Human Gene Module / Chromosome 17 / MED13

MED13mediator complex subunit 13

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
17 / 0
Aliases
MED13, ARC250,  DRIP250,  HSPC221,  THRAP1,  TRAP240
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
17q23.2
Associated Disorders
ADHD, ASD
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.

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.

Reports related to MED13 (4 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
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
858+C 286-! frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
3054+AAGGACTCC 1018- inframe_deletion De novo - Simplex 25363768 Iossifov I , et al. (2014)
G>A p.Arg512Ter stop_gained De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.1252G>A p.Ala418Thr missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.4947C>G p.Tyr1649Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.4198C>T p.Arg1400Ter stop_gained De novo - - 28554332 Bowling KM , et al. (2017)
c.125del p.Pro42LeufsTer6 frameshift_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.392T>G p.Leu131Ter stop_gained Familial Maternal Multi-generational 29740699 Snijders Blok L , et al. (2018)
c.977C>T p.Thr362Ile missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.975_977delTAC p.Thr326del inframe_deletion 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.1618C>A p.Pro540Thr missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.1745T>A p.Leu582Ter stop_gained De novo - - 29740699 Snijders Blok L , et al. (2018)
c.4487delC p.Thr1496Metfs frameshift_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.6178C>A p.Gln2060Lys missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
c.6191C>T p.Ala2064Val missense_variant De novo - - 29740699 Snijders Blok L , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

2S

Score Delta: Increased from 2 to 3.3 + acc + S

2

Strong Candidate

See all Category 2 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.

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."

4/1/2018
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.
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
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
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).
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.
CNVs associated with MED13(1 CNVs)
17q23.2 7 Deletion 13  /  22
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