Intellectual disability - microarray and sequencing
Gene: SLC25A12Comment 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
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
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 AmberCreated: 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 GreenCreated: 19 Jul 2018, 1:07 p.m.
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
Variants in this GENE are reported as part of current diagnostic practice
Gene: slc25a12 has been classified as Green List (High Evidence).
Publications for gene: SLC25A12 were set to 27290639; 25655951; 24515575; 19641205
Source Victorian Clinical Genetics Services was added to SLC25A12.
Gene: slc25a12 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: SLC25A12 were set to Epileptic encephalopathy, early infantile, 39,612949; Hypomyelination, global cerebral; Epileptic encephalopathy with global cerebral demyelination; Delayed psychomotor development
Publications for gene: SLC25A12 were set to 27290639; 25655951; 24515575; 19641205
Publications for gene: SLC25A12 were set to 27290639; 25655951; 24515575; 19641205
SLC25A12 was added to Intellectual disability panel. Sources: Literature
SLC25A12 was created by Zornitza Stark