Intellectual disability - microarray and sequencing
Gene: KCNH5
Comment on list classification: As reviewed by Dmitrijs Rots, there is sufficient evidence for the association of this gene to intellectual disability. Hence, this gene can be promoted to green rating at the next GMS review.Created: 8 Aug 2023, 8:50 p.m. | Last Modified: 8 Aug 2023, 8:50 p.m.
Panel Version: 5.240
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, 8:43 p.m. | Last Modified: 8 Aug 2023, 8:43 p.m.
Panel Version: 5.235
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
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, 9:45 p.m. | Last Modified: 5 Aug 2023, 9:45 p.m.
Panel Version: 5.230
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Neurodevelopmental disorder and Epilepsy
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
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
INFANTILE EPILEPTIC ENCEPHALOPATHY
Publications
One heterozygous variant described in a 13 year old boy in the literature who presented with autism and developmental delay. No other evidence from literature or other sources to support link.Created: 31 Oct 2017, 10:36 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to Developmental and epileptic encephalopathy 112, OMIM:620537
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Gene: kcnh5 has been classified as Amber List (Moderate Evidence).
Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Phenotypes for gene: KCNH5 were changed from developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071 to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Phenotypes for gene: KCNH5 were changed from INFANTILE EPILEPTIC ENCEPHALOPATHY to developmental and epileptic encephalopathy, MONDO:0100062; intellectual disability, MONDO:0001071
Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Publications for gene: KCNH5 were set to 23647072; 35874597; 36307226; 24133262
Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments 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 23647072
Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mode of pathogenicity for gene: KCNH5 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mode of pathogenicity for gene: KCNH5 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Mode of inheritance for gene: KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: KCNH5 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tag Q3_23_promote_green tag was added to gene: KCNH5.
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Model of inheritance for gene KCNH5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
KCNH5 was added to Intellectual disabilitypanel. Sources: Expert Review Red
KCNH5 was created by ellenmcdonagh