Human Gene Module / Chromosome 12 / MED13L

MED13LMediator complex subunit 13-like

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
15 / 34
Rare Variants / Common Variants
84 / 0
Aliases
MED13L, PROSIT240,  THRAP2,  TRAP240L
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
12q24.21
Associated Disorders
DD/NDD, EPS, ID, ASD, EP
Relevance to Autism

Two de novo loss-of-function variants in the MED13L gene have been identified in ASD probands from the Simons Simplex Collection (refs).

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].

Reports related to MED13L (34 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 two 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
Rare Variants   (84)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 29511999 Smol T , et al. (2018)
- - copy_number_loss De novo NA - 29959045 Trring PM , et al. (2018)
- - copy_number_gain De novo NA - 25758992 Adegbola A , et al. (2015)
- - copy_number_loss De novo NA - 25758992 Adegbola A , et al. (2015)
G>CT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
- - copy_number_gain Familial Maternal - 25758992 Adegbola A , et al. (2015)
c.173T>A p.Leu58Ter stop_gained De novo NA - 29511999 Smol T , et al. (2018)
c.2065C>T p.Gln689Ter stop_gained Unknown - - 29511999 Smol T , et al. (2018)
c.1009+1G>C - splice_site_variant De novo NA - 29511999 Smol T , et al. (2018)
c.2345-3C>G - splice_site_variant De novo NA - 29511999 Smol T , et al. (2018)
c.6225+1G>A - splice_site_variant De novo NA - 29511999 Smol T , et al. (2018)
c.5173C>T p.Gln1725Ter stop_gained De novo NA - 29158550 Popp B , et al. (2017)
c.5281C>T p.Pro1761Ser stop_gained De novo NA - 29511999 Smol T , et al. (2018)
c.5764C>T p.Gln1922Ter stop_gained De novo NA - 29511999 Smol T , et al. (2018)
c.2071C>T p.Gln691Ter stop_gained De novo NA - 29959045 Trring PM , et al. (2018)
c.6488C>T p.Ser2163Leu missense_variant Unknown - - 29511999 Smol T , et al. (2018)
c.5684G>A p.Arg1895Lys stop_gained De novo NA - 29959045 Trring PM , et al. (2018)
c.2600C>T p.Thr867Ile missense_variant De novo NA - 29511999 Smol T , et al. (2018)
c.2605C>T p.Pro869Ser missense_variant De novo NA - 29511999 Smol T , et al. (2018)
c.2930C>T p.Ala977Val missense_variant De novo NA - 29511999 Smol T , et al. (2018)
- - copy_number_loss Familial Maternal Multiplex 28371282 Yamamoto T , et al. (2017)
c.2344G>T p.Asp782Tyr stop_gained De novo NA - 28191889 Stessman HA , et al. (2017)
c.6008C>T p.Ser2003Leu missense_variant De novo NA - 29511999 Smol T , et al. (2018)
c.6488C>T p.Ser2163Leu missense_variant De novo NA - 29511999 Smol T , et al. (2018)
c.6530C>A p.Ser2177Tyr missense_variant De novo NA - 29511999 Smol T , et al. (2018)
c.5861_5890+1del - frameshift_variant De novo NA - 29959045 Trring PM , et al. (2018)
c.2524C>T p.Arg842Ter stop_gained De novo NA - 27500536 Caro-Llopis A , et al. (2016)
c.5588+1G>A - splice_site_variant De novo NA Multiplex 29511999 Smol T , et al. (2018)
c.2605C>T p.Pro869Ser missense_variant De novo NA Simplex 32646507 Yi Z et al. (2020)
c.3392G>A p.Cys1131Tyr missense_variant De novo NA - 29959045 Trring PM , et al. (2018)
c.5852T>C p.Val1951Ala missense_variant De novo NA - 30091983 Gieldon L , et al. (2018)
c.2722A>G p.Thr908Ala missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.6485C>T p.Thr2162Met missense_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.5614C>T p.Arg1872Cys missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.5364+1dup - splice_site_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.2594T>A p.Phe865Tyr missense_variant De novo NA - 30008475 Thiffault I , et al. (2018)
c.4076G>A p.Trp1359Ter stop_gained De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.4420A>T p.Lys1474Ter stop_gained De novo NA Simplex 25712080 Cafiero C , et al. (2015)
c.3392G>A p.Cys1131Tyr missense_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.1152dup p.Ile385HisfsTer18 frameshift_variant Unknown - - 29511999 Smol T , et al. (2018)
c.2117G>A p.Gly706Glu missense_variant De novo NA - 31209962 Aspromonte MC , et al. (2019)
c.6260del p.Pro2087GlnfsTer4 frameshift_variant De novo NA - 31178897 Gao C , et al. (2019)
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.2399dup p.Thr801AsnfsTer9 frameshift_variant De novo NA - 29158550 Popp B , et al. (2017)
c.1903dup p.Ser635LysfsTer8 frameshift_variant De novo NA - 29511999 Smol T , et al. (2018)
c.5695G>A p.Gly1899Arg missense_variant De novo NA - 27500536 Caro-Llopis A , et al. (2016)
c.5364+1G>T - splice_site_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.2928G>A p.Trp976Ter stop_gained De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.4456del p.Gln1486SerfsTer25 frameshift_variant De novo NA - 29511999 Smol T , et al. (2018)
c.6289dup p.Leu2097ProfsTer11 frameshift_variant De novo NA - 29511999 Smol T , et al. (2018)
c.6280C>T p.Pro2094Ser missense_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.1718C>T p.Pro573Leu missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.257del p.Phe86SerfsTer9 frameshift_variant De novo NA - 28371282 Yamamoto T , et al. (2017)
c.830_845del p.Arg277GlnfsTer5 frameshift_variant De novo NA - 29511999 Smol T , et al. (2018)
c.124dup p.Asp42GlyfsTer13 frameshift_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.3914_3915del p.His1305LeufsTer59 frameshift_variant Unknown - - 29511999 Smol T , et al. (2018)
c.6277dup p.Gln2093ProfsTer15 frameshift_variant De novo NA - 29959045 Trring PM , et al. (2018)
c.2579A>G p.Asp860Gly missense_variant De novo NA Simplex 28645799 Asadollahi R , et al. (2017)
c.2395_2396del p.Gln799GlyfsTer10 frameshift_variant De novo NA - 27824329 Wang T , et al. (2016)
c.1708_1709del p.Ser570PhefsTer27 frameshift_variant De novo NA - 29511999 Smol T , et al. (2018)
c.2340_2343del p.Thr781MetfsTer19 frameshift_variant De novo NA - 29511999 Smol T , et al. (2018)
c.6611A>G p.Asn2204Ser missense_variant Unknown - Multiplex 31038196 Callaghan DB , et al. (2019)
c.3719dup p.Asn1241GlufsTer9 frameshift_variant De novo NA Simplex 30564305 Guo H , et al. (2018)
c.3945_3946del p.Ile1315MetfsTer49 frameshift_variant De novo NA - 29511999 Smol T , et al. (2018)
c.5156_5157del p.Arg1719LysfsTer20 frameshift_variant De novo NA - 29511999 Smol T , et al. (2018)
c.3942_3943del p.Ile1315GlnfsTer49 frameshift_variant De novo NA - 31231135 Bruel AL , et al. (2019)
c.3279delinsAA p.Asn1093LysfsTer32 frameshift_variant De novo NA - 30091983 Gieldon L , et al. (2018)
c.607dup p.Ser203PhefsTer32 frameshift_variant De novo NA Simplex 25712080 Cafiero C , et al. (2015)
c.3765del p.Cys1256ValfsTer2 frameshift_variant De novo NA Simplex 25712080 Cafiero C , et al. (2015)
c.5949_5950del p.Gln1984AlafsTer31 frameshift_variant De novo NA - 25758992 Adegbola A , et al. (2015)
c.2504del p.Pro835LeufsTer46 frameshift_variant De novo NA Simplex 28645799 Asadollahi R , et al. (2017)
c.6118_6125del p.Gly2040AsnfsTer32 frameshift_variant De novo NA Simplex 25167861 Redin C , et al. (2014)
c.1708_1709del p.Ser570PhefsTer27 frameshift_variant De novo NA Simplex 25356899 Hamdan FF , et al. (2014)
c.1708_1709del p.Ser570PhefsTer27 frameshift_variant De novo NA Simplex 31406558 Munnich A , et al. (2019)
CTGTGT>CT - frameshift_variant De novo NA 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.1708_1709del p.Ser570PhefsTer27 frameshift_variant De novo NA Simplex 25969726 Codina-Sol M , et al. (2015)
c.329G>A p.Trp110Ter stop_gained De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1416_1419del p.Gln473LysfsTer11 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1690C>T p.Arg564Ter stop_gained De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.5695G>A p.Gly1899Arg missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.6005C>T p.Ser2002Leu missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4106del p.Gly1369GlufsTer19 frameshift_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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.

Score Delta: Score remained at 2S

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.

7/1/2020
2S
icon
2S

Score remained at 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.

1/1/2020
2S
icon
2S

Score remained at 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.

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.

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.

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.

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.

7/1/2018
2.1 + S
icon
2S

Decreased from 2.1 + S 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.

10/1/2017
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).

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).

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).

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).

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).

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).

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).

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
icon
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.
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
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
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).
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.
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.
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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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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