCNC1 variants.
• Identification of variants using whole-exome sequencing or gene panel testing.
• Functional assessment of KCNC1 variants using Xenopus laevis oocyte expression and voltage-clamp electrophysiology.

Main Results:

• Six patients presented with Developmental and Epileptic Encephalopathy (DEE) linked to a recurrent de novo KCNC1 variant (p.Ala421Val).
• Functional studies revealed loss of function for p.Ala421Val and other tested variants, characterized by reduced whole-cell currents.
• Three patients exhibited Developmental Encephalopathy without seizures, associated with different KCNC1 loss-of-function variants.

Conclusions:

• This study expands the phenotypic spectrum of KCNC1-related disorders to include infantile-onset DEE and non-epileptic developmental encephalopathy.
• Loss of K_v3.1 channel function is a consistent mechanism underlying these diverse neurodevelopmental phenotypes.
• Further research is needed to elucidate definitive electrophysiological distinctions between these KCNC1-associated phenotypes.