Human Gene Module / Chromosome 9 / DOCK8

DOCK8dedicator of cytokinesis 8

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
22 / 0
Aliases
DOCK8, HEL-205,  MRD2,  ZIR8
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
9p24.3
Associated Disorders
ASD, DD/NDD
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.

Reports related to DOCK8 (8 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 -
Rare Variants   (22)
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)
- - copy_number_gain Unknown - - 29191242 Glessner JT , et al. (2017)
- - copy_number_gain De novo - Simplex 29930340 Krgovic D , et al. (2018)
- - copy_number_gain Unknown Not maternal - 29930340 Krgovic D , et al. (2018)
c.1312+2T>C p.? splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
5985+T 1995-! frameshift_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.5288G>A p.Arg1763Gln missense_variant Unknown - Simplex 30564305 Guo H , et al. (2018)
c.670G>A p.Asp292Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.979G>C p.Gly395Arg 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.Arg1486His missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.4531G>C p.Val1611Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.4558C>G p.Pro1620Ala missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
- - copy_number_loss Familial Maternal Multi-generational 29930340 Krgovic D , et al. (2018)
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.Ala362ArgfsTer10 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.5348_5351del p.Tyr1883LeufsTer36 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

3

Score Delta: Score remained at 3.3

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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.
ExAC Score

Score 0.00013543398043996

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
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).
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.
CNVs associated with DOCK8(1 CNVs)
9p24.3 29 Deletion-Duplication 47  /  273
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