Intellectual disability - microarray and sequencing
Gene: DOCK3 Green List (high evidence)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.
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
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
Phenotypes for gene: DOCK3 were changed from Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292 to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia OMIM:618292; neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia MONDO:0032661
Publications for gene: DOCK3 were set to 29130632, 28195318; 30976111
Publications for gene: DOCK3 were set to 29130632, 28195318
Gene: dock3 has been classified as Green List (High Evidence).
Phenotypes for gene: DOCK3 were changed from to Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, 618292
Source Victorian Clinical Genetics Services was added to DOCK3.
DOCK3 was added to Intellectual disability panel. Sources: Literature
DOCK3 was created by Zornitza Stark
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.