Intellectual disability - microarray and sequencing
Gene: DLG4 Green List (high evidence)As a result of watchlist tag audit the watchlist tag was removed from DLG4- this is now a green gene with sufficient evidence/reviewCreated: 13 Jan 2020, 3:38 p.m. | Last Modified: 13 Jan 2020, 3:38 p.m.
Panel Version: 3.0
Green List (high evidence)
Further cases reported with mutations in DLG4 related to ID.
PMID:29460436 reports on three unrelated individuals who all have Marfanoid habitus (MH) combined with intellectual disability (ID). Two individuals reported to have de novo variants p.(Glu615Serfs*4) p.(Phe383Glyfs*31) and another individual had a splice variant p.(Gly558Profs*37) but as fathers DNA was not available de novo could not be confirmed.
PMID:23020937 51 participants from the German Mental Retardation Network where one individual is reported to have severe ID and a de novo mutation p.(Thr654Ile) in DLG4.
Therefore enough evidence to change rating of DLG4 from Amber to Green.Created: 25 Jul 2019, 8:14 a.m. | Last Modified: 25 Jul 2019, 8:14 a.m.
Panel Version: 2.975
Green List (high evidence)
Moutton et al. (PMID: 29460436) report on 3 unrelated patients with de novo DLG4 truncating variants and a common phenotype consisting of intellectual disability and marfanoid features.
Two of the subjects were find to harbor de novo frameshift variants resulting in reduced mRNA expression as a result of NMD.
A third patient had a splice variant. The de novo occurrence could not be confirmed since only the mother of this individual was available for testing. RT-qPCR on total RNA from leucocytes did not demonstrate altered DLG4 expression. This variant was however shown to lead to retention of 4 nucleotides at the 5' end of intron 16 following deep cDNA high-throuput sequencing. Theoretically this would lead to premature truncation of the protein.
DLG4 is intolerant to loss-of-function variants (pLI=1).
3 individuals with de novo LoF variants had been reported by Lelieveld et al. (PMID:27479843) as discussed in the current study and commented by a previous reviewer.
An additional individual with stopgain SNV and a relevant phenotype exists in Decipher as part of the DDD study (DDD4K.03156 - PMID:28135719)
One individual with missense variant has been reported by Rauch et al. (PMID: 23020937) in a cohort of 51 patients with non-syndromic intellectual disability.
All de novo coding variants summarized in denovo-db (http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=DLG4)LG4).
As a result this gene could possibly be considered for upgrade to Green status.Created: 19 Oct 2018, 12:30 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Intellectual disability; Marfanoid habitus
Publications
Red List (low evidence)
I don't know
Not in OMIM related to a disease. Is a probable Gene2Phenotype DD gene for intellectual disability. Reported as a candidate gene in PMID 27479843. Within 17p13.1 microduplication region reported in PMID 25123844 in two unrelated patients. Further cases of the microduplication reported in PMID: 19617690. In a meta-analysis of whole exome sequencing data on 2,104 ID trios, this gene was found to be enriched for de novo mutations as a candidate ID gene PMID 17417632.Created: 27 Oct 2017, 2:46 p.m.
Publications
Red List (low evidence)
Phenotypes for gene: DLG4 were changed from Intellectual disability; Marfanoid habitus to Intellectual disability; Marfanoid habitus; Intellectual developmental disorder 62 #618793
Tag watchlist was removed from gene: DLG4.
Mode of inheritance for gene: DLG4 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Gene: dlg4 has been classified as Green List (High Evidence).
Publications for gene: DLG4 were set to 27479843; 25123844; 19617690; 29460436; 23020937; 28135719
Phenotypes for gene: DLG4 were changed from to Intellectual disability; Marfanoid habitus
Publications for gene: DLG4 were set to 27479843; 25123844; 19617690; 29460436; 23020937; 28135719
Publications for gene: DLG4 were set to 27479843; 25123844; 19617690
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.
Expert Review Amber was added to DLG4. Panel: Intellectual disability Publications for gene DLG4 was set to ['27479843', '25123844', '19617690']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
DLG4 was created by ellenmcdonagh
DLG4 was added to Intellectual disabilitypanel. Sources: Expert Review Red
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.