Human Gene Module / Chromosome 12 / MED13L

MED13LMediator complex subunit 13-like

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
23 / 54
Rare Variants / Common Variants
114 / 0
EAGLE Score
35
Strong Learn More
Aliases
MED13L, PROSIT240,  THRAP2,  TRAP240L
Associated Syndromes
-
Chromosome Band
12q24.21
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features. Three de novo protein-truncating variants in MED13L were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified MED13L as a candidate gene with a false discovery rate (FDR) 0.01. Additional de novo loss-of-function variants and potentially damaging missense variants in the MED13L gene were reported in ASD probands from 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 MED13L as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

The protein encoded by this gene is a subunit of the Mediator complex, a large complex of proteins that functions as a transcriptional coactivator for most RNA polymerase II-transcribed genes. The encoded protein is involved in early development of the heart and brain. Defects in this gene are a cause of transposition of the great arteries, dextro-looped (DTGA) [MIM:608808].

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MED13L (54 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
2 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing Redin C , et al. (2014) No -
3 Support De novo mutations in moderate or severe intellectual disability Hamdan FF , et al. (2014) No Speech delay, motor delay
4 Recent Recommendation The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) Yes -
6 Support Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome Cafiero C , et al. (2015) No -
7 Recent Recommendation Redefining the MED13L syndrome Adegbola A , et al. (2015) No Autistic features
8 Support Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders Codina-Sol M , et al. (2015) Yes -
9 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
10 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
11 Support De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy? Caro-Llopis A , et al. (2016) No Autistic behavior
12 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
13 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
14 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
15 Support MED13L haploinsufficiency syndrome: A de novo frameshift and recurrent intragenic deletions due to parental mosaicism Yamamoto T , et al. (2017) No DD, ID
16 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
17 Support Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation Asadollahi R , et al. (2017) No Hypotonia, dysmorphic features
18 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No -
19 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
20 Support Exome Pool-Seq in neurodevelopmental disorders Popp B , et al. (2017) No Hypotonia
21 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
22 Recent Recommendation MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype Smol T , et al. (2018) No Autistic features
23 Support Is MED13L-related intellectual disability a recognizable syndrome? Trring PM , et al. (2018) No ASD or autistic features
24 Support Clinical genome sequencing in an unbiased pediatric cohort Thiffault I , et al. (2018) No Congenital heart defects
25 Support Diagnostic value of partial exome sequencing in developmental disorders Gieldon L , et al. (2018) No Epilepsy/seizures, autistic features
26 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
27 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
28 Support Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders Gao C , et al. (2019) No -
29 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
30 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No -
31 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
32 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
33 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
34 Support Report of a de novo c.2605C > T (p.Pro869Ser) change in the MED13L gene and review of the literature for MED13L-related intellectual disability Yi Z et al. (2020) No DD, ID, autistic features
35 Support - Alonso-Gonzalez A et al. (2021) Yes -
36 Support - Valentino F et al. (2021) No -
37 Support - Pode-Shakked B et al. (2021) No -
38 Support - Xiang J et al. (2021) No -
39 Support - Chang KT et al. (2022) No -
40 Support - Brea-Fernández AJ et al. (2022) No -
41 Support - Carvalho LML et al. (2022) No -
42 Support - Hu C et al. (2022) Yes -
43 Support - Levchenko O et al. (2022) No -
44 Support - Zhou X et al. (2022) Yes -
45 Support - Spataro N et al. (2023) No -
46 Recent Recommendation - Timberlake AT et al. (2023) No ASD
47 Support - Wang J et al. (2023) Yes -
48 Support - Tuncay IO et al. (2023) Yes -
49 Support - Cirnigliaro M et al. (2023) Yes -
50 Support - Siavrien E et al. (2023) No -
51 Support - Sanchis-Juan A et al. (2023) No -
52 Support - Sheth F et al. (2023) Yes DD, ID
53 Support - Ana Karen Sandoval-Talamantes et al. (2023) Yes -
54 Support - Luigi Vetri et al. (2024) No -
Rare Variants   (114)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 29511999 Smol T , et al. (2018)
- - copy_number_loss Unknown - - 36980980 Spataro N et al. (2023)
- - copy_number_loss De novo - - 29959045 Trring PM , et al. (2018)
- - copy_number_gain De novo - - 25758992 Adegbola A , et al. (2015)
- - copy_number_loss De novo - - 25758992 Adegbola A , et al. (2015)
G>CT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_loss De novo - Simplex 37512036 Siavrien E et al. (2023)
c.173T>A p.Leu58Ter stop_gained De novo - - 29511999 Smol T , et al. (2018)
- - copy_number_gain Familial Maternal - 25758992 Adegbola A , et al. (2015)
c.1009+1G>C - splice_site_variant De novo - - 29511999 Smol T , et al. (2018)
c.2345-3C>G - splice_site_variant De novo - - 29511999 Smol T , et al. (2018)
c.6225+1G>A - splice_site_variant De novo - - 29511999 Smol T , et al. (2018)
- - copy_number_gain Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.5920C>T p.Arg1974Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.2065C>T p.Gln689Ter stop_gained Unknown - - 29511999 Smol T , et al. (2018)
c.5173C>T p.Gln1725Ter stop_gained De novo - - 29158550 Popp B , et al. (2017)
c.5281C>T p.Pro1761Ser stop_gained De novo - - 29511999 Smol T , et al. (2018)
c.5764C>T p.Gln1922Ter stop_gained De novo - - 29511999 Smol T , et al. (2018)
c.72+1G>T - splice_site_variant De novo - - 34356170 Valentino F et al. (2021)
c.5210A>G p.Lys1737Arg missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.685G>C p.Asp229His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2071C>T p.Gln691Ter stop_gained De novo - - 29959045 Trring PM , et al. (2018)
c.5684G>A p.Arg1895Lys stop_gained De novo - - 29959045 Trring PM , et al. (2018)
c.4150A>G p.Thr1384Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5593C>T p.Arg1865Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4956-2A>T - splice_site_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.2600C>T p.Thr867Ile missense_variant De novo - - 29511999 Smol T , et al. (2018)
c.2605C>T p.Pro869Ser missense_variant De novo - - 29511999 Smol T , et al. (2018)
c.2930C>T p.Ala977Val missense_variant De novo - - 29511999 Smol T , et al. (2018)
c.2344G>T p.Asp782Tyr stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.6008C>T p.Ser2003Leu missense_variant De novo - - 29511999 Smol T , et al. (2018)
c.6488C>T p.Ser2163Leu missense_variant De novo - - 29511999 Smol T , et al. (2018)
c.6488C>T p.Ser2163Leu missense_variant Unknown - - 29511999 Smol T , et al. (2018)
c.6530C>A p.Ser2177Tyr missense_variant De novo - - 29511999 Smol T , et al. (2018)
c.5861_5890+1del - frameshift_variant De novo - - 29959045 Trring PM , et al. (2018)
c.4137G>A p.Pro1379%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Multiplex 28371282 Yamamoto T , et al. (2017)
c.2524C>T p.Arg842Ter stop_gained De novo - - 27500536 Caro-Llopis A , et al. (2016)
c.5588+1G>A - splice_site_variant De novo - Multiplex 29511999 Smol T , et al. (2018)
c.6583C>T p.His2195Tyr missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.2605C>T p.Pro869Ser missense_variant De novo - Simplex 32646507 Yi Z et al. (2020)
c.3392G>A p.Cys1131Tyr missense_variant De novo - - 29959045 Trring PM , et al. (2018)
c.5852T>C p.Val1951Ala missense_variant De novo - - 30091983 Gieldon L , et al. (2018)
c.2722A>G p.Thr908Ala missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.6485C>T p.Thr2162Met missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.5614C>T p.Arg1872Cys missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.5364+1dup - splice_site_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2594T>A p.Phe865Tyr missense_variant De novo - - 30008475 Thiffault I , et al. (2018)
c.4076G>A p.Trp1359Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4420A>T p.Lys1474Ter stop_gained De novo - Simplex 25712080 Cafiero C , et al. (2015)
c.3392G>A p.Cys1131Tyr missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.311-42655G>C - intron_variant Familial Both parents - 37492102 Tuncay IO et al. (2023)
c.311-42838A>T - intron_variant Familial Both parents - 37492102 Tuncay IO et al. (2023)
c.2117G>A p.Gly706Glu missense_variant De novo - - 31209962 Aspromonte MC , et al. (2019)
c.6260del p.Pro2087GlnfsTer4 frameshift_variant De novo - - 31178897 Gao C , et al. (2019)
c.2399dup p.Thr801AsnfsTer9 frameshift_variant De novo - - 29158550 Popp B , et al. (2017)
c.1903dup p.Ser635LysfsTer8 frameshift_variant De novo - - 29511999 Smol T , et al. (2018)
c.5695G>A p.Gly1899Arg missense_variant De novo - - 27500536 Caro-Llopis A , et al. (2016)
c.5364+1G>T - splice_site_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3550T>C p.Leu1184%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1152dup p.Ile385HisfsTer18 frameshift_variant Unknown - - 29511999 Smol T , et al. (2018)
c.2928G>A p.Trp976Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.6301G>T p.Val2101Leu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.6317C>T p.Ala2106Val missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.4456del p.Gln1486SerfsTer25 frameshift_variant De novo - - 29511999 Smol T , et al. (2018)
c.6289dup p.Leu2097ProfsTer11 frameshift_variant De novo - - 29511999 Smol T , et al. (2018)
c.6280C>T p.Pro2094Ser missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.1718C>T p.Pro573Leu missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.257del p.Phe86SerfsTer9 frameshift_variant De novo - - 28371282 Yamamoto T , et al. (2017)
c.2746G>T p.Glu916Ter stop_gained De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.830_845del p.Arg277GlnfsTer5 frameshift_variant De novo - - 29511999 Smol T , et al. (2018)
c.124dup p.Asp42GlyfsTer13 frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.6277dup p.Gln2093ProfsTer15 frameshift_variant De novo - - 29959045 Trring PM , et al. (2018)
c.4670dup p.Ala1558SerfsTer6 frameshift_variant De novo - - 38256219 Luigi Vetri et al. (2024)
c.2579A>G p.Asp860Gly missense_variant De novo - Simplex 28645799 Asadollahi R , et al. (2017)
c.2395_2396del p.Gln799GlyfsTer10 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.1708_1709del p.Ser570PhefsTer27 frameshift_variant De novo - - 29511999 Smol T , et al. (2018)
c.2340_2343del p.Thr781MetfsTer19 frameshift_variant De novo - - 29511999 Smol T , et al. (2018)
c.6488C>T p.Ser2163Leu missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.3719dup p.Asn1241GlufsTer9 frameshift_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.3914_3915del p.His1305LeufsTer59 frameshift_variant Unknown - - 29511999 Smol T , et al. (2018)
c.3945_3946del p.Ile1315MetfsTer49 frameshift_variant De novo - - 29511999 Smol T , et al. (2018)
c.5156_5157del p.Arg1719LysfsTer20 frameshift_variant De novo - - 29511999 Smol T , et al. (2018)
c.4273C>A p.Pro1425Thr missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.6611A>G p.Asn2204Ser missense_variant Unknown - Multiplex 31038196 Callaghan DB , et al. (2019)
c.631G>T p.Val211Leu missense_variant Unknown - Extended multiplex 37543562 Sheth F et al. (2023)
c.3942_3943del p.Ile1315GlnfsTer49 frameshift_variant De novo - - 31231135 Bruel AL , et al. (2019)
c.2019A>T p.Leu673Phe missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.3292_3296delinsA p.Ala1098ThrfsTer15 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.5054dup p.Thr1686HisfsTer28 frameshift_variant Unknown - Unknown 35198885 Chang KT et al. (2022)
c.3279delinsAA p.Asn1093LysfsTer32 frameshift_variant De novo - - 30091983 Gieldon L , et al. (2018)
c.607dup p.Ser203PhefsTer32 frameshift_variant De novo - Simplex 25712080 Cafiero C , et al. (2015)
c.3765del p.Cys1256ValfsTer2 frameshift_variant De novo - Simplex 25712080 Cafiero C , et al. (2015)
c.5949_5950del p.Gln1984AlafsTer31 frameshift_variant De novo - - 25758992 Adegbola A , et al. (2015)
c.6331del p.Gln2111SerfsTer18 frameshift_variant De novo - Simplex 35887114 Levchenko O et al. (2022)
c.2318del p.Ser773LeufsTer28 frameshift_variant De novo - Simplex 35597848 Carvalho LML et al. (2022)
c.2504del p.Pro835LeufsTer46 frameshift_variant De novo - Simplex 28645799 Asadollahi R , et al. (2017)
c.6118_6125del p.Gly2040AsnfsTer32 frameshift_variant De novo - Simplex 25167861 Redin C , et al. (2014)
c.2320del p.Ile774PhefsTer27 frameshift_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.572del p.Leu191Ter frameshift_variant Unknown - - 38003033 Ana Karen Sandoval-Talamantes et al. (2023)
c.1654_1655insATAT p.Ile552AsnfsTer47 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1284_1285insTTTAAGCTTTT p.Lys429PhefsTer7 frameshift_variant De novo - - 34858471 Xiang J et al. (2021)
c.1708_1709del p.Ser570PhefsTer27 frameshift_variant De novo - Simplex 25356899 Hamdan FF , et al. (2014)
c.1708_1709del p.Ser570PhefsTer27 frameshift_variant De novo - Simplex 31406558 Munnich A , et al. (2019)
CTGTGT>CT - frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1708_1709del p.Ser570PhefsTer27 frameshift_variant De novo - Simplex 25969726 Codina-Sol M , et al. (2015)
c.329G>A p.Trp110Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.5588_1G>A p.? splice_site_variant De novo (germline mosaicism) - Multiplex 28708303 Chrot E , et al. (2017)
c.1416_1419del p.Gln473LysfsTer11 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1690C>T p.Arg564Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.541_556delinsA p.Val181_His186delinsAsn inframe_indel De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.5695G>A p.Gly1899Arg missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.6005C>T p.Ser2002Leu missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4106del p.Gly1369GlufsTer19 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

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."

1/1/2021
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
7/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features.

Reports Added
[Report of a de novo c.2605C > T (p.Pro869Ser) change in the MED13L gene and review of the literature for MED13L-related intellectual disability2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
2S
icon
2S

Decreased from 2S to 2S

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features.

Reports Added
[Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders.2019] [Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019] [Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
4/1/2019
2S
icon
2S

Decreased from 2S to 2S

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features.

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
1/1/2019
2S
icon
2S

Decreased from 2S to 2S

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
7/1/2018
2
icon
2S

Decreased from 2 to 2S

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080). Phenotypic characterization of 66 individuals with MED13L-related intellectual disability in Smol et al., 2018 determined that autistic features were present in 28% (16/58) of this cohort. Phenotypic evaluation of eight individuals with de novo MED13L variants in Trring et al., 2018 demonstrated that two individuals were diagnosed with autism, while a third individual presented with autistic features.

Reports Added
[Is MED13L-related intellectual disability a recognizable syndrome?2018] [Clinical genome sequencing in an unbiased pediatric cohort.2018] [Diagnostic value of partial exome sequencing in developmental disorders.2018]
10/1/2017
2
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2

Decreased from 2 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

Reports Added
[High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017] [Exome Pool-Seq in neurodevelopmental disorders.2017]
7/1/2017
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

Reports Added
[Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation.2017] [Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
4/1/2017
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome.2015] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Redefining the MED13L syndrome.2015] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?2016] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [MED13L haploinsufficiency syndrome: A de novo frameshift and recurrent intragenic deletions due to parental mosaicism.2017] [De novo mutations in moderate or severe intellectual disability.2014] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
10/1/2016
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

Reports Added
[Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
7/1/2016
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?2016]
1/1/2016
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome.2015] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Redefining the MED13L syndrome.2015] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
4/1/2015
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

Reports Added
[Redefining the MED13L syndrome.2015] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015]
1/1/2015
3
icon
2

Decreased from 3 to 2

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in MED13L was identified in a patient from the Deciphering Developmental Disorders Study presenting with ASD and developmental delay (PMID 25533962). Variants in MED13L that result in haploinsufficiency are also associated with intellectual disability with or without congenital heart defects (PMIDs 23403903, 24781760, 25712080).

10/1/2014
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3

Increased from to 3

Description

Two de novo LoF variants in the MED13L gene (one splice-site, one nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Krishnan Probability Score

Score 0.57189423822695

Ranking 740/25841 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 0.99999999867715

Ranking 104/18225 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 0.998

Ranking 9/239 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 0.71654119428162

Ranking 1269/18665 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
Larsen Cumulative Evidence Score

Score 18

Ranking 112/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.59306800301297

Ranking 102/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
MED19 Mediator of RNA polymerase II transcription subunit 19 Human Protein Binding 219541 A0JLT2
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