Intellectual disability - microarray and sequencing
Gene: SLC25A12 Green List (high evidence)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
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
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.
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
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
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.