Early onset or syndromic epilepsy

Gene: GABRA5

Green List (high evidence)

AD EIEE79 - severe neurological disorder characterised by onset of refractory seizures in the first few months of life. Butler et al, 2018 (29961870)- male infant who developed seizures during sleep at 4 months of age(myoclonic, tonic, oral automations, tonic-clonic generalised and migrating partial seizures) and had increased to up to 100 seizures per day by 6 months of age. Controlled by a combination of AED's - de novo het missense variant V294L - trio based WGS. In vitro functional expression studies in HEK293 cells showed that the mutant subunit was expressed at the surface and incorporated into the channel, but the mutant channel was 10 times more sensitive to GABA than the wt. Hernandez et al, 2019 (31056671) - 2 unrelated boys presented with focal, tonic and generalised intractable seizures at 3-4 months of age. De nov het missense variants detected - V294F and S413F - by NGS sequencing of a targeted 480 gene panel. In vitro functional expression studies of mutations in rat primary hippocampal neurons and HEK293 cells showed variable abnormalities, including decreased expression of the mutant V294F protein at dendritic GABAergic synapses compared to wt, and both variants resulted in decreased GABA-evoked current amplitudes compared to wild type. May et al, 2018 (30033060) - WES in a discovery cohort of 238 independent, mianly familial cases of classical forms of genetic generalised epilepsy and 549 ethnically matched population controls. Found 4 families with GABRA5 variants all missense. 2 of these families also have variants in another GABR gene (unclear which or both responsible for disease). In one family they detected the P453L variant in the proband, but it doesn't appear to segregate with disease in two other affected relatives and several other affecteds not tested. In the final family the S238N variant was detected - found in two aff sibs and their aff maternal uncle. Mother apparently unaffected on the pedigree provided. Met1Ille (or Met1?) and the S238N variant both appear to significantly reduce the current amplitudes of GABAa receptors with respect to wt.

Created: 23 Sep 2019, 1:14 p.m. | Last Modified: 23 Sep 2019, 1:14 p.m.

Panel Version: 1.336

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Publications

• 29961870
• 31056671
• 30033060

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.

Created: 26 Sep 2019, 4:03 p.m. | Last Modified: 26 Sep 2019, 4:03 p.m.

Panel Version: 1.339

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.

Created: 19 Sep 2019, 12:56 p.m. | Last Modified: 19 Sep 2019, 12:56 p.m.

Panel Version: 1.335

Added missense tag because, as Konstantinos Varvagiannis notes, only missense GABRA5 variants reported to date for Epileptic Encephalopathy.

Created: 10 Sep 2019, 3:10 p.m. | Last Modified: 10 Sep 2019, 3:11 p.m.

Panel Version: 1.328

Green List (high evidence)

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.
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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).
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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.

Created: 8 Sep 2019, 1:31 p.m. | Last Modified: 8 Sep 2019, 1:31 p.m.

Panel Version: 1.299

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Epileptic encephalopathy, early infantile, 79 (MIM 618559)

Publications

• 29961870
• 31056671