Human Gene Module / Chromosome 13 / CDK8

CDK8cyclin dependent kinase 8

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 5
Rare Variants / Common Variants
17 / 0
Aliases
CDK8, K35
Associated Syndromes
-
Chromosome Band
13q12.13
Associated Disorders
DD/NDD, ADHD, ID, EPS, ASD
Relevance to Autism

Calpena et al., 2019 reported eight different heterozygous missense variants in the CDK8 gene in twelve unrelated subjects presenting with a syndromic developmental disorder characterized by overlapping phenotypes including hypotonia, intellectual disability, behavioral disorders, variable facial dysmorphism, and congenital heart disease; seven of ten of the older individuals in this cohort had formal diagnoses of autism spectrum disorder and/or ADHD.

Molecular Function

This gene encodes a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are known to be important regulators of cell cycle progression. This kinase and its regulatory subunit, cyclin C, are components of the Mediator transcriptional regulatory complex, involved in both transcriptional activation and repression by phosphorylation of the carboxy-terminal domain of the largest subunit of RNA polymerase II. This kinase regulates transcription by targeting the cyclin-dependent kinase 7 subunits of the general transcription initiation factor IIH, thus providing a link between the Mediator complex and the basal transcription machinery.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CDK8 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder Calpena E , et al. (2019) No ASD, ADHD
2 Support Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants Uehara T et al. (2020) No -
3 Support - Miyamoto S et al. (2021) No DD, ID, epilepsy/seizures
4 Support - Zhou X et al. (2022) Yes -
5 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.83G>C p.Gly28Ala missense_variant De novo - - 33067521 Uehara T et al. (2020)
c.467A>G p.Asn156Ser missense_variant De novo - - 33067521 Uehara T et al. (2020)
c.185C>T p.Ser62Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.697A>G p.Ile233Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1178G>A p.Ser393Asn missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.79G>C p.Val27Leu missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.85C>G p.Arg29Gly missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.88G>A p.Gly30Ser missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.185C>T p.Ser62Leu missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.291T>G p.Phe97Leu missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.185C>T p.Ser62Leu missense_variant De novo - Simplex 33958710 Miyamoto S et al. (2021)
c.533G>A p.Arg178Gln missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.563C>T p.Ala188Val missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.578T>G p.Val193Gly missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.669A>G p.Ile223Met missense_variant De novo - Simplex 30905399 Calpena E , et al. (2019)
c.563C>T p.Ala188Val missense_variant Unknown - Multi-generational 30905399 Calpena E , et al. (2019)
c.563C>T p.Ala188Val missense_variant Unknown Not maternal Multi-generational 30905399 Calpena E , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Calpena et al., 2019 reported eight different heterozygous missense variants in the CDK8 gene in twelve unrelated subjects presenting with a syndromic developmental disorder characterized by overlapping phenotypes including hypotonia, intellectual disability, behavioral disorders, variable facial dysmorphism, and congenital heart disease; seven of ten of the older individuals in this cohort had formal diagnoses of autism spectrum disorder and/or ADHD.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

4/1/2021
S
icon
S

Score remained at S

Description

Calpena et al., 2019 reported eight different heterozygous missense variants in the CDK8 gene in twelve unrelated subjects presenting with a syndromic developmental disorder characterized by overlapping phenotypes including hypotonia, intellectual disability, behavioral disorders, variable facial dysmorphism, and congenital heart disease; seven of ten of the older individuals in this cohort had formal diagnoses of autism spectrum disorder and/or ADHD.

Reports Added
[Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies2021]
10/1/2020
S
icon
S

Score remained at S

Description

Calpena et al., 2019 reported eight different heterozygous missense variants in the CDK8 gene in twelve unrelated subjects presenting with a syndromic developmental disorder characterized by overlapping phenotypes including hypotonia, intellectual disability, behavioral disorders, variable facial dysmorphism, and congenital heart disease; seven of ten of the older individuals in this cohort had formal diagnoses of autism spectrum disorder and/or ADHD.

Reports Added
[Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Calpena et al., 2019 reported eight different heterozygous missense variants in the CDK8 gene in twelve unrelated subjects presenting with a syndromic developmental disorder characterized by overlapping phenotypes including hypotonia, intellectual disability, behavioral disorders, variable facial dysmorphism, and congenital heart disease; seven of ten of the older individuals in this cohort had formal diagnoses of autism spectrum disorder and/or ADHD.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.41779730755763

Ranking 21243/25841 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 0.94665334902217

Ranking 2740/18225 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
Sanders TADA Score

Score 0.84012683917028

Ranking 3137/18665 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 -0.10092909768864

Ranking 12385/20870 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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