Human Gene Module / Chromosome 9 / DOCK8

DOCK8dedicator of cytokinesis 8

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 12
Rare Variants / Common Variants
30 / 0
Aliases
DOCK8, HEL-205,  MRD2,  ZIR8
Associated Syndromes
-
Chromosome Band
9p24.3
Associated Disorders
DD/NDD, ADHD, ASD
Relevance to Autism

A total of two de novo loss-of-function variants in the DOCK8 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Autism Clinical and Genetic Resources in China (ACGC) cohort (De Rubeis et al., 2014; Wang et al., 2016). The 9p24.3 locus, which contains the DOCK8 gene, overlaps with linkage regions identified in large autism extended pedigrees (Allen-Brady et al., 2009; Coon et al., 2010). Two unrelated patients with intellectual disability and additional phenotypes were found to carry heterozygous disruptions of the DOCK8 gene (one by deletion, the another by translocation breakpoint) in Griggs et al., 2008.

Molecular Function

This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DOCK8 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities Griggs BL , et al. (2007) No -
2 Support A high-density SNP genome-wide linkage scan in a large autism extended pedigree Allen-Brady K , et al. (2008) Yes -
3 Support Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees Coon H , et al. (2010) Yes -
4 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
5 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
6 Recent Recommendation Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multiple neurodevelopmental disorders Glessner JT , et al. (2017) Yes -
7 Support Rare structural variants in the DOCK8 gene identified in a cohort of 439 patients with neurodevelopmental disorders Krgovic D , et al. (2018) No ASD, MDD
8 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
9 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
10 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
11 Support - Capkova Z et al. (2021) Yes ADHD
12 Support - Zhou X et al. (2022) Yes -
Rare Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 18060736 Griggs BL , et al. (2007)
- - copy_number_loss Unknown - - 18060736 Griggs BL , et al. (2007)
- - intron_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_gain Unknown - - 29191242 Glessner JT , et al. (2017)
- - copy_number_gain Unknown - Simplex 33455084 Capkova Z et al. (2021)
- - copy_number_gain De novo - Simplex 29930340 Krgovic D , et al. (2018)
c.1312+2T>C - splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
- - copy_number_gain Unknown Not maternal - 29930340 Krgovic D , et al. (2018)
c.1593+48C>G - missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1594-1G>C - splice_site_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1594C>T p.Pro532Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Paternal Multiplex 33455084 Capkova Z et al. (2021)
- - copy_number_loss Familial Maternal Multiplex 29930340 Krgovic D , et al. (2018)
c.5535T>C p.Ile1845%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5288G>A p.Arg1763Gln missense_variant Unknown - Simplex 30564305 Guo H , et al. (2018)
c.670G>A p.Asp224Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.979G>C p.Gly327Arg missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.3043C>T p.Arg1015Cys missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.4157G>A p.Arg1386His missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.4531G>C p.Val1511Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.4558C>G p.Pro1520Ala missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.860A>G p.Gln287Arg missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5690dup p.Leu1897PhefsTer3 frameshift_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3023G>A p.Arg1008Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.3032G>A p.Arg1011His missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.3194G>A p.Arg1065Gln missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.3307C>A p.His1103Asn missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.5288G>A p.Arg1763Gln missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.879_880del p.Lys294ArgfsTer12 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.5348_5351del p.Val1783AlafsTer46 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A total of two de novo loss-of-function variants in the DOCK8 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Autism Clinical and Genetic Resources in China (ACGC) cohort (De Rubeis et al., 2014; Wang et al., 2016). The 9p24.3 locus, which contains the DOCK8 gene, overlaps with linkage regions identified in large autism extended pedigrees (Allen-Brady et al., 2009; Coon et al., 2010). Two unrelated patients with intellectual disability and additional phenotypes were found to carry heterozygous disruptions of the DOCK8 gene (one by deletion, the another by translocation breakpoint) in Griggs et al., 2008. A copy number variant meta-analysis using 7849 cases and 10.799 controls from five cohorts with multiple neurodevelopmental and neuropsychiatric disorders, including an ASD case-control cohort from the Childrens Hospital of Philadelphia (CHOP) identified the DOCK8 gene as reaching genome-wide significance for duplications (P value of 7.50E-07); DOCK8 duplications were also statistically enriched in ASD cases from the CHOP cohort compared to controls (7 duplications in cases vs. none in controls, P value of 0.00384).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

1/1/2021
2
icon
2

Score remained at 2

Description

A total of two de novo loss-of-function variants in the DOCK8 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Autism Clinical and Genetic Resources in China (ACGC) cohort (De Rubeis et al., 2014; Wang et al., 2016). The 9p24.3 locus, which contains the DOCK8 gene, overlaps with linkage regions identified in large autism extended pedigrees (Allen-Brady et al., 2009; Coon et al., 2010). Two unrelated patients with intellectual disability and additional phenotypes were found to carry heterozygous disruptions of the DOCK8 gene (one by deletion, the another by translocation breakpoint) in Griggs et al., 2008. A copy number variant meta-analysis using 7849 cases and 10.799 controls from five cohorts with multiple neurodevelopmental and neuropsychiatric disorders, including an ASD case-control cohort from the Childrens Hospital of Philadelphia (CHOP) identified the DOCK8 gene as reaching genome-wide significance for duplications (P value of 7.50E-07); DOCK8 duplications were also statistically enriched in ASD cases from the CHOP cohort compared to controls (7 duplications in cases vs. none in controls, P value of 0.00384).

Reports Added
[Duplication of 9p24.3 in three unrelated patients and their phenotypes, considering affected genes, and similar recurrent variants2021]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A total of two de novo loss-of-function variants in the DOCK8 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Autism Clinical and Genetic Resources in China (ACGC) cohort (De Rubeis et al., 2014; Wang et al., 2016). The 9p24.3 locus, which contains the DOCK8 gene, overlaps with linkage regions identified in large autism extended pedigrees (Allen-Brady et al., 2009; Coon et al., 2010). Two unrelated patients with intellectual disability and additional phenotypes were found to carry heterozygous disruptions of the DOCK8 gene (one by deletion, the another by translocation breakpoint) in Griggs et al., 2008. A copy number variant meta-analysis using 7849 cases and 10.799 controls from five cohorts with multiple neurodevelopmental and neuropsychiatric disorders, including an ASD case-control cohort from the Childrens Hospital of Philadelphia (CHOP) identified the DOCK8 gene as reaching genome-wide significance for duplications (P value of 7.50E-07); DOCK8 duplications were also statistically enriched in ASD cases from the CHOP cohort compared to controls (7 duplications in cases vs. none in controls, P value of 0.00384).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A total of two de novo loss-of-function variants in the DOCK8 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Autism Clinical and Genetic Resources in China (ACGC) cohort (De Rubeis et al., 2014; Wang et al., 2016). The 9p24.3 locus, which contains the DOCK8 gene, overlaps with linkage regions identified in large autism extended pedigrees (Allen-Brady et al., 2009; Coon et al., 2010). Two unrelated patients with intellectual disability and additional phenotypes were found to carry heterozygous disruptions of the DOCK8 gene (one by deletion, the another by translocation breakpoint) in Griggs et al., 2008. A copy number variant meta-analysis using 7849 cases and 10.799 controls from five cohorts with multiple neurodevelopmental and neuropsychiatric disorders, including an ASD case-control cohort from the Childrens Hospital of Philadelphia (CHOP) identified the DOCK8 gene as reaching genome-wide significance for duplications (P value of 7.50E-07); DOCK8 duplications were also statistically enriched in ASD cases from the CHOP cohort compared to controls (7 duplications in cases vs. none in controls, P value of 0.00384).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

A total of two de novo loss-of-function variants in the DOCK8 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Autism Clinical and Genetic Resources in China (ACGC) cohort (De Rubeis et al., 2014; Wang et al., 2016). The 9p24.3 locus, which contains the DOCK8 gene, overlaps with linkage regions identified in large autism extended pedigrees (Allen-Brady et al., 2009; Coon et al., 2010). Two unrelated patients with intellectual disability and additional phenotypes were found to carry heterozygous disruptions of the DOCK8 gene (one by deletion, the another by translocation breakpoint) in Griggs et al., 2008. A copy number variant meta-analysis using 7849 cases and 10.799 controls from five cohorts with multiple neurodevelopmental and neuropsychiatric disorders, including an ASD case-control cohort from the Childrens Hospital of Philadelphia (CHOP) identified the DOCK8 gene as reaching genome-wide significance for duplications (P value of 7.50E-07); DOCK8 duplications were also statistically enriched in ASD cases from the CHOP cohort compared to controls (7 duplications in cases vs. none in controls, P value of 0.00384).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
7/1/2018
3
icon
3

Decreased from 3 to 3

Description

A total of two de novo loss-of-function variants in the DOCK8 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Autism Clinical and Genetic Resources in China (ACGC) cohort (De Rubeis et al., 2014; Wang et al., 2016). The 9p24.3 locus, which contains the DOCK8 gene, overlaps with linkage regions identified in large autism extended pedigrees (Allen-Brady et al., 2009; Coon et al., 2010). Two unrelated patients with intellectual disability and additional phenotypes were found to carry heterozygous disruptions of the DOCK8 gene (one by deletion, the another by translocation breakpoint) in Griggs et al., 2008. A copy number variant meta-analysis using 7849 cases and 10.799 controls from five cohorts with multiple neurodevelopmental and neuropsychiatric disorders, including an ASD case-control cohort from the Childrens Hospital of Philadelphia (CHOP) identified the DOCK8 gene as reaching genome-wide significance for duplications (P value of 7.50E-07); DOCK8 duplications were also statistically enriched in ASD cases from the CHOP cohort compared to controls (7 duplications in cases vs. none in controls, P value of 0.00384).

Reports Added
[Rare structural variants in the DOCK8 gene identified in a cohort of 439 patients with neurodevelopmental disorders.2018]
10/1/2016
icon
3

Increased from to 3

Description

A total of two de novo loss-of-function variants in the DOCK8 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Autism Clinical and Genetic Resources in China (ACGC) cohort (De Rubeis et al., 2014; Wang et al., 2016). The 9p24.3 locus, which contains the DOCK8 gene, overlaps with linkage regions identified in large autism extended pedigrees (Allen-Brady et al., 2009; Coon et al., 2010). Two unrelated patients with intellectual disability and additional phenotypes were found to carry heterozygous disruptions of the DOCK8 gene (one by deletion, the another by translocation breakpoint) in Griggs et al., 2008.

Krishnan Probability Score

Score 0.44721854051334

Ranking 13726/25841 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 0.0001354339804399

Ranking 12929/18225 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 0.85402063590059

Ranking 3610/18665 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 -0.065531593254363

Ranking 11002/20870 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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