KCNC2 – Developmental and Epileptic Encephalopathy

KCNC2 encodes the Kv3.2 voltage-gated potassium channel subunit, which is critical for high-frequency firing in cortical GABAergic interneurons. Heterozygous variants in KCNC2 have been described in patients presenting with developmental and epileptic encephalopathy (DEE) characterized by global motor delay (HP:0001270) and generalized myoclonic-atonic seizures (HP:0011170). Recent studies report de novo missense changes disrupting channel gating and neuronal inhibition in unrelated probands, supporting a direct gene–disease relationship.

Genetic Evidence

Autosomal dominant DEE due to KCNC2 variants is supported by 18 unrelated de novo cases in a multi-center cohort ([PMID:35314505]) and at least 11 additional probands from case reports: c.1163T>C (p.Phe388Ser) ([PMID:37203270]), c.374G>A (p.Cys125Tyr) ([PMID:38194456]), c.1408C>T (p.Pro470Ser) and c.1146T>G (p.Phe382Leu) ([PMID:36087422]), c.1411G>C (p.Val471Leu) ([PMID:31972370]), c.1213A>G (p.Arg405Gly) in two unrelated patients ([PMID:36090251]), and germline mosaicism in two affected siblings with c.1309A>G (p.Thr437Ala) indicating segregation ([PMID:35366058]).

Variant Spectrum

All reported pathogenic alleles are missense variants with no common founder alleles. Functional classification reveals both gain-of-function (GoF) and loss-of-function (LoF) mechanisms correlating with phenotype severity.

Functional Evidence

Electrophysiological analysis in Xenopus oocytes showed GoF for three DEE-associated variants and LoF for milder generalized epilepsies ([PMID:35314505]). Cryo-EM guided modeling and patch-clamp recordings for p.Cys125Tyr and p.Phe382Leu demonstrate hyperpolarizing activation shifts, delayed deactivation, and increased conductance, consistent with channel stabilization in the open state ([PMID:38194456], [PMID:36087422]). Personalized structural biology on p.Val469Leu revealed pore occlusion and distinct gating defects ([PMID:36035247]). Targeted pharmacology using fluoxetine and norfluoxetine normalized Kv3.2-V473A currents and improved clinical outcomes in two siblings ([PMID:39881864]).

Mechanism and Clinical Utility

These convergent data establish that KCNC2 haploinsufficiency and aberrant gating disrupt inhibitory interneuron function, leading to network hyperexcitability. The robust genotype–phenotype and functional concordance warrant inclusion of KCNC2 in DEE gene panels and suggest Kv3 channel inhibitors as precision therapies.

References

• Neurology • 2022 • Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants PMID:35314505
• International Journal of Developmental Neuroscience • 2023 • Novel KCNC2 variant associated with developmental and epileptic encephalopathy PMID:37203270
• Proceedings of the National Academy of Sciences USA • 2024 • A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction PMID:38194456
• Seizure • 2022 • Investigation of novel de novo KCNC2 variants causing severe developmental and early-onset epileptic encephalopathy PMID:36087422
• Frontiers in Pharmacology • 2024 • Case Report: Targeted treatment by fluoxetine/norfluoxetine of a KCNC2 variant causing developmental and epileptic encephalopathy PMID:39881864
• American Journal of Medical Genetics Part A • 2022 • Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy characterized by long-read sequencing PMID:35366058

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