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Intellectual disability

Gene: SLC38A3

Green List (high evidence)
SLC38A3 (solute carrier family 38 member 3)
EnsemblGeneIds (GRCh38): ENSG00000188338
EnsemblGeneIds (GRCh37): ENSG00000188338
OMIM: 604437, Gene2Phenotype
SLC38A3 is in 4 panels

3 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Created: 30 Jan 2023, 5:50 p.m.
Last Modified: 30 Jan 2023, 5:50 p.m.
Panel version: 4.53

Catherine Snow (Genomics England)

Green List (high evidence)

New gene added by Konstantinos Varvagiannis. There is sufficient evidence to promote to Green at the next GMS panel update.
Gene phenotype relationship captured by OMIM, G2P and PanelApp Australia.
Marafi et al PMID: 34605855 describes 7 families accounting for 10 individuals all with ID or global DD
Created: 3 Aug 2022, 11:56 a.m. | Last Modified: 3 Aug 2022, 11:56 a.m.
Panel Version: 3.1648

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Developmental and epileptic encephalopathy 102, 619881

Created: 3 Aug 2022, 11:56 a.m.
Last Modified: 3 Aug 2022, 11:56 a.m.
Panel version: 3.1648

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Marafi et al (2021 - PMID: 34605855) describe the phenotype of 10 individuals, belonging to 7 families (6/7 consanguineous), harboring biallelic deleterious SLC38A3 variants. One subject (from fam3) was previously reported in the context of a larger cohort of consanguineous families investigated with exome sequencing (2017, PMID: 31130284).

The phenotype overall corresponded to a DEE and features included axial hypotonia (10/10), severe global DD or ID (10/10), seizures (8/10, onset : 1w-15m, NOT observed in 2/10 aged 1y3m and 4y | s. types: tonic-clonic in 3/8, tonic 2/8, focal 2/8 with secondary generalization, myoclonic 1/8, gelastic 1/8 | EEG burst-suppression, hypsarrhythmia in few). Microcephaly was observed in (8/10) and was more commonly postnatal and/or progressive. Variable abnormalities were observed upon brain imaging incl. cerebral (5/10) or cerebellar atrophy (2/10) and abnormal CC (6/10), abnormal myelination for age (6/10). Other phenotypes included visual impairment (9/10), peripheral hypertonia (8/9) constipation (8/9) and dysphagia (7/9), FTT (4/8), movement disorder (3/10). Metabolic studies indicated (transient) elevation of lactate (7/8 - also pyruvate in 2) and elevated plasma ammonia (4/7).

Individuals from the 1st family were investigated with ES, and the SLC38A3 splice site variant (NM_006841.6:c.855+1G>T) was the most likely candidate, additional SNVs not contributing to the NDD phenotype. Other affected subjects were ascertained through GeneMatcher/collaborations.

In total, 3 different missense and 4 pLoF (1 fs, 2 nonsense, 1 splicing) variants were identified with individuals from 2 families being hmz or cmd htz for missense variants. Variants were absent/ultrarare with no homozygotes in public/in-house databases with several in silico predictions in favor of a deleterious effect. Regions of AOH (around SLC38A3/total) are provided for some individuals/families.

Sanger sequencing was used for confirmation and segregation studies (apart from carrier parents in 7/7 fam, 11 unaffected sibs tested in 6/7 fam).

The solute carrier (SLC) superfamily of transmembrane transporters - highly expressed in mammalian brain - is involved in exchange of amino-acids (AAs), nutrients, ions, neurotransmitters and metabolites etc across biological membranes with >100 SLC-encoding genes associated with NDDs.

SLC38A3 specifically encodes SNAT3, a sodium-coupled neutral amino-acid transporter, principal transporter of Asn, His, Gln (precursor for GABA and glutamate), expressed in brain, liver, kidney, retina and pancreas. In the brain, it localizes to peri-synaptic astrocytes playing an important role in glutamate/GABA-glutamine cycle.

While the pLoF variants are predicted to undergo NMD or result in non-functional protein, protein modelling suggested that missense ones affect protein activity or stability.

Biochemical and metabolic screening was carried out for several individuals with plasma AAs reported normal (10/10), urinary OAs normal in 9/9, CSF AAs (incl. GABA/glutamine) normal in 2 sibs, CSF lactate normal in 1 indiv. studied. As discussed above plasma ammonia was elevated in 4/7 (2 fam), and 7/10 had elevated lactate and/or pyruvate (2/7).

Untargeted metabolomic profiles performed in biofluids (plasma from 3 subjects, CSF:1, urine:1) were suggestive of altered AA and nitrogen metabolism. In particular, alterations in levels of AA known to be transported by SNAT3 were found. 676 molecules overall showed deviation in plasma samples, 630 in urine and 241 in CSF (albeit with no consistent pattern). Perturbations in several biochemical pathways were shown to occur (incl. Gln-,Asn- and His- pathways).

Slc38a3-/- mice have reductions in brain glutamate and GABA neurotransmitters in homogenized brain tissue (GABA analytes being normal in plasma samples or the single CSF sample available from affected subjects). Snat3-deficient mice had elevation of plasma urea and normal ammonia levels (urea was low in all human samples and ranged from -2 to -3.5 SD in plasma, ammonia was elevated in 4/7). Slc38a3-/- mice have impaired growth, lethargy and ataxic gait, altered plasma AAs, normal glutamine in plasma with abundance in brain and exhibit early lethality. Plasma AAs were normal in 4 affected individuals, impaired growth observed in 4 and gait impairment was observed in 9/10. Hypoglycemia, previously reported in Slc38a3-/- mice, was not observed in any of the patients although this is presumably explained by diet/feeding intervals with abnormalities in pentose phosphate pathway in one individual hypothesized to be reflective of abn. glucose metabolism. The human phenotypes of microcephaly and seizures were not observed in mice. For mouse studies PMIDs cited by the authors : 27362266, 26490457.

There is currently no SLC38A3-related phenotype reported in OMIM. In G2P this gene is incl. in the DD panel (biallelic, confidence: strong, SLC38A3-associated epileptic encephalopathy). SLC38A3 is listed among the primary ID genes in SysID. In PanelApp Australia, SLC38A3 is included with green rating in the epilepsy, ID and microcephaly panels.

Consider inclusion with green rating (10 individuals, 7 families, 7 variants, role of SLCs and SLC38A3, alterations in AA/nitrogen metabolism etc) or amber rating (if discordances with mouse model considered).

Please consider inclusion in other panels e.g. for microcephaly, CC abnormalities, metabolic disorders, etc.
Sources: Literature, Other
Created: 30 Mar 2022, 1:11 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia

Publications

Created: 30 Mar 2022, 1:11 p.m.

Panel version: 3.1529

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • Developmental and epileptic encephalopathy 102, 619881
OMIM
604437
Clinvar variants
Variants in SLC38A3
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Jan 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_rating was removed from gene: SLC38A3.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to SLC38A3. Source Expert Review Green was added to SLC38A3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

3 Aug 2022, Gel status: 2

Added Tag

Catherine Snow (Genomics England)

Tag Q3_22_rating tag was added to gene: SLC38A3.

3 Aug 2022, Gel status: 2

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: slc38a3 has been classified as Amber List (Moderate Evidence).

3 Aug 2022, Gel status: 0

Set Phenotypes

Catherine Snow (Genomics England)

Phenotypes for gene: SLC38A3 were changed from Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia to Developmental and epileptic encephalopathy 102, 619881

30 Mar 2022, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: SLC38A3 was added gene: SLC38A3 was added to Intellectual disability. Sources: Literature,Other Mode of inheritance for gene: SLC38A3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC38A3 were set to 34605855 Phenotypes for gene: SLC38A3 were set to Infantile axial hypotonia; Global developmental delay; Intellectual disability; Seizures; Spasticity; Microcephaly; Cerebral atrophy; Cerebellar atrophy; Abnormality of the corpus callosum; Dysphagia; Constipation; Increased serum lactate; Hyperammonemia Penetrance for gene: SLC38A3 were set to Complete Review for gene: SLC38A3 was set to GREEN