Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Early onset or syndromic epilepsy v1.339 | GABRA5 | Rebecca Foulger Classified gene: GABRA5 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.339 | GABRA5 | Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green: GABRA5 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-70 in OMIM, and there are three cases from 2 publications (PMIDs 29961870 and 31056671) of GABRA5 variants associated with early infantile epileptic encephalopathy for a diagnostic rating. A Green rating is supported by a recent review by Helen Lord. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.339 | GABRA5 | Rebecca Foulger Gene: gabra5 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.336 | GABRA5 | Helen Lord reviewed gene: GABRA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961870, 31056671, 30033060; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.335 | GABRA5 |
Rebecca Foulger commented on gene: GABRA5: Summary of evidence (see Konstantinos Varvagiannis' reviews for details): 3 literature cases from 2 papers of patients with epileptic encephalopathy and GABRA5 missense variants: PMID:29961870, Butler et al. 2018 report a 2 year old boy with EIEE (seizure onset age 4 months) and a p.V294L variant in GABRA5. Cognitive and motor development slowed at the time of seizure onset. A de novo variant in MIA2 was also detected but was considered unlikely to contribute to the patients phenotypes due to allele frequencies in the gnomAD database. PMID:31056671, Hernandez et al. 2019 screened a cohort of patients with epilepsy and ID and report 2 individuals with EIEE and GABRA5 missense variants (V294F and S413F). Seizures included focal, febrile, focal and tonic, epileptic spasms and status epilepticus. Both had severe ID and delayed motor development. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.328 | GABRA5 | Rebecca Foulger changed review comment from: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date for Epileptic Encephalopathy.; to: Added missense tag because, as Konstantinos Varvagiannis notes, only missense GABRA5 variants reported to date for Epileptic Encephalopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.328 | GABRA5 | Rebecca Foulger changed review comment from: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date.; to: Added missense tag because, as Konstantinos Varvagiannis notes, only missense variants reported to date for Epileptic Encephalopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.328 | GABRA5 | Rebecca Foulger commented on gene: GABRA5 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.328 | GABRA5 | Rebecca Foulger Phenotypes for gene: GABRA5 were changed from Epileptic encephalopathy, early infantile, 79 (MIM 618559) to Epileptic encephalopathy, early infantile, 79, 618559 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.327 | GABRA5 | Rebecca Foulger Publications for gene: GABRA5 were set to 29961870 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.326 | GABRA5 | Rebecca Foulger Tag missense tag was added to gene: GABRA5. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.299 | GABRA5 | Konstantinos Varvagiannis reviewed gene: GABRA5: Rating: GREEN; Mode of pathogenicity: None; Publications: 29961870, 31056671; Phenotypes: Epileptic encephalopathy, early infantile, 79 (MIM 618559); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.299 | GABRA5 | Konstantinos Varvagiannis Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.299 | GABRA5 |
Konstantinos Varvagiannis gene: GABRA5 was added gene: GABRA5 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: GABRA5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: GABRA5 were set to 29961870 Phenotypes for gene: GABRA5 were set to Epileptic encephalopathy, early infantile, 79 (MIM 618559) Penetrance for gene: GABRA5 were set to unknown Review for gene: GABRA5 was set to GREEN Added comment: Heterozygous pathogenic GABRA5 variants cause Epileptic encephalopathy, early infantile, 79 (MIM 618559) [entry recently updated in OMIM]. At least 3 relevant individuals with this diagnosis have been reported to date: - Butler et al. (2018 - PMID: 29961870) described a 2 y.o. boy with early infantile epileptic encephalopathy (seizure onset at the age of 4m). The boy was found to harbor a de novo missense variant (NM_000810.3:c.880G>C - p.Val294Leu) identified following trio-WGS and confirmed by Sanger sequencing. Studies in HEK293 cells demonstrated expression at the surface and incorporation of the mutant subunit in the channel. The α5(V294L)β2γ2s receptors were 10 times more sensitive to GABA compared to wt, but were more likely to desensitize leading to reduced maximum GABA-evoked currents. - Hernandez et al. (2019 - PMID: 31056671) reported on 2 unrelated individuals with early-onset epileptic encephalopathy due to de novo GABRA5 variants identified by targeted NGS sequencing (480 epilepsy-related genes): A 3y 10m male with seizure onset at the age of 4m, severe motor delay and ID, frontotemporal atrophy and thin CC upon MRI imaging was found to harbor a de novo missense variant (NM_000810.3:c.880G>T / p.Val294Phe). A further unrelated subject (a 7 y.o. male) with seizure onset at the age of 3 months, severe DD and ID and cortical atrophy / thin CC upon MRI imaging was heterozygous for another missense variant which had occurred as a de novo event (NM_000810.3:c.1238C>T - p.Ser413Phe). Functional studies: Expression of HA-tagged α5(V294F) subunits at dendritic GABAergic synapses of rat hippocampal neurons was decreased compared to wt, in contrast with the expression of α5(S413F) subunits which was similar to wt. As the α5(V294F) appeared accumulated in the soma of the neurons, the authors performed additional studies – using HEK293T cells – to show that while the α5(S413F) spread outside the ER, α5(V294F) subunits localized to the ER. This was suggestive of a trafficking defect/ER retention. Co-expression of wt or mutant HA-tagged subunits, with β3 and γ2 subunits in HEK293T cells was carried out to assess assembly and trafficking to cell membranes. Reduced surface levels as well as total (whole cell lysate) levels were shown for α5(V294F). Surface levels and total levels of the α5(S413F) were not changed compared to wt. Surface levels of the β3 subunit were however lower in the case of α5(S413F), a finding which could be suggestive of a dominant negative effect. Both GABRA5 mutations resulted in decreased GABA-evoked current amplitudes in both neuronal and non-neuronal (HEK293T) cells. ------- The corresponding phenotype in OMIM is Epileptic encephalopathy, early infantile, 79 (618559). GABRA5 is not associated with any phenotype in G2P. This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx). ------- As a result, GABRA5 can be considered for inclusion in the ID and epilepsy panels probably as green (relevant phenotype, 3 unrelated individuals, 3 variants, supporting functional studies for all variants) or amber. Sources: Literature |