Early onset or syndromic epilepsy
Gene: KCNH5
Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence for the association of this gene to epilepsy. Hence, this gene can be promoted to green rating at the next GMS review.Created: 8 Aug 2023, 8:35 p.m. | Last Modified: 8 Aug 2023, 8:35 p.m.
Panel Version: 4.78
PMID:23647072 - A 13 year-old boy with epileptic encephalopathy, autism spectrum disorder (ASD) and language delay was identified with de novo variant in KCNH5 gene (c.980G > A/ p.Arg327His).
PMID:35874597 - Three unrelated cases were identified with three different de novo variants in KCNH5 gene - c.980G > A (p.Arg327His), c.2020-4A > G (splicing) and c.962G > A (p.Ser321Asn). All of them experienced seizures, two of them presented with epileptic encephalopathy, one of them presented with ASD, and one did not relapse after drug withdrawal.
PMID:36307226 - 17 patients were identified with KCNH5 missense variants (16/17 de novo, 1/17 inherited) from a screen of 893 patients with developmental and epileptic encephalopathy. p.Arg333His was present in nine individuals and four additional novel variants were found. All of them presented with epilepsy, which included focal and generalised seizures. Cognitive outcome for the ten individuals with more than 5 years of age ranged from normal (3/10) to mild (3/10), moderate (2/10), severe (1/10) and profound (1/10) intellectual disability (ID).
In addition, structural modelling suggested that p.Arg327His would destabilise the resting and early activation states of the KCNH5 channel by weakening ionic interactions and this favouring channel opening (PMID:24133262).
This gene has been associated KCNH5-related epilepsy and epileptic encephalopathy in Gene2Phenotype (with 'strong' rating in the DD panel), but has not yet been associated with any phenotypes in OMIM.Created: 8 Aug 2023, 8:33 p.m. | Last Modified: 8 Aug 2023, 8:33 p.m.
Panel Version: 4.77
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
developmental and epileptic encephalopathy, MONDO:0100062; epilepsy, MONDO:0005027
Publications
PMID: 36307226 reports 17 individuals with similar phenotype - 13 having two recurrent missense variants located in a hotspot. Additionally PMID: 35874597 four cases are independently ported - also with de novo missense in the mutational hotspot.
Enough evidence for green rating.Created: 5 Aug 2023, 9:44 p.m. | Last Modified: 5 Aug 2023, 9:44 p.m.
Panel Version: 4.77
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
NDD with seizures
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Kept rating as Red based on Red post-Webex review from Helen Lord.Created: 9 Sep 2019, 10:24 a.m. | Last Modified: 9 Sep 2019, 10:24 a.m.
Panel Version: 1.315
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
1 case reported on OMIM - missense change R327H in a boy who developed intractable tonic clonic seizures - Veeramah et al, 2013 (23647072). Structural modelling by Yang et al, 2013 (24133262) suggests it would destabilise the resting and early activation states of the KCNH5 channel by weakening ionic interactions and this favouring channel opening (GLF) - OMIM say it is a VUS as its contribution to epileptic encephalpathy is not confirmed. No other cases in HGMDPro.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
There is currently only one paper implicating KCNH5 in epilepsy, but it is included on a diagnostic panel (Amplexa CHE-114 epilepsy panel ). Veeramah et al (PMID:23647072) identified an individual with a hetrozygous denovo missense mutation (c.980G>A or p.R327H). However no further disease gene implications have been reported since.Created: 4 Jul 2019, 12:30 p.m. | Last Modified: 8 Jul 2019, 2:47 p.m.
Panel Version: 0.62
Amplexa CHE-114 epilepsy panel
Sources: Expert listCreated: 21 Feb 2019, 2:05 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
epilepsy
Publications
Variants in this GENE are reported as part of current diagnostic practice
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; epilepsy, MONDO:0005027 to Developmental and epileptic encephalopathy 112, OMIM:620537
Mode of pathogenicity for gene: KCNH5 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
Publications for gene: KCNH5 were set to 24133262; 23647072
Phenotypes for gene: KCNH5 were changed from epilepsy to developmental and epileptic encephalopathy, MONDO:0100062; epilepsy, MONDO:0005027
Mode of inheritance for gene: KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Tag Q3_23_promote_green tag was added to gene: KCNH5.
Source Wessex and West Midlands GLH was added to KCNH5.
Source NHS GMS was added to KCNH5.
Publications for gene: KCNH5 were set to 23647072
Source Expert Review Red was added to KCNH5. Mode of inheritance for gene KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Added phenotypes epilepsy for gene: KCNH5 Rating Changed from No List (delete) to Red List (low evidence)
gene: KCNH5 was added gene: KCNH5 was added to Genetic epilepsy syndromes. Sources: Expert list Mode of inheritance for gene: KCNH5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNH5 were set to 23647072 Phenotypes for gene: KCNH5 were set to epilepsy Penetrance for gene: KCNH5 were set to unknown Review for gene: KCNH5 was set to RED gene: KCNH5 was marked as current diagnostic