Early onset or syndromic epilepsy

Gene: GABRA2

Green List (high evidence)

AD EIEE78 - onset of refractory seizures in first few days or months of life followed by severe delay & impaired intellectual development. Orenstein et al, 2018 (29422393) - male infant born to AJ descent who developed refractory seizures at 10 weeks. De novo het missense variant identified N335H by exome sequencing. Butler et al, 2018 (29961870) - 11 year old girl who had intractable seizures at 6 weeks of age (clustered focal seizures, infantile spasms, tonic, tonic-clonic, and myoclonic seizures). De novo het missense variant T292K by NGS of a targeted gene panel. In vitro functional expression studies in HEK293 cells showed that the mutation caused an increase in basal leak current of the channel and did not generate currents in response to GABA, likely due to the mutant channel being trapped in an open state. There was also a significant reduction in the total amount of mutant protein and mutant receptor expression at the cell surface compared to wt. Maljevic et al, 2019 (31032849) - 3 unrelated children under 5 years of age with onset of refractory seizures in first days or month of life (focal-clonic seizures and absences). Detected de novo het missense variants L219V and M263T. Also reported 2 children with an attenuated form - 2 sibs where the proband had onset of tonic-clonic seizures at 17 years of age (Diagnosed with ASD at 17 months and regression of acquisitions at 2.5 years and mild/mod intellectual development with speech delay). His 13 year old sister also had mild/mod impaired ID with onset of complex partial seizures at 2 years of age but no autistic features. Brain imaging in both of these was normal. het missense variant F325L which was carried by there unaffected father who was mosaic for the variant. In vitro functional expression studies in Xenopus oocytes showed that all of these missense variants caused a significant reduction in GABA-induced current amplitudes compared to wt and some showed variable dose-response effects. Consistent with a LOF mechanism. Sanchis-Juan et al, 2019 (preprint not on pubmed yet) - patient with EIEE (from 15 months of age) and dev delay - de novo missense variant P280L identified by WGS. These 7 reported variants are located close to the desensitisation gate, the activation gate or the M1-M3 inter-subunit interfaces of the receptor. 6/7 variants had equivalent pathogenic mutations in other Cys-loop receptors reported in the literature highlighting the importance of these regions.

Created: 23 Sep 2019, 1:16 p.m. | Last Modified: 23 Sep 2019, 1:16 p.m.

Panel Version: 1.336

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

Publications

• 29422393
• 31032849

Comment on list classification: Updated rating from Grey to Green: GABRA2 was added to the panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but linked to EIEE-78 in OMIM, and there are sufficient cases from from the literature (PMIDs:29422393, 29961870, 31032849, https://doi.org/10.1101/678219) of GABRA2 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, 4:02 p.m. | Last Modified: 26 Sep 2019, 4:02 p.m.

Panel Version: 1.338

Summary of evidence (see Konstantinos Varvagiannis' reviews for details): Sufficient cases in OMIM and the literature to associate GABRA2 with 'Epileptic encephalopathy, early infantile, 78, 618557'.

PMID:29422393, Orenstein et al., 2018 report a male of unrelated Ashkenazi Jewish parents with EIEE-78 and poor cognitive development, and a de novo heterozygous variant in GABRA2 (N335H). Functional studies were not performed but the variant was absent in ExAC and gnomAD controls.

PMID:29961870, Butler et al. 2018 report an 11 year old girl with EIEE-78 who had multiple seizures starting age 6 weeks, and a de novo heterozygous variant in GABRA2 (T292K).

PMID:31032849, Maljevic et al., 2019 decribe 5 patients (3 sporadic cases and 2 siblings) with four novel de novo GABRA2 missense variants (Val284Ala, Leu291Val, Met263Thr, Phe325Leu). All patients had seizures (Table 1) with onset 1day - 17years. The siblings inherited the variant from a mosaic father.

https://doi.org/10.1101/678219: Sanchis-Juan et al., 2019 identified a de novo missense variant in GABRA2 gene (Pro280Leu) in a 10 year old girl with EIEE and developmental delay.

Created: 19 Sep 2019, 12:41 p.m. | Last Modified: 26 Sep 2019, 3:54 p.m.

Panel Version: 1.336

Added 'missense' tag based on Konstantinos Varvagiannis' comment that all variants to-date are missense variants.

Created: 10 Sep 2019, 3:06 p.m. | Last Modified: 10 Sep 2019, 3:06 p.m.

Panel Version: 1.326

Green List (high evidence)

Heterozygous pathogenic GABRA2 variants cause Epileptic encephalopathy, early infantile, 78 (MIM 618557) [new OMIM entry].

At least 8 relevant individuals have been reported to date in the following studies:
- Orenstein et al. (2018 - PMID: 29422393) - 1 individual
- Butler et al. (2018 - PMID: 29961870) - 1 subject
- Maljevic et al. (2019 - PMID: 31032849 - 3 unrelated children as well as 2 affected sibs
- Sanchis-Juan et al. (2019 - bioRxiv / https://doi.org/10.1101/678219) - 1 further patient

In all affected individuals the variants were missense and - in almost all cases - had occurred as de novo events. The 2 sibs reported by Maljevic however, had inherited a missense variant from their unaffected mosaic parent.

Clinical descriptions for individuals from the 3 studies are provided in OMIM and also summarized, Maljevic - Table 1 (7 patients) and/or in the suppl. table 1 by Sanchis-Juan et al. (8 patients) (https://www.biorxiv.org/content/biorxiv/early/2019/06/21/678219/DC2/embed/media-2.xlsx). Seizures, DD and ID (relevant to the current panel) are among the reported features. Functional studies have been performed for most of the variants and are summarized for each one in the OMIM entry for GABRG2 and the aforementioned table as well.

The following variants have been reported (NM_000807.2): c.1003A>C - p.Asn335His (dn) / c.875C>A - Thr292Lys (dn) / c.871C>G - p.Leu291Val (dn) / c.788T>C - p.Met263Thr (dn) / c.851T>C - p.Val284Ala (dn) / c.975C>A - p.Phe325Leu (inherited from mosaic parent) / c.839C>T - p.Pro280Leu (dn - Sanchis-Juan et al).

As commented by Jenkins and Escayg (2019 - PMID: 31032848 / both among the authors of the 1st report) as well as by Sanchis-Juan et al., both loss- and gain- of function effects explain the pathogenicity of the various mutations reported to date. [In gnomAD GABRA2 has a Z-score for missense variants of 3.13 as well as a pLI of 1].
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GABRA2 is not associated with any phenotype in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
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As a result, GABRA2 can be considered for inclusion in the epilepsy and ID panels probably as green (several relevant individuals, several reported variants with supporting functional studies for most, etc.).

[Consider inclusion in other possibly relevant gene panels eg. for ASD which was feature in some patients at relevant age and/or among those evaluated].

Created: 8 Sep 2019, 4:16 p.m. | Last Modified: 10 Sep 2019, 7:17 a.m.

Panel Version: 1.325

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

Phenotypes
Epileptic encephalopathy, early infantile, 78 (MIM 618557)

Publications

• 29422393
• 29961870
• 31032849
• 31032848
• doi.org/10.1101/678219