Human Gene Module / Chromosome 7 / DOCK4

DOCK4Dedicator of cytokinesis 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 11
Rare Variants / Common Variants
9 / 4
Aliases
DOCK4, WUGSC:H_GS034D21.1
Associated Syndromes
-
Chromosome Band
7q31.1
Associated Disorders
ASD
Relevance to Autism

Assocation between the DOCK4 gene and ASD has been observed in two studies (Maestrini et al., 2010; Liang et al., 2014). Deletions involving the DOCK4 gene has also been implicated in ASD and dyslexia (Maestrini et al., 2010; Pagnamenta et al., 2010).

Molecular Function

Involved in regulation of adherens junction between cells. Plays a role in cell migration. Functions as a guanine nucleotide exchange factor (GEF), which activates Rap1 small GTPase by exchanging bound GDP for free GTP.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DOCK4 (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility Maestrini E , et al. (2009) Yes -
2 Support Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia Pagnamenta AT , et al. (2010) No -
3 Recent Recommendation Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation Ueda S , et al. (2013) No -
4 Recent Recommendation The atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics Xiao Y , et al. (2013) No -
5 Positive Association Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population Liang S , et al. (2014) Yes -
6 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
7 Positive Association A Pooled Genome-Wide Association Study of Asperger Syndrome Warrier V , et al. (2015) Yes Asperger syndrome
8 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
9 Support Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function Guo D , et al. (2019) No -
10 Support - Guo D et al. (2022) Yes -
11 Support - Zhou X et al. (2022) Yes -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.832A>G p.Ile278Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4832A>G p.His1611Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3477A>G p.Ser1159%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Paternal Multiplex 19401682 Maestrini E , et al. (2009)
- - copy_number_loss Familial Maternal Multiplex 19401682 Maestrini E , et al. (2009)
c.1442G>A p.Arg481Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4962A>G p.Val1654= synonymous_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.4250G>A p.Arg1417His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
G>A p.Met1Ile initiator_codon_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.38-88385G>C - intron_variant - - - 26176695 Warrier V , et al. (2015)
c.37+49780T>G A/C intron_variant - - - 24599690 Liang S , et al. (2014)
c.37+49780T>G Risk allele, A intron_variant - - - 19401682 Maestrini E , et al. (2009)
c.37+49780T>G A/C; risk allele, A intron_variant - - - 19401682 Maestrini E , et al. (2009)
SFARI Gene score
2

Strong Candidate

Assocation between an intronic SNP in the DOCK4 gene (rs2217262) and ASD has been observed in two independent cohorts (Maestrini et al., 2010; Liang et al., 2014). An intronic SNP in the DOCK4 gene (rs7785891) showed nominally significant association with Asperger syndrome after individual gentoyping following its identification using pooled DNA analysis, although it did not remain significant after Bonferroni correction (Warrier et al., 2015). Deletions involving the DOCK4 gene have also been implicated in ASD and dyslexia (Maestrini et al., 2010; Pagnamenta et al., 2010). Guo et al., 2019 found that Dock4 knockout (KO) mice displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning, and that mice with conditional deletion of Dock4 in hippocampal CA1 neurons recapitulated the social preference deficit observed in KO mice. Furthermore, the authors observed that Rac1 replenishment in hippocampal CA1 neurons of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice.

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Assocation between an intronic SNP in the DOCK4 gene (rs2217262) and ASD has been observed in two independent cohorts (Maestrini et al., 2010; Liang et al., 2014). An intronic SNP in the DOCK4 gene (rs7785891) showed nominally significant association with Asperger syndrome after individual gentoyping following its identification using pooled DNA analysis, although it did not remain significant after Bonferroni correction (Warrier et al., 2015). Deletions involving the DOCK4 gene have also been implicated in ASD and dyslexia (Maestrini et al., 2010; Pagnamenta et al., 2010). Guo et al., 2019 found that Dock4 knockout (KO) mice displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning, and that mice with conditional deletion of Dock4 in hippocampal CA1 neurons recapitulated the social preference deficit observed in KO mice. Furthermore, the authors observed that Rac1 replenishment in hippocampal CA1 neurons of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Assocation between an intronic SNP in the DOCK4 gene (rs2217262) and ASD has been observed in two independent cohorts (Maestrini et al., 2010; Liang et al., 2014). An intronic SNP in the DOCK4 gene (rs7785891) showed nominally significant association with Asperger syndrome after individual gentoyping following its identification using pooled DNA analysis, although it did not remain significant after Bonferroni correction (Warrier et al., 2015). Deletions involving the DOCK4 gene have also been implicated in ASD and dyslexia (Maestrini et al., 2010; Pagnamenta et al., 2010). Guo et al., 2019 found that Dock4 knockout (KO) mice displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning, and that mice with conditional deletion of Dock4 in hippocampal CA1 neurons recapitulated the social preference deficit observed in KO mice. Furthermore, the authors observed that Rac1 replenishment in hippocampal CA1 neurons of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Assocation between an intronic SNP in the DOCK4 gene (rs2217262) and ASD has been observed in two independent cohorts (Maestrini et al., 2010; Liang et al., 2014). An intronic SNP in the DOCK4 gene (rs7785891) showed nominally significant association with Asperger syndrome after individual gentoyping following its identification using pooled DNA analysis, although it did not remain significant after Bonferroni correction (Warrier et al., 2015). Deletions involving the DOCK4 gene have also been implicated in ASD and dyslexia (Maestrini et al., 2010; Pagnamenta et al., 2010). Guo et al., 2019 found that Dock4 knockout (KO) mice displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning, and that mice with conditional deletion of Dock4 in hippocampal CA1 neurons recapitulated the social preference deficit observed in KO mice. Furthermore, the authors observed that Rac1 replenishment in hippocampal CA1 neurons of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice.

Reports Added
[Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function.2019]
7/1/2018
icon
4

Increased from to 4

Description

Assocation between an intronic SNP in the DOCK4 gene (rs2217262) and ASD has been observed in two independent cohorts (Maestrini et al., 2010; Liang et al., 2014). An intronic SNP in the DOCK4 gene (rs7785891) showed nominally significant association with Asperger syndrome after individual gentoyping following its identification using pooled DNA analysis, although it did not remain significant after Bonferroni correction (Warrier et al., 2015). Deletions involving the DOCK4 gene have also been implicated in ASD and dyslexia (Maestrini et al., 2010; Pagnamenta et al., 2010).

Krishnan Probability Score

Score 0.50092370181085

Ranking 2053/25841 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 0.99853573271734

Ranking 1176/18225 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 0.94909710303697

Ranking 17952/18665 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 10

Ranking 183/461 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 0.47822352473568

Ranking 675/20870 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
ARRB1 arrestin, beta 1 Human Protein Binding 408 P49407
DOCK9 dedicator of cytokinesis 9 Human Protein Binding 23348 Q9BZ29
ELMO1 engulfment and cell motility 1 Human Protein Binding 9844 Q92556
ELMO3 Engulfment and cell motility protein 3 Human Protein Binding 79767 Q96BJ8-2
ERMAP Erythroid membrane-associated protein Human Protein Binding 114625 Q96PL5
VSIG8 V-set and immunoglobulin domain-containing protein 8 Human Protein Binding 284677 Q5VU13
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