Human Gene Module / Chromosome 17 / MED13

MED13mediator complex subunit 13

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
7 / 14
Rare Variants / Common Variants
38 / 0
EAGLE Score
9.3
Moderate Learn More
Aliases
MED13, ARC250,  DRIP250,  HSPC221,  THRAP1,  TRAP240
Associated Syndromes
-
Chromosome Band
17q23.2
Associated Disorders
ADHD, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

A de novo loss-of-function (LoF) variant in the MED13 gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), MED13 was determined to be an ASD candidate gene in Yuen et al., 2017. Genetic and phenotypic characterization of a cohort of 13 individuals affected with intellectual disability or developmental delay and harboring protein-altering variants in the MED13 gene in Snijders Blok et al., 2018 demonstrated that five of these cases also had autism spectrum disorder (ASD), while three cases were also diagnosed with ADHD. Additional de novo loss-of-function variants in the MED13 gene were reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified MED13 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

The MED13 gene encodes a component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MED13 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Recent Recommendation Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
4 Recent Recommendation De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder Snijders Blok L , et al. (2018) No ASD, ADHD
5 Support - Woodbury-Smith M et al. (2022) Yes -
6 Support - Brea-Fernández AJ et al. (2022) No -
7 Support - Levchenko O et al. (2022) No -
8 Recent Recommendation - Zhou X et al. (2022) Yes -
9 Support - Spataro N et al. (2023) No -
10 Support - Sanchis-Juan A et al. (2023) No -
11 Support - Sheth F et al. (2023) Yes DD, ID
12 Support - et al. () Yes -
13 Support - et al. () No -
14 Support - et al. () Yes -
Rare Variants   (38)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.124C>T p.Pro42Ser missense_variant Unknown - - 38003033 et al. ()
c.697A>G p.Ile233Val missense_variant Unknown - - 38438125 et al. ()
c.4225C>T p.Arg1409Ter stop_gained De novo - Simplex 38300321 et al. ()
c.1534C>T p.Arg512Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.814+3A>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.5272C>T p.Arg1758Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.992C>G p.Pro331Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
G>A p.Arg512Ter stop_gained De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.4198C>T p.Arg1400Ter stop_gained De novo - - 28554332 Bowling KM , et al. (2017)
c.1534C>T p.Arg512Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.5100G>A p.Lys1700%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1745T>A p.Leu582Ter stop_gained De novo - - 29740699 Snijders Blok L , et al. (2018)
c.4947C>G p.Tyr1649Ter stop_gained Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.4584dup p.Ala1529SerfsTer2 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1792G>T p.Val598Leu missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.977C>T p.Thr326Ile missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.979C>T p.Pro327Ser missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.980C>A p.Pro327Gln missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.1252G>A p.Ala418Thr missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1618C>A p.Pro540Thr missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.2812A>G p.Ile938Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2571T>C p.Tyr857%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.977C>T p.Thr326Ile missense_variant Unknown - Unknown 35887114 Levchenko O et al. (2022)
c.6191C>T p.Ala2064Val missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.6337C>A p.Leu2113Ile missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.4402C>T p.Pro1468Ser missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.908_909insG p.Ser304PhefsTer29 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.4802C>A p.Ser1601Ter stop_gained Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.975_977del p.Thr326del inframe_deletion De novo - - 29740699 Snijders Blok L , et al. (2018)
c.977C>T p.Thr326Ile missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.5732G>T p.Ser1911Ile missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.5839T>G p.Ser1947Ala missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.125del p.Pro42LeufsTer6 frameshift_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
g.60060310:AGGAGTCCTT>A -1018 inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.857del p.Pro286LeufsTer86 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2593_2594delinsC p.Gly865GlnfsTer5 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.4487del p.Thr1496MetfsTer11 frameshift_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.392T>G p.Leu131Ter stop_gained Familial Maternal Simplex 29740699 Snijders Blok L , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

A de novo loss-of-function (LoF) variant in the MED13 gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), MED13 was determined to be an ASD candidate gene in Yuen et al., 2017. Genetic and phenotypic characterization of a cohort of 13 individuals affected with intellectual disability or developmental delay and harboring protein-altering variants in the MED13 gene in Snijders Blok et al., 2018 demonstrated that five of these cases also had autism spectrum disorder (ASD), while three cases were also diagnosed with ADHD.

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
Description

A de novo loss-of-function (LoF) variant in the MED13 gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), MED13 was determined to be an ASD candidate gene in Yuen et al., 2017. Genetic and phenotypic characterization of a cohort of 13 individuals affected with intellectual disability or developmental delay and harboring protein-altering variants in the MED13 gene in Snijders Blok et al., 2018 demonstrated that five of these cases also had autism spectrum disorder (ASD), while three cases were also diagnosed with ADHD.

Reports Added
[New Scoring Scheme]
4/1/2017
icon
2

Increased from to 2

Description

A de novo loss-of-function (LoF) variant in the MED13 gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), MED13 was determined to be an ASD candidate gene in Yuen et al., 2017.

Krishnan Probability Score

Score 0.53040523014218

Ranking 1549/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99999999994409

Ranking 64/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.97

Ranking 57/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.62940574834226

Ranking 813/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.43662243904638

Ranking 1067/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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