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Intellectual disability

Gene: MED23

Green List (high evidence)

MED23 (mediator complex subunit 23)
EnsemblGeneIds (GRCh38): ENSG00000112282
EnsemblGeneIds (GRCh37): ENSG00000112282
OMIM: 605042, Gene2Phenotype
MED23 is in 2 panels

5 reviews

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic pathogenic variants in MED23 cause Mental retardation, autosomal recessive 18 (MIM 614249).

5 individuals from 3 unrelated families have been reported.
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Hashimoto et al. (PMID: 21868677) report on 2 sisters from a broader consanguineous Algerian family (of 5 total affected sibs) with mild to moderate ID. Both were homozygous for a missense variant (NM_015979.2:c.1850G>A or p.R617Q). Other causes (chromosomal and fragile-X syndrome) were previously excluded.

MED23 encodes a subunit of the Mediator complex, a key regulator of gene expression. The authors demonstrated dysregulation of JUN and FOS, similar to what is observed in other neurological disorders (with ID) due to mutations in Mediator subunits (eg. MED12) or genes for proteins interacting with Mediator. This was secondary to perturbation of the interaction between the Mediator and enhancer-bound transcription factors (TCF4 and ELK1).
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Trehan et al. (PMID: 25845469) describe 2 sibs born to non-consanguineous parents. Both presented with profound ID, heart defects (one with VSD, the other with ASD) and spasticity.

Array-CGH failed to demonstrate any pathogenic CNV and exome sequencing identified compound heterozygosity for 2 MED23 variants as the most likely cause for their disorder (NM_015979.3:c.[3656A>G];[4006C>T] corresponding to p.H1219R and p.R1336X). Similar mRNA levels were demonstrated in patient fibroblasts when compared to controls and Western blot revealed no alteration of MED23 steady state protein levels. As a result NMD was ruled out. [Note: The nonsense variant appears to affect all transcripts but to be localized in the ultimate coding exon of one of them].

Dysregulation of JUN and SON was demonstrated similar to the previous article.

According to the authors, a role for Med23 in cardiovascular development has been previously suggested using zebrafish and mouse models, potentially giving an explanation for the patients' heart defects.
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Lionel et al. (PMID: 27311965) report on an additional individual with severe DD and ID as well as seizures. This individual, born to consanguineous parents, harbored a novel missense variant (NM_015979.3:c.1937A>G or p.Q646R) in the homozygous state.

Response of the seizures to ketogenic diet was shown. A previous liver-specific Med23-knockout mouse model had demonstrated reduced hepatic glyconeogenesis and lower blood glucose levels. As a result the response to ketogenic diet observed in the patient was thought to be due to provision of an alternative energy source to the brain.
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In ClinVar 4 MED23 variants have been submited as pathogenic/likely pathogenic. There appears to be a second submission of the variant initially reported by Hashimoto et al. (R617Q) as well as an additional variant (R224G).
[Other variants seem to affect both ARG1 (exonic region) and MED23 (intronic) and have been submitted as (likely) pathogenic for Arginase deficiency].
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MED23 is included in gene panels for ID offered by several diagnostic laboratories (incl. Radboudumc).
It is also included in the DD panel of G2P, associated with Mental retardation autosomal recessive type 18.
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As a result, this gene could be considered for upgrade to green.
Created: 17 Dec 2018, 5:28 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

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

Helen Brittain (Genomics England Curator)

Comment when marking as ready: Two reported cases to date. Considered amber and watchlist on current evidence.
Created: 5 Mar 2018, 1:31 p.m.

Louise Daugherty (Genomics England Curator)

Comment on list classification: Removed Watchlist tag. Changed from Amber to Green. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association
Created: 30 Jan 2019, 10:31 a.m.
Comment on publications: Added publications suggested from external expert review to support upgrading of the gene to Green
Created: 30 Jan 2019, 10:28 a.m.
Comment on list classification: Changed rating of gene from Red to Amber. This gene was rated as Amber in v2.467 and incorrectly automatically demoted to Red in v2.468. This was due to a defect in the automatic PanelApp uploading tool where a reference gene list was added as a new Source (Victorian Clinical Genetics Services), and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Created: 29 Sep 2018, 9:35 p.m.
Comment on list classification: Changed rating from Red to Amber, but passed onto clinical team, potentially this gene could be rated Green.
Created: 19 Feb 2018, 12:50 p.m.
Comment on publications: Added publications to support cases where variants in MED23 resulted in an intellectual disability phenotype. Currently there are two unrelated families in the literature, one a large Algerian consanguineous family (5 affecteds) with ID PMID: 21868677 (2011), the other, two brothers in a nonconsanguineous family with ID, PMID: 25845469 (2015) with two additonal novel mutations in MED23 that caused an ID phenotype (submitted to Clinvar) from Undiagnosed Diseases Program Translational Research Laboratory, USA. However, in addition to this, there is another pathogenic variant associated specifically MED23 and ID in ClinVar from a submitter in Iran (Genomic Research Center Shahid Beheshti University of Medical Sciences) from a clinical test. To be reviewed by clinical team.
Created: 15 Feb 2018, 4:52 p.m.

Caroline Wright (Sanger)

Red List (low evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
MENTAL RETARDATION AUTOSOMAL RECESSIVE TYPE 18

Publications

  • 0

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Mental retardation, autosomal recessive 18, 614249
  • MRT18
  • Intellectual disability
OMIM
605042
Clinvar variants
Variants in MED23
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Jan 2019, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: med23 has been classified as Green List (High Evidence).

30 Jan 2019, Gel status: 2

Removed Tag

Louise Daugherty (Genomics England Curator)

Tag watchlist was removed from gene: MED23.

30 Jan 2019, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: MED23 were set to 21868677; 25845469; 25527630; 22129135

29 Sep 2018, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: med23 has been classified as Amber List (Moderate Evidence).

29 Sep 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to MED23.

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

12 Mar 2018, Gel status: 2

Added New Source, Set publications

Ellen McDonagh (Genomics England Curator)

Expert Review Amber was added to MED23. Panel: Intellectual disability Publications for gene MED23 was set to ['21868677', '25845469', '25527630', '22129135']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 1

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

MED23 was added to Intellectual disabilitypanel. Source: Expert Review Red Model of inheritance for gene MED23 was set to BIALLELIC, autosomal or pseudoautosomal

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

MED23 was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen