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Intellectual disability

Gene: DLG4

Green List (high evidence)

DLG4 (discs large MAGUK scaffold protein 4)
EnsemblGeneIds (GRCh38): ENSG00000132535
EnsemblGeneIds (GRCh37): ENSG00000132535
OMIM: 602887, Gene2Phenotype
DLG4 is in 4 panels

6 reviews

Louise Daugherty (Genomics England Curator)

As a result of watchlist tag audit the watchlist tag was removed from DLG4- this is now a green gene with sufficient evidence/review
Created: 13 Jan 2020, 3:38 p.m. | Last Modified: 13 Jan 2020, 3:38 p.m.
Panel Version: 3.0

Catherine Snow (Genomics England)

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

Konstantinos Varvagiannis (Other)

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).

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

Caroline Wright (Sanger)

Red List (low evidence)

Ellen McDonagh (Genomics England Curator)

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

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
Phenotypes
  • Intellectual disability
  • Marfanoid habitus
  • Intellectual developmental disorder 62 #618793
Tags
microduplication
OMIM
602887
Clinvar variants
Variants in DLG4
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

11 May 2020, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: DLG4 were changed from Intellectual disability; Marfanoid habitus to Intellectual disability; Marfanoid habitus; Intellectual developmental disorder 62 #618793

13 Jan 2020, Gel status: 3

Removed Tag

Louise Daugherty (Genomics England Curator)

Tag watchlist was removed from gene: DLG4.

2 Sep 2019, Gel status: 3

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: DLG4 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

1 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: dlg4 has been classified as Green List (High Evidence).

25 Jul 2019, Gel status: 2

Set publications

Catherine Snow (Genomics England)

Publications for gene: DLG4 were set to 27479843; 25123844; 19617690; 29460436; 23020937; 28135719

25 Jul 2019, Gel status: 2

Set Phenotypes

Catherine Snow (Genomics England)

Phenotypes for gene: DLG4 were changed from to Intellectual disability; Marfanoid habitus

25 Jul 2019, Gel status: 2

Set publications

Catherine Snow (Genomics England)

Publications for gene: DLG4 were set to 27479843; 25123844; 19617690; 29460436; 23020937; 28135719

25 Jul 2019, Gel status: 2

Set publications

Catherine Snow (Genomics England)

Publications for gene: DLG4 were set to 27479843; 25123844; 19617690

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

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.

29 Nov 2017, Gel status: 2

Added New Source, Set publications

Ellen McDonagh (Genomics England Curator)

Expert Review Amber was added to DLG4. Panel: Intellectual disability Publications for gene DLG4 was set to ['27479843', '25123844', '19617690']

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 0

Created

Ellen McDonagh (Genomics England Curator)

DLG4 was created by ellenmcdonagh

13 Nov 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

DLG4 was added to Intellectual disabilitypanel. Sources: Expert Review Red