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Intellectual disability

Gene: MED13

Amber List (moderate evidence)

MED13 (mediator complex subunit 13)
EnsemblGeneIds (GRCh38): ENSG00000108510
EnsemblGeneIds (GRCh37): ENSG00000108510
OMIM: 603808, Gene2Phenotype
MED13 is in 3 panels

2 reviews

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Grey to Amber. Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Not yet associated with a disorder in OMIM. Probable rating in Gene2Phenotype for 'Neurodevelopment disorder' based on PMID:29740699 (Snijders Blok et al., 2018) who report on 13 patients. 11 variants were de novo and 1 (patient B) was inherited from an affected mother (patient C). All patients had developmental delay to some extent (speech delay in most cases, with motor development delayed in 7/13). ID is mild/borderline in at least 9 cases. There is not a clear genotype-phenotype correlation between variants, and it's unclear how some variants are deleterious, and therefore Amber rating is appropriate until further studies are published.
Created: 21 Sep 2019, 8:46 a.m. | Last Modified: 21 Sep 2019, 8:46 a.m.
Panel Version: 2.1043

Konstantinos Varvagiannis (Other)

I don't know

Snijders Blok et al. (2018 - PMID: 29740699) report on 13 individuals with MED13 mutations.

Features included DD with speech difficulties (both universal) and motor delay in some. ID was observed in at least 9/13 and in most cases was in the borderline/mild range (moderate ID reported for 1 individual). Other features were ASD (5/13), ADHD, eye/vision abnormalities and in few individuals obstipation or congenital heart anomalies. Some possibly overlapping facial characteristics were also noted.

MED13 and MED13L are mutually exclusive components of the CDK8 kinase module that regulates the activity of the Mediator complex. The Mediator transmits signals from various transcription factors to RNA polymerase II (Pol II). Reversible binding of the CDK8 kinase controls Mediator - Pol II interaction (prevents Pol II recruitment) and thus acts as a molecular switch in Pol II - mediated transcription. DD and ID are features of the MED13L- and CDK8- related disorders.

3 stopgain, 2 frameshift, 6 missense variants and 1 in-frame deletion were reported. In 11 cases, the variants had occurred as de novo events, while 1 individual had inherited a nonsense variant from a similarly affected mother (unknown inheritance in her case).

Effect of a stopgain variant was studied with similar (total) transcript levels between the affected patient and his parents/controls upon qPCR. Sanger sequencing of cDNA amplicons was suggestive of the presence of an aberrant transcript at ~70% levels relative to the normal transcript. Truncated protein was undetectable by Western Blot in mononuclear blood cells from affected subjects. Total MED13 protein levels were not clearly different when comparing an affected individual with his unaffected parent (?).

Missense variants and the inframe deletion clustered either in the N- or the C-terminal domain, with the N-terminal ones all (T326I, T326del, P327S, P327Q / NM_005121.2 - NP_005112.2) affecting positions of a known phosphodegron sequence, important for the protein's ubiquitination and degradation. Another previously studied variant (T326A) had been shown to prevent degradation. As a result, the variants affecting aa 326-327 might lead to altered (increased) levels of MED13.

The remaining missense variants affected the C-terminal portion (Q2060L, A2064V).

As a result the impact of the different subcategories of variants remains unclear/inconclusive.

MED13 is not associated with any phenotype in OMIM. This gene is part of the DD panel of G2P, associated with "MED13 - Neurodevelopment disorder" (dis. confidence : probable / mutation consequence : LoF / GDD, speech/language delay, ID, autistic behavior among the assigned phenotypes).

MED13 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

ID is part of the phenotype of MED13-related disorder. However as the severity in most individuals - when present - was in the borderline/mild range (not relevant for the present panel) and/or the underlying effect of mutations remains unclear, amber rating seems more appropriate.
Sources: Radboud University Medical Center, Nijmegen, Literature
Created: 31 Aug 2019, 10:36 a.m. | Last Modified: 31 Aug 2019, 10:37 a.m.
Panel Version: 2.1021

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Attention deficit hyperactivity disorder; Abnormality of the eye; Constipation

Publications

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
Phenotypes
  • Delayed speech and language development
  • Motor delay
  • Intellectual disability
  • Autistic behavior
  • Attention deficit hyperactivity disorder
  • Abnormality of the eye
  • Constipation
OMIM
603808
Clinvar variants
Variants in MED13
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

21 Sep 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: med13 has been classified as Amber List (Moderate Evidence).

21 Sep 2019, Gel status: 0

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: med13 has been removed from the panel.

31 Aug 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: MED13 was added gene: MED13 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature Mode of inheritance for gene: MED13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MED13 were set to 29740699 Phenotypes for gene: MED13 were set to Delayed speech and language development; Motor delay; Intellectual disability; Autistic behavior; Attention deficit hyperactivity disorder; Abnormality of the eye; Constipation Penetrance for gene: MED13 were set to unknown Review for gene: MED13 was set to AMBER gene: MED13 was marked as current diagnostic