Early onset or syndromic epilepsy

Gene: KCNC2

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 9:39 a.m. | Last Modified: 1 Feb 2023, 9:39 a.m.

Panel Version: 3.29

Green List (high evidence)

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 14 Apr 2022, 1:10 p.m. | Last Modified: 14 Apr 2022, 1:10 p.m.

Panel Version: 2.515

Numerous KCNC2 variants reported in patients with phenotypes ranging from mild generalized epilepsies to severe developmental and epileptic encephalopathies, together with supportive functional studies (PMID 35314505).

Created: 14 Apr 2022, 1:09 p.m. | Last Modified: 14 Apr 2022, 1:09 p.m.

Panel Version: 2.514

Green List (high evidence)

Shwarz et al, 2022 35314505 - Novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalised epilepsy (GGE), developmental epileptic encephalopathy (DEE), including eaely onset absence epilepsy (EOAE) focal epeilepsy (FE) and myoclonic-atonic epilepsy (MAE). 10/18 variants were de nov and 8/18 were classed as modifying variants. functional analysis of 4 variants demonstrated GOF in 3 severely affected DEE cases and LOF in 1 case with a milder GGE phenotype.

Sanger sequencing of KCNC2 - classed the de novo variants as pathogenic 10/18 and the other 8 as likely pathogenic (either inherited from an unaffected parent = 4 or where a positive fh determined). All the 16 unique variants were missense changes. 15/16 not in control cohorts.

TAhe KCNC2 variants were located across the six transmembrane segements of the Kv3.2 subunit as well as the long cytoplasmic N and C terminal regions. The localisation of variants did not correlate with a specific phenotype.

Functional analysis of 4 diff variants dependent on location and phenotype C125W & E135G (T1 domain important for tetramerisation of the channel), F219S (just before the first tranmembrane domain), T437A (within the P domain) - all de novo and none found in gnomAD. F219S showed complete LOF, therefore a dominant negative effect on WT channels. The other 3 variants demonstrate a GOF in the channel kinetics (although one of these appears to show both a LOF and GOF effect).

8/18 patients were seizure free from drugs although all the drug responsive cases became seizure free using vaproic acid as monotherapy or in conjunction incidung in severe DEE.

In the Vetri et al paper, 31972370 - patient had DEE and a de novo missense variant was identified by WES.

In the Rademacher et al paper 32392612 - patient had NF1-related WEST syndrome and a de novo missense variant was identified by WES.

Created: 23 Mar 2022, 11:09 a.m. | Last Modified: 23 Mar 2022, 11:09 a.m.

Panel Version: 2.500

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
epilepsy

Publications

• 35314505

I don't know

PMID: 31972370. De novo missense variant (p.Val471Leu) identified in a child with early severe developmental and epileptic encephalopathy, spastic tetraplegia, opisthotonos attacks.

PMID: 32392612. De novo missense variant (p.Asp167Tyr) identified in a neurofibromatosis type 1 related West syndrome patient. Functional analysis showed a significant reduction of the mean potassium current and a shift in the voltage dependence of steady-state activation. Maternally inherited NF1 variant (p.T1951Nfs*5) also identified, the mother was "clinically unremarkable".
Sources: Literature

Created: 4 Dec 2021, 7:50 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epileptic encephalopathy; spastic tetraplegia; opisthotonus attacks; intellectual disability; West syndrome

Publications

• 32392612
• 31972370