Intellectual disability - microarray and sequencing
Gene: DONSON Amber List (moderate evidence)I don't know
Following advice from Genomics England Clinical Team DONSON will be classified as Amber. Advice was "ID is not present in all and where it is, it is reported as mild. I therefore do not think ID is likely to be the presenting feature here on the current evidence. I think the microcephaly route is more likely to pick up these families. I would rate as amber and upgrade if new evidence of more significant, or a consistent pattern, of DD/ID emerges."Created: 24 Jun 2019, 9:12 a.m. | Last Modified: 24 Jun 2019, 9:12 a.m.
Panel Version: 0.188
Comment on list classification: Expert review by Konstantinos Varvagiannis on DONSON. At least 7 variants identified in 29 individuals from 21 families from various populations in PMIDs:28191891 and 28630177.
The most prevalent phenotype for mutations in DONSON is microcephalic dwarfism, however the features described in the table is broad as several individuals have height within the normal percentiles. Similarly, DD and more specifically ID has been observed in some patients (when it happened to be the case it was most commonly mild). No data for ID/DD was provided for 4 of the individuals and normal development was reported for 6 individuals from 4 families.
This is a borderline case as there is conflicting phenotype evidence within the variants. Therefore rating as amber and requesting feedback from clinical team.Created: 20 May 2019, 11 a.m.
I don't know
It seems that the phenotypes related to DONSON biallelic mutations (PMIDs: 28630177, 28191891) can be extremely variable with pre-/perinatally lethal cases to variable degrees of microcephaly (-2.4 to -10.7 SD), short stature (several individuals with height within the normal percentiles), limb anomalies (many without such anomalies, or at least significant). Similarly, DD and more specifically ID has been observed in some patients (when it happened to be the case it was most commonly mild).
This is most evident in the supplementary information of PMID: 28191891, specifically the following table: https://media.nature.com/original/nature-assets/ng/journal/v49/n4/extref/ng.3790-S2.xlsx
Clinical synopses for the DONSON-related phenotypes: https://www.omim.org/clinicalSynopsis/table?mimNumber=617604,251230
The gene is not associated with any phenotype in G2P.
DONSON is included in gene panels for ID offered by diagnostic laboratories (incl. Radboudumc).
As a result, gene could be considered for inclusion in the ID panel probably as amber (or green) following further review and/or if the phenotype is thought to be relevant.
[Consider also inclusion in other relevant panels apart from microcephaly, eg. limb disorders etc.]
Sources: Literature, Radboud University Medical Center, NijmegenCreated: 18 Dec 2018, 1:11 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Microcephaly, short stature, and limb abnormalities (MIM 617604); Microcephaly-micromelia syndrome (MIM 251230)
Publications
Variants in this GENE are reported as part of current diagnostic practice
Tag watchlist tag was added to gene: DONSON.
Source Expert Review was added to DONSON. Source Expert Review Amber was added to DONSON. Added phenotypes Microcephaly, short stature, and limb abnormalities 617604; Microcephaly-micromelia syndrome 251230 for gene: DONSON Rating Changed from No List (delete) to Amber List (moderate evidence)
gene: DONSON was added gene: DONSON was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen Mode of inheritance for gene: DONSON was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DONSON were set to 28630177; 28191891 Phenotypes for gene: DONSON were set to Microcephaly, short stature, and limb abnormalities (MIM 617604); Microcephaly-micromelia syndrome (MIM 251230) Penetrance for gene: DONSON were set to unknown Review for gene: DONSON was set to AMBER gene: DONSON 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.