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Intellectual disability

Gene: DOCK3

Green List (high evidence)

DOCK3 (dedicator of cytokinesis 3)
EnsemblGeneIds (GRCh38): ENSG00000088538
EnsemblGeneIds (GRCh37): ENSG00000088538
OMIM: 603123, Gene2Phenotype
DOCK3 is in 1 panel

3 reviews

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Red to Green based on external reviews and curation. Zornitza notes two families in her 2018 review: two siblings from Helbig et al., 2017 (PMID:28195318) plus a boy from Iwata-Otsubo et al. (2018, PMID:29130632). Konstantinos' 2019 review includes an additional 2019 paper with 3 unrelated patients harbouring biallelic DOCK3 variants and global developmental delay. Therefore there are now sufficient cases (5 unrelated) for inclusion on the ID panel as Green.
Created: 25 May 2019, 10:33 a.m.
Helbig et al., 2017 (PMID:28195318) report 2 Ashkenazi and Yemeni Jewish siblings with severe developmental disability amongst phenotypes. WES of the siblings identified a heterozygous maternally-inherited c.382C>G (p.Gln128*) plus a paternally-inherited 458kb heterozygous deletion in 3p21.2 (which includes part of DOCK3).

PMID:30976111 (Wiltrout et al., 2019) report 3 unrelated patients with biallelic DOCK3-related global developmental delay (together with dysmorphic features in 2/3 cases).
Created: 25 May 2019, 10:11 a.m.
Helbig et al., 2017 (PMID:28195318) report 2 Ashkenazi and Yemeni Jewish siblings with severe developmental disability amongst phenotypes. WES of the siblings identified a heterozygous maternally-inherited c.382C>G (p.Gln128*) plus a paternally-inherited 458kb heterozygous deletion in 3p21.2 (which includes part of DOCK3).
Created: 25 May 2019, 10:05 a.m.

Konstantinos Varvagiannis (Other)

I don't know

Wiltrout et al. (2019 - PMID: 30976111) report on 3 additional unrelated individuals with biallelic DOCK3 variants and summarize the phenotype of 3 previously published subjects (Helbig et al. 2017 and Iwata-Otsubo et al. 2018, PMIDs : 28195318, 29130632). Overlapping features included hypotonia, DD, wide-based gait/ataxia.

Although ID has not been commented on for many individuals, attainment of motor and language milestones was severely delayed for some of them (as evident from table 1). Many had extensive prior workup for metabolic and genetic causes of DD/ID, incl. CMA, fragile X testing, Angelman syndrome methylation testing and UBE3A sequencing, MECP2, PTEN sequencing, etc.

Variants reported to date include (NM_004947.4 / NG_028012.1):
- Wiltrout et al. P1 : c.1038-2A>G or IVS12-2A>G in trans with c.3107-3110delACTT or p.(Tyr1036Leufs*8)
- Wiltrout et al. P2 : c.1175G>A p. (Arg392Gln) in trans with c.3887A>G: p.(Lys1296Arg)
- Wiltrout et al P3 : c.5020A>T: p.(Met1674Leu) in trans with c.5020A>T: p.(Met1674Leu)
- Helbig et al. (2 sibs) : c.382C>G:p.(Gln128*) in trans with a 458 kb intragenic DOCK3 deletion
- Iwata-Otsubo et al. : Homozygous intragenic 170 kb DOCK3 deletion (exons 6-12)
(Both aforementioned deletions did not span other genes)

The Arg392Gln variant has an AF of 0.001 among Europeans in gnomAD with 3 homozygous individuals of South Asian descent in the same database. (The variant was found in trans with another missense variant in one affected individual and was included in functional studies - details below).

As noted by Wiltrout et al.:
- DOCK3 encodes the dedicator of cytokinesis 3 protein, with expression specifically in the brain and spinal cord.
- DOCK3 has guanine nucleotide exchange factor activity (GEFs activate GTPases by exchanging bound GDP for free GTP).
- In Cos7 cells both DOCK3 wt and mutants (Arg392Gln, Lys1296Arg, Met1647Leu) induced Rac1 activation, though the level of activated Rac1 was significantly lower for the 3 mutants tested when compared to wt (P<0.05).
- In mice, Dock3 knockout resulted to somewhat similar features incl. ataxic gait, limb weakness and impairment in learning (article cited: Chen et al. 2009 - PMID: 19129390).

In OMIM, DOCK3 is associated with Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia (MIM 618292). The gene is not part of the DD panel in G2P. DOCK3 is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx among the co-authors of the current study).

All taken into account, this gene could be considered for upgrade following review by the Genomics England clinical team.
Created: 15 Apr 2019, 6:38 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292

Publications

Variants in this GENE are reported as part of current diagnostic practice

Zornitza Stark (Australian Genomics)

I don't know

Two families with biallelic variants in this gene reported, consider inclusion as Amber.
Created: 22 Jun 2018, 10:52 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292
OMIM
603123
Clinvar variants
Variants in DOCK3
Penetrance
None
Publications
Panels with this gene

History Filter Activity

25 May 2019, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: DOCK3 were set to 29130632, 28195318; 30976111

25 May 2019, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: DOCK3 were set to 29130632, 28195318

25 May 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: dock3 has been classified as Green List (High Evidence).

23 May 2019, Gel status: 1

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: DOCK3 were changed from to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292

28 Sep 2018, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to DOCK3.

22 Jun 2018, Gel status: 0

Added New Source

Zornitza Stark (Australian Genomics)

DOCK3 was added to Intellectual disability panel. Sources: Literature

22 Jun 2018, Gel status: 0

Created

Zornitza Stark (Australian Genomics)

DOCK3 was created by Zornitza Stark