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Intellectual disability
Gene: DLG4

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

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

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

Created: 19 Oct 2018, 12:30 a.m.

Panel version: 2.510

Caroline Wright (Sanger)

Red List (low evidence)

Created: 5 Nov 2017, 2:42 a.m.

Panel version: 0

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

Created: 27 Oct 2017, 2:46 p.m.

Panel version: Imported from Intellectual disability update Oct 2017 panel version 0.2

Lu Raymond (university of cambridge )

Red List (low evidence)

Created: 23 Feb 2016, 11:34 a.m.

Panel version: 0.306

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