Early onset or syndromic epilepsy

Gene: SLC1A2

Green List (high evidence)

Comment on mode of inheritance: There are at least 16 individuals reported in literature with heterozygous missense varinats in SLC1A2 and a DEE. There are also 2 unrelated patients reported with biallelic SLC1A2 variants and syndromic early-onset epilepsy with vision loss. A supportive mouse model showed that knockout slc1a2-/- mice develop severe epilepsy. Functional effects of the 2 recessive variants were assessed as LoF in HEK293T and COS-7 cell transfection experiments (PMID: 40174554). Hence, the mode of inheritance should remain as BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 10 Sep 2026, 10:13 a.m. | Last Modified: 10 Sep 2026, 10:13 a.m.

Panel Version: 9.80

PMID: 40174554 Kovermann et al., 2025
Report of 18 individuals harbouring 13 different SLC1A2 variants (7 cases previously published, including the homozygous splice variant case in PMID:28915517).
Based on functional studies, variants were categorised as: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G>C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R and I546T did not mediate significant changes to EAAT2 expression or function.
1 newly reported biallelic case: patient homozygous for SLC1A2 c.1316C>T, p.Ala439Val - variant is rare in gnomAD v4, no homz, categorised as LoF in the study. The two individuals with the homozygous variants had neurodevelopmental impairment and epilepsy with seizure onset between 2 and 4 years of age, had normal intelligence or mild ID, and both were able to walk independently and to talk in full sentences. Both had severe vision loss, and one had bilateral hypoplasia of the optic nerves.
In contrast, 2 individuals heterozygous for F249Sfs∗17 and A432D variants (also in the LoF category) had a more severe NDD phenotype without vision loss.

Functional: PMID: 9180080 Tanaka et al., 1997 - homozygous Slc1a2−/− mice have severe epilepsy with neurodegeneration resulting from reduced glial L-Glu uptake.

SLC1A2 is only associated with AD Developmental and epileptic encephalopathy 41, MIM:617105 in OMIM, and Definitive for association with AD developmental and epileptic encephalopathy, 41 in ClinGen (Oct 2020, Aminoacidopathy GCEP) - resources accessed 10th Sept 2026.

Created: 10 Sep 2026, 9:52 a.m. | Last Modified: 10 Sep 2026, 10:07 a.m.

Panel Version: 9.80

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Developmental and epileptic encephalopathy 41, OMIM:617105; developmental and epileptic encephalopathy, 41, MONDO:0014916

Publications

• 9180080
• 28915517
• 40174554

PMID:28915517 reports one case of homozygous c.1421+1G>C in a case of epileptic seizures with visual impairment. The nonconsanguineous German parents of the case, were heterozygous for c.1421+1G>C. The authors observe that haploinsufficiency is not the underlying genetic mechanism in autosomal dominant SLC1A2-related
epileptic encephalopathy, they suggest the autosomal dominant variants, which are in between the first two transmembrane domains of the SLC1A2 protein, result in a gain-of-function, possibly by abnormal channel conductance (PMID: 27445142). In contrast, loss-of-function appears to the mechanism in the homozygous patient; RT-PCR of the patients' fibroblasts revealed two abarrant SLC1A2 products, with deletion of the highly conserverd exon 9 in one and a cryptic splicing product, with termination at p.Leu474 in the other. Clearly further functional studies will be required to clafiry the mechanisms by which SLC1A2 variants result in epilepsy and other phenotypic features.

Created: 19 Apr 2022, 10:18 a.m. | Last Modified: 14 Jul 2022, 1:12 p.m.

Panel Version: 2.545

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 23934111
• 27476654

Green List (high evidence)

hom variant reported in PMID 28915517 - can't access full paper to see anymore details

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

I don't know

Comment on mode of inheritance: Kept Mode of Inheritance as 'BOTH monoallelic and biallelic' based on post-Webex review by Helen Lord.

Created: 7 Sep 2019, 12:03 p.m. | Last Modified: 7 Sep 2019, 12:03 p.m.

Panel Version: 1.297

Mode of inheritance 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 is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD EIEE41. EPI4K consortium 2016, 2 unrealted girls with EIEE41 2 diff de novo het missense variants). Also noted that the EPI4L project, 2013 - reported another girl with EIEE41 (de novo missense - one of the ones reported in 2016, are these the same patient?). Guella et al, 2017 - 2 unrelated boys with EIEE41 (both had de novo het missense variants. No functional studies done. Wagner et al, 2018, novel hom splicing variant - functional studies on the cDNA level confirmed a LOF.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy, early infantile, 617105

Publications

• 27476654
• 28777935

Green List (high evidence)

changed rating from amber to green

Created: 6 Dec 2017, 4:54 p.m.

PMID:28915517 (2017) showed that mutations in SLC1A2 are related to epileptic seizures, SLC1A2-related epilepsy is not only caused by heterozygous de novo mutations but can also be inherited in an autosomal recessive fashion, and the genetic mechanism of autosomal dominant SLC1A2-related epileptic encephalopathy is other than haploinsufficiency.

Created: 6 Dec 2017, 4:52 p.m.

Comment on list classification: changed from amber to green, more than missense variants identified, a novel homozygous splicing variant PMD: 28915517. A mouse model also shows that complete lack of protein expression leads to a phenotype including epileptic encephalopathy, which is fatal in many cases PMIDs: 25834045; 9180080

Created: 6 Dec 2017, 3:48 p.m.

Comment on mode of inheritance: recent paper PMID:28915517 suggest that not only de novo mutations but also biallelic variants in SLC1A2 can cause epilepsy and that there is an additional autosomal recessive mode of inheritance.

Created: 6 Dec 2017, 3:40 p.m.

Four unrelated cases with Epileptic encephalopathy, early infantile, 41 (EIEE41) PMID: 27476654, 28777935. Gene added via ID panel update, this gene is more relevant on this panel. In vitro functional studies of the variants and studies of patient cells were not performed, but it has been postulated a toxic gain-of-function effect, perhaps related to glutamate toxicity (PMID:28777935). Only missense variants have been reported in OMIM.

Created: 6 Dec 2017, 3:20 p.m.

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

Phenotypes
Epileptic encephalopathy, early infantile, 41, 617105

Publications

• 27476654
• 28777935
• 23934111
• 9180080