Early onset or syndromic epilepsy
Gene: SLC32A1This gene is not currently associated with a disease phenotype in OMIM, but checked PMID:34038384 to make sure it is the same gene listed in the publication as on this panel and it is, so added the gene-checked tagCreated: 16 Oct 2023, 7:40 p.m. | Last Modified: 16 Oct 2023, 7:40 p.m.
Panel Version: 4.118
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 11 Oct 2023, noon | Last Modified: 11 Oct 2023, noon
Panel Version: 4.110
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Comment on list classification: As reviewed by Helen Lord (Oxford Medical Genetics Laboratories) and Zornitza Stark (Australian Genomics), there are 8 unrelated cases with genetic epilepsy with febrile seizures plus and 4 unrelated cases with a neurodevelopmental disorder comprising intellectual disability and infantile-onset epilepsy and there are supporting functional evidence. Hence, this gene can be promoted to GREEN at the next GMS update.
Although this gene has not yet been associated with phenotypes in OMIM, it has been added to Gene2Phenotype with 'moderate' rating in the DD panel.Created: 4 May 2023, 3:05 p.m. | Last Modified: 4 May 2023, 3:09 p.m.
Panel Version: 4.25
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214
Publications
34038384: Heron et al, 2021: WGS on 3 members of a GEFS+ family and subsequent looked at WES data for other epilepsy patients - 8 previously unreported missense variants identified in SLC32A1. No developmental delay or intellectual disability reported.
Two variants cosegregated with phenotype in 2 large GEFS+ families containing 8 & 10 affected individuals respectively and 6 further variants in smaller families with GEFS+ or idipathic generalised epilepsy. de novo in 1 family, although sib with idiopathic generalised epilepsy who doesn't have the variant - family F.
Predict that the pathogenic mechanism associated with these variants is predicted to be altered GABAergic signaling leading to increased seizure susceptibility.
SLC32A1 codes for the VGAT protein - sole molecule known to transport the inhibitory transmitters GABA and glycine into synaptic vesicles and is therefore eseential for neuronal function.
Hom VGAT knockout ice have an embryonic lethal phenotype (with immobile stiff embryos). Het VGAT knockout mice have specific defects in senosry processing and glycinergic transmission, without a clear behavioural phenotype.While the mice were not tested for seizures, no phenotypic abnormalities were observed.
VGAT has 9 transmembrane domains, a large cytosolic N-terminal domain and a small C-terminal domain located in the vesicle lumen. The 5 variants in families A, C, E, F and G are located in adjacent predicted transmembrane domains. 4 of these are clustered witihn 10 AA residues in the 8th transmembrane domain - suggests hotspot. The variant in family H is in the vesicle trageted sequence and in families B and D - the cytosolic loops.
They speculate that the missense variants associated with seizures in humans may have a more specific effect on VGAT function than just LOF.
Platzer et al, 2022, Annals of Neurology, https://doi.org/10.1002/ana.26485:
exome sequencing, idenitifed 4 individuals with a developmental and epileptic encephalopathy and de novo missense variants in SLC32A1. Main phenotype comprises moderate to severe intellectual disability, infantile onset within the first 18 months of life and a chorieform, dystonic, or dyskinetic movement disorder.
The variants in individuals 2, 3 and 4 are located in the transmembrane domain, in the helices that line the substrate transport pathway. The p.Val263Met and p.(Phe322Cys) variants are predicted to likely affect substrate uptake on the cytosolic side or the transport process itself. The evidence for causality of the de novo variant in individul 1 is less compelling; however it does increase the presynaptic release probibiltly so suggests it could be pathogeni but via a diff mechanism to those in the transmembrane domain.Created: 30 Aug 2022, 8:13 a.m. | Last Modified: 30 Aug 2022, 8:13 a.m.
Panel Version: 2.582
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
developmental and epileptic encephalopathy
Publications
8 unrelated families reported, including segregation evidence in two large pedigrees. Variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition.
Sources: LiteratureCreated: 13 Sep 2021, 8:13 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Genetic epilepsy with febrile seizures plus
Publications
Tag gene-checked tag was added to gene: SLC32A1.
Tag Q2_23_promote_green was removed from gene: SLC32A1.
Source NHS GMS was added to SLC32A1. Source Expert Review Green was added to SLC32A1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: slc32a1 has been classified as Amber List (Moderate Evidence).
Gene: slc32a1 has been classified as Amber List (Moderate Evidence).
Gene: slc32a1 has been classified as Amber List (Moderate Evidence).
Tag Q2_23_promote_green tag was added to gene: SLC32A1.
Phenotypes for gene: SLC32A1 were changed from developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214 to developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214
Phenotypes for gene: SLC32A1 were changed from developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214 to developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214
Phenotypes for gene: SLC32A1 were changed from Genetic epilepsy with febrile seizures plus to developmental and epileptic encephalopathy, MONDO:0100062; generalized epilepsy with febrile seizures plus, MONDO:0018214
Publications for gene: SLC32A1 were set to 34038384; 36073542
Publications for gene: SLC32A1 were set to 34038384
gene: SLC32A1 was added gene: SLC32A1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SLC32A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC32A1 were set to 34038384 Phenotypes for gene: SLC32A1 were set to Genetic epilepsy with febrile seizures plus Review for gene: SLC32A1 was set to GREEN