Intellectual disability
Gene: SLC25A12

SLC25A12 (solute carrier family 25 member 12)
EnsemblGeneIds (GRCh38): ENSG00000115840
EnsemblGeneIds (GRCh37): ENSG00000115840
OMIM: 603667, Gene2Phenotype
SLC25A12 is in 9 panels

4 reviews

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Amber to Green based on additional publications reviewed by Konstantinos Varvagiannis and mouse model which includes developmental delay. PMID:31403263 (Kavanaugh et al., 2019) report a 12 year old patient with novel compound het SLC25A12 variants (p.A432V missense, and probable splice variant c.1447‐2_1447‐1delAG), each variant inherited from one parent. Clinical presentation included severe intellectual disability, and profound global developmental delay. Profound global DD was previously reported by PMID:24515575 (Falk et al, 2014), and pyschomotor delay previously reported by PMID:19641205 (Wilbom et al., 2009).
Created: 20 Sep 2019, 8:22 p.m. | Last Modified: 20 Sep 2019, 8:22 p.m.

Panel Version: 2.1037

Created: 20 Sep 2019, 8:22 p.m.
Last Modified: 20 Sep 2019, 8:22 p.m.
Panel version: 2.1037

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Kavanaugh et al. (2019 - PMID: 31403263) provide extensive clinical details on a further individual with biallelic SLC25A12 pathogenic variants. Features included among others hypotonia, DD and severe ID, epilepsy and white matter anomalies and were in-line with previous reports. Prior testing by mtDNA sequencing and aCGH were non-diagnostic. WES revealed a missense and a splicing variant [NM_003705.4:c.1295C>T (p.A432V) and c.1447-2_1447-1delAG]. Sanger sequencing was used for confirmation and segregation studies. The apparent splicing effect (deletion of the acceptor site) was not further studied.

Apart from the previously discussed studies (Falk et. al - PMID: 24515575 / Wibom et al. - PMID: 19641205) additional possibly relevant subject has been reported by Pronicka et al. (PMID: 27290639). This individual investigated for a suspected mitochondrial disorder, was homozygous for NM_003705.4:c.1335C>A (p.Asn445Lys) and presented with hypotonia, ptosis, epilepsy, abnormal lactic acid and unspecific changes upon muscle biopsy.

The subject reported by Retterer et al. - PMID: 26633542 with a clinical presentation suggestive of mitochondrial disorder was found to harbor the same variants as the patient described by Kavanaugh et al. As a result, he could represent the same individual reported in a larger cohort (there is however no overlap between the authors of the 2 articles).

Although briefly reviewed, the :

a. Function of the AGC1 protein (mitochondrial aspartate-glutamate carrier isoform 1) encoded by this gene, supplying aspartate to the cytosol and - as component of the malate-aspartate shuttle - enabling mitochondrial oxidation of cytosolic NADH, providing energy for neurons in the central nervous system] (as summarized by Wibom et al.)
b. Expression in relevant tissues (neurons and muscle)
c. Functional effects of variants in 2 studies (eg. significantly diminished / abolished AGC1 activity in the reports by Falk et al. and Wibom et al. respectively)
d. Mouse models probably recapitulating the human phenotypes (neurodevelopmental delay, motor abnormalities, abnormal brain growth and myelination - discussed in detail by Kavanaugh et al.)
e. Overlapping features of the reported individuals

seem to support the role of this gene in these individuals' phenotype.

The corresponding OMIM entry is Epileptic encephalopathy, early infantile, 39 (MIM 612949). SLC25A12 is not associated with any phenotype in G2P.

This gene is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboudumc, VCGS, GeneDx and many others).

As a result, SLC25A12 can probably be upgraded to green in the current panel.

[Please consider inclusion in other possibly relevant panels eg. mitochondrial disorders, etc.].
Created: 6 Sep 2019, 9:48 p.m. | Last Modified: 6 Sep 2019, 9:48 p.m.

Panel Version: 2.1022

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 6 Sep 2019, 9:48 p.m.
Last Modified: 6 Sep 2019, 9:48 p.m.
Panel version: 2.1022

Louise Daugherty (Genomics England Curator)

Comment on list classification: New gene added by external expert review, who notes that there are 2 reported families. Delayed psychomotor development is part of the phenotype however, arrested psychomotor development seems to affect mainly motor skills.Publications support gene-disease association and rating of this gene to Amber
Created: 19 Jul 2018, 1:21 p.m.

Comment on publications: Added publications suggested from external expert and review to support upgrading of the gene to Green
Created: 19 Jul 2018, 1:07 p.m.

Created: 19 Jul 2018, 1:07 p.m.

Panel version: 2.198

Zornitza Stark (Australian Genomics)

I don't know

Individuals from two unrelated families reported, functional evidence. Consider including as Amber.
Created: 22 Jun 2018, 2:42 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 39

Publications

24515575, 19641205

Variants in this GENE are reported as part of current diagnostic practice

Created: 22 Jun 2018, 2:42 p.m.

Panel version: 2.109

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
Victorian Clinical Genetics Services

Phenotypes

Epileptic encephalopathy, early infantile, 39,612949
Hypomyelination, global cerebral
Epileptic encephalopathy with global cerebral demyelination
Delayed psychomotor development

OMIM

603667

Clinvar variants

Variants in SLC25A12

Penetrance

None

Publications

Panels with this gene

History Filter Activity

20 Sep 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: slc25a12 has been classified as Green List (High Evidence).

20 Sep 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: SLC25A12 were set to 27290639; 25655951; 24515575; 19641205

29 Sep 2018, Gel status: 2