Intellectual disability - microarray and sequencing
Gene: DOCK6 Green List (high evidence)Green List (high evidence)
Changed from Amber to Green. Appropriate phenotype, sufficient cases, external review comment and internal clinical review all support gene-disease association.Created: 21 Feb 2019, 3:59 p.m.
Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases, external review comment and internal clinical review all support gene-disease association.Created: 21 Feb 2019, 3:57 p.m.
Green List (high evidence)
PMID: 25824905 is a report on 10 unrelated individuals with DOCK6-related Adams-Oliver syndrome with review of 5 further patients published until 2015. As the authors comment, developmental delay or intellectual disability ranging from mild to severe was a feature in all patients for whom sufficient information could be obtained (also summarized in table 1).
PMID: 27077170 is a review on Adams-Oliver syndrome. The authors cite the previous article and further note that severe intellectual and neurologic impairments appear to be consistent findings in Adams-Oliver syndrome due to biallelic DOCK6 mutations.
Loss-of-function variants appear to cause the disorder (all the following have been reported : nonsense, frameshift, splice site, deletions).
DOCK6 is included in gene panels for intellectual disability offered by different diagnostic laboratories.
As a result, this gene can possibly be considered for upgrade to green.Created: 30 Nov 2018, 9:15 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment when marking as ready: Marked it as green as ID and neurologic impairments appear to be consistent findings in DOCK6-AOS, with findings in keeping with disturbed intracranial vasculogenesis (PMID:25824905 )Created: 20 Nov 2017, 12:48 p.m.
I don't know
Probable DD gene for Adams-Oliver syndrome 2 in Gene2Phenotype and attached with the 'Global developmental delay' HPO term. Eighth patient reported in PMID 25091416, and discuss an unexpected high frequency of likely detrimental variants in this gene in allele frequency database. Two cases reported in PMID 21820096 with DOCK6 homozygous truncating mutations, however only one case displayed severe global developmental delay, whereas the other unrelated case had appropriate development except speech delay.Created: 27 Oct 2017, 2:46 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Adams-Oliver syndrome 2 614219
Publications
Gene: dock6 has been classified as Green List (High Evidence).
Phenotypes for gene: DOCK6 were changed from Adams-Oliver syndrome 2 614219 to Adams-Oliver syndrome 2, 614219; intellectual disability, developmental delay
Tag watchlist was removed from gene: DOCK6.
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
DOCK6 was added to Intellectual disability panel. Sources: Expert Review Amber
DOCK6 was created by Ellen McDonagh
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.