Early onset or syndromic epilepsy

Gene: KCND2

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: Promoting from red to amber with a recommendation for green rating following GMS review. 4 unrelated cases with a V404 missense variant and epilepsy.

Created: 12 Dec 2021, 12:15 p.m. | Last Modified: 12 Dec 2021, 12:15 p.m.

Panel Version: 2.482

6 new unrelated cases with developmental delay reported in PMID: 34245260 (Zhang et al 2021), 3 of whom had seizures. All had heterozygous missense variants of KCND2 in sites known to be critical for channel gating (E323K, P403A, two individuals, V404L, two individuals and V404M). Functional studies suggest that these missense changes cause both a partial loss-of-function (LOF) and gain-of-function (GOF). The V404 change appears to increase epileptic seizure susceptibility with the 3 patients with a V404 change showing this phenotype.

PMID:24501278 - Lee et al, 2014 - reports pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. A de novo heterozygous missense variant was identified by WES - V404M.

PMID: 29581270 - Lin et al, 2018 - performed functional work that shows V404M enhances inactivation of channels that have not yet opened and dramatically impairs the inactivation of channels that have opened.

PMID:16934482 - Singh et al, 2006 - reports a patient with cognative impairment who also went on to have seizures starting from age 13 with a 5 bp deletion in KCND2 leading to premature stop codon. The proband's asymptomatic father also shared this variant.

Created: 12 Dec 2021, 12:06 p.m. | Last Modified: 12 Dec 2021, 12:49 p.m.

Panel Version: 2.482

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

Phenotypes
seizures

Publications

• 34245260

I don't know

Kept rating as Red based on two post-Webex Red reviews from Helen Lord and Alison Callaway.

Created: 9 Sep 2019, 9:39 a.m. | Last Modified: 9 Sep 2019, 9:39 a.m.

Panel Version: 1.306

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Red List (low evidence)

OMIM: Lee et al, 2014 (24501278) - pair of monozygotic twin boys with infantile onset severe refractory epilepsy and autism. Identified a de novo het missense variant - V404M by WES. In vitro functional expression studies in Xenopus oocytes suggests impaired closed-state inactivation of the potassium channel. Lin et al, 2018 (29581270) - functional work on this variant - V404M enhances inactivation of channels that have not yet opened while dramatically impairing the inactivation of channels that have opened. Also a truncating variant has been reported in a patient with temporal lobe epilepsy - inherited from asymptomatic father - Singh et al, 2006 (16934482).

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

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

Red List (low evidence)

PMID 16934482 details a possible link with KCND2 and temporal lobe epilepsy. Single case with a frameshifft variant, but appears to have been inherited from her father who is said to be asymptomatic. The authors also analysed the electrophysiological properties of wildtype and channels with the frameshift variant in HEK293 cells; current density of the variant channels was significantly lower than wildtype channels.

Created: 23 Aug 2019, 10:28 a.m. | Last Modified: 23 Aug 2019, 10:28 a.m.

Panel Version: 1.256

Publications

• 16934482

Comment on mode of pathogenicity: Gain of function mechanism reported.

Created: 4 Jul 2019, 10:14 a.m. | Last Modified: 4 Jul 2019, 10:14 a.m.

Panel Version: 0.51

There is currently only one paper implicating KCND2 in epilepsy, but it is included on a diagnostic panel (Amplexa CHE-114 epilepsy panel ). Lee et al. (PMID:24501278) reports on identical twins who have severe, intractable seizures. A de novo gain of function missense mutation variant was identified in the KCND2 gene. As there is no further associations of KCND2 and epilepsy in the literature KCND2 will remain red.

Created: 4 Jul 2019, 10:12 a.m. | Last Modified: 8 Jul 2019, 2:46 p.m.

Panel Version: 0.62

Red List (low evidence)

Amplexa CHE-114 epilepsy panel
Sources: Expert list

Created: 21 Feb 2019, 2:03 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
autism; epilepsy

Publications

• 24501278

Variants in this GENE are reported as part of current diagnostic practice