Intellectual disability - microarray and sequencing
Gene: DCPS Green List (high evidence)Comment on list classification: Following advice from Genomics England Clinical Team DCPS will be classified as Green. Advice was "I agree the third case is borderline. Their development is not a clear problem, although they are relatively young and were noted to have hypotonia. This might be a consequence of them having biallelic missense variants and potentially therefore less severe... evidence for or against that might emerge in time.
It looks like there are 6 individuals (from 3 families) in the first two papers however, and they have a relevant phenotype for the ID panel. On that basis I would include it as green."Created: 24 Jun 2019, 9:37 a.m. | Last Modified: 24 Jun 2019, 9:37 a.m.
Panel Version: 0.192
Comment on list classification: Expert review by Konstantinos Varvagiannis on DCPS. Biallelic pathogenic DCPS variants cause Al-Raqad syndrome (OMIM 616459). 7 patients from 3 families have been reported to date, all summarised in PMID 30289615, most individuals belong to broader consanguineous families and have been previously described (PMIDs : 25712129, 25701870). The additional affected individual described in PMID 30289615 appears to exhibit different phenotypes, especially phenotypes associated with DD/ID.
Therefore unsure of rating due to patient three not exhibiting consistent phenotypes and the variant is missense, have currently requested advice from the clinical team.Created: 16 May 2019, 2:39 p.m.
Green List (high evidence)
Biallelic pathogenic DCPS variants cause Al-Raqad syndrome (OMIM 616459).
7 patients from 3 families have been reported to date, all summarized in PMID 30289615 (first reports on the disorder - PMIDs : 25712129, 25701870).
Most individuals belong to consanguineous families although a compound heterozygous patient belonging to a broader consanguineous family (in PMID 25701870) and a further individual was born to unrelated parents originating from the same region (in PMID 30289615) have been described.
Overall, 2 splice site and 2 missense variants have been reported. Functional studies were carried out and support pathogenicity of the variants in the first 2 studies.
Developmental delay and intellectual disability are universal features.
DCPS is included in gene panels for intellectual disability offered by different diagnostic labs.
As a result this gene can be considered for inclusion in this panel as green.
Sources: Expert Review, LiteratureCreated: 12 Nov 2018, 10:55 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Al-Raqad syndrome (OMIM 616459)
Publications
Variants in this GENE are reported as part of current diagnostic practice
Source Expert Review Green was added to DCPS. Added phenotypes Al-Raqad syndrome, 616459 for gene: DCPS Publications for gene DCPS were changed from 25712129; 25701870; 30289615 to 25701870; 30289615; 25712129 Rating Changed from No List (delete) to Green List (high evidence)
gene: DCPS was added gene: DCPS was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: DCPS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DCPS were set to 25712129; 25701870; 30289615 Phenotypes for gene: DCPS were set to Al-Raqad syndrome (OMIM 616459) Penetrance for gene: DCPS were set to Complete Review for gene: DCPS was set to GREEN gene: DCPS was marked as current diagnostic
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.