Early onset or syndromic epilepsy

Gene: KCNA1

Green List (high evidence)

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

Created: 26 Sep 2024, 10:58 a.m. | Last Modified: 26 Sep 2024, 10:58 a.m.

Panel Version: 6.6

Comment on list classification: There is sufficient evidence available for the association of monoallelic KCNA1 variants with epilepsy/ epileptic encephalopathy and hence this gene can be promoted to green rating in the next GMS review.

Created: 27 Feb 2024, 2:28 p.m. | Last Modified: 27 Feb 2024, 2:28 p.m.

Panel Version: 4.171

PMID:30055040 reported the identification of three heterozygous de novo variants (p.Pro403Ser, p.Pro405Leu, and p.Pro405Ser) in the pore region found in four patients from three families with severe developmental and epileptic encephalopathy (DEE). PMID:34778950 reported the comparison of the three variants from PMID:30055040 with a de novo variant in the voltage sensor (p.Ala261Ter) that was identified in two patients with mild, carbamazepine-responsive, focal epilepsy.

PMID:32316562 reported from the analyses of 47 deleterious KCNA1 variants that were identified from previous literature and genetic archives that epilepsy or seizure-related variants tend to cluster in the S1,S2,S5,S6 transmembrane domains and in the pore domain.

PMID:31586945 reported the identification of a homozygous KCNA1 variant (p.Val368Leu) in a patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy. This variant involves a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG).

Monoallelic variants in this gene have only been associated with episodic ataxia/ myokymia syndrome (MIM #160120) in OMIM, but not with epilepsy/ epileptic encephalopathy, and biallelic variants are not reported with any phenotypes in OMIM. Both monoallelic and biallelic variants have been associated with KCNA1-related epileptic encephalopathy in Gene2Phenotype (with 'limited' rating in the DD panel for both MOIs).

Created: 27 Feb 2024, 2:08 p.m. | Last Modified: 27 Feb 2024, 4:33 p.m.

Panel Version: 4.171

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epilepsy, MONDO:0005027

Publications

• 30055040
• 31586945
• 32316562
• 34778950

Red List (low evidence)

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted KCNA1 from Green to Amber.

Created: 25 Nov 2019, 8:40 p.m. | Last Modified: 25 Nov 2019, 8:40 p.m.

Panel Version: 1.434

Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.

Created: 7 Oct 2019, 9:47 a.m. | Last Modified: 7 Oct 2019, 9:47 a.m.

Panel Version: 1.351

Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)

Created: 5 Sep 2019, 2:53 p.m. | Last Modified: 5 Sep 2019, 2:53 p.m.

Panel Version: 1.262

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.

Created: 15 Aug 2019, 10:12 a.m. | Last Modified: 15 Aug 2019, 10:12 a.m.

Panel Version: 1.232

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

There have been several recent reports that show de novo missense variants in specific regions of this gene are associated with epileptic encephalopathy, supported by functional studies, and gene now meets criteria to be green for this phenotype

Created: 21 Feb 2024, 1:01 p.m. | Last Modified: 21 Feb 2024, 1:01 p.m.

Panel Version: 4.164

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epilep

Publications

• 24578548
• 3055040
• 34778950

Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least 2 variants identified in unrelated cases who display seizures (PMIDs 29056246, 11026449), together with a supportive mouse model (PMID 9581771)

Created: 3 Sep 2018, 1:45 p.m.

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)