Genetic epilepsy syndromesGene: KCND2
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
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
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
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
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
Variants in this GENE are reported as part of current diagnostic practice
Source Wessex and West Midlands GLH was added to KCND2.
Source NHS GMS was added to KCND2.
Publications for gene: KCND2 were set to 24501278; 16934482
Publications for gene: KCND2 were set to 24501278
Source Expert Review Red was added to KCND2. Mode of inheritance for gene KCND2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Mode of pathogenicity for gene KCND2 was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Added phenotypes epilepsy; autism for gene: KCND2 Rating Changed from No List (delete) to Red List (low evidence)
gene: KCND2 was added gene: KCND2 was added to Genetic epilepsy syndromes. Sources: Expert list Mode of inheritance for gene: KCND2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCND2 were set to 24501278 Phenotypes for gene: KCND2 were set to autism; epilepsy Penetrance for gene: KCND2 were set to unknown Review for gene: KCND2 was set to RED gene: KCND2 was marked as current diagnostic