Renal ciliopathies

Gene: DLG5

I don't know

There is very little evidence supporting this gene being causative of an AD disorder, PMID:32631816 cites 4 cases, 2 with het missense variants and 2 with comp het/hom variants. One of the cases with a heterozygous variant is de novo, however the variant is present in 9 hets and 1 hom in gnomad v4.1 indicating it is highly unlikely to be causative of a fetal disorder. The second het variant is shared with 2 family members but little evidence is available to call it C4/5.

A heterozygous LOF variant has been reported in association with Müllerian agenesis, but this is only one case so is insufficient evidence to prove a link (PMID: 35361250).

There are 3 cases in the literature with biallelic variants, 2 reported in paper above.
One has kidney dysfunction in the form of SRNS, with accompanying oedema, ascites, pleural effusions, hypertension, proteinuria (7.5 g/day), a serum creatine level of 0.8 mg/dL and a serum albumin of 20 g/L. The patient was treated with cyclosporin A but has had several relapses and has progressed to stage 3 chronic kidney disease.
The second case has communicating hydrocephalus, coarse facial features, a cleft lip and palate, broad hands/feet, contractures of the hands, short trunk/chest and intermittent dystonia. The patient failed to achieve developmental milestones. The patient had a normal echocardiogram. Although renal scans were normal, the patient was known to have renal tubular leak and salt wasting requiring administration of supplements.
A third case with hydrocephalus and renal dysplasia is reported by PMID: 30791088
Therefore this gene may be causative of AR hydrocephalus/renal issues
Inheritance should be changed to biallelic only.

Created: 24 Dec 2024, 2:03 p.m. | Last Modified: 24 Dec 2024, 2:03 p.m.

Panel Version: 3.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
CAKUT; hydrocephalus

Publications

• 32631816

Variants in this GENE are reported as part of current diagnostic practice

Comment on phenotypes: Gene-checked tag removed as this gene now has a relevant phenotype listed in OMIM (Yuksel-Vogel-Bauser syndrome, OMIM:620703)

Created: 3 Apr 2024, 11:19 a.m. | Last Modified: 3 Apr 2024, 11:19 a.m.

Panel Version: 3.5

Green List (high evidence)

With reference to the review of the published evidence by Tracy Lester (Genetics laboratory, Oxford UK), a change of mode of inheritance is suggested from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal. Four biallelic DLG5 variants have been reported in three unrelated cases (PMID: 30791088, 32631816). Three monoallelic DLG5 variants have been reported (PMID: 32631816, 35361250). The de novo variant c.745C>T(p.Arg249Trp) is present in 9 heterozygotes and 1 homozygote in gnomad v4.1, while the phenotype is mild for the heterozygous carriers of c.4526AG>TT (p.Gln1509Leu)(PMID: 32631816). A further monoallelic DLG5 variant was reported in a case with Müllerian agenesis (PMID: 35361250).

Created: 22 Apr 2025, 5:33 p.m. | Last Modified: 22 Apr 2025, 5:33 p.m.

Panel Version: 3.20

Comment on phenotypes: Phenotypes reported by Gen2Phen https://www.ebi.ac.uk/gene2phenotype/search?panel=ALL&search_term=DLG5

Created: 3 May 2022, 3:52 p.m. | Last Modified: 3 May 2022, 3:52 p.m.

Panel Version: 1.64

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Cystic kidneys, hydrocephalus, retinal abnormality, cleft palate; rhizomelic limb shortening

Publications

• 32631816

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Changed the mode of inheritance to be inline with that recommended by the NHS reviewer. Removed the Q3_21_MOI and Q3_21_NHS_review tags.

Created: 16 Mar 2022, 3:58 p.m. | Last Modified: 16 Mar 2022, 3:58 p.m.

Panel Version: 1.61

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 10:44 a.m. | Last Modified: 8 Mar 2022, 10:44 a.m.

Panel Version: 1.51

Comment on list classification: Green review from Julia Baptista (Royal Devon and Exeter NHS Foundation Trust) suggesting mode of inheritance of both biallelic and monoallelic further supports promotion to green rating.

Created: 18 Aug 2021, 5:06 p.m. | Last Modified: 18 Aug 2021, 5:06 p.m.

Panel Version: 1.42

Comment on list classification: Promoting this gene from grey to amber, but it could be promoted to green following GMS review. 4 cases, 2 biallelic and 2 monoallelic so mode of inheritance should also be considered. Supportive mouse knockout model.

Created: 18 Jan 2021, 10:01 a.m. | Last Modified: 18 Jan 2021, 10:01 a.m.

Panel Version: 1.38

Comment on mode of inheritance: Note, 2 reported cases with biallelic variants, 2 with monoallelic. Mouse model was biallelic knockout

Created: 18 Jan 2021, 9:59 a.m. | Last Modified: 18 Jan 2021, 9:59 a.m.

Panel Version: 1.37

PMID: 32631816 Marquez et al 2020 - report 5 patients from 4 unrelated families with different phenotypes including those associated with ciliopathies. In 2 families, the pro bands were found by WES to be heterozygous for variants in DLG5. In the other two families, the pro bands were compound heterozygous or homozygous for variants. All variants reported are predicted to result in amino acid changes. All had a renal component to their phenotype (bilateral multicystic dysplastic kidneys, hydronephrosis, steroid resistant nephrotic syndrome, renal tubular leak and salt wasting). They found a loss of cilia in cystic kidney tissue in one patient examined. Knockdown of dlg5 in Xenopus embryos resulted in enlarged appearance of kidney tubules and they appear to have fewer cilia. 3 out of 4 tested DLG5 patient variants were ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.

PMID: 17765678 - Nechiporuk et al 2007 -  Dlg5(-/-) mice develop fully penetrant hydrocephalus and kidney cysts

Created: 18 Jan 2021, 9:58 a.m. | Last Modified: 18 Jan 2021, 9:58 a.m.

Panel Version: 1.35

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 32631816
• 17765678

Green List (high evidence)

Four unrelated families reported, supportive Xenopus animal model data. Mutlisystem ciliopathy with prominent renal features.
Sources: Literature

Created: 4 Aug 2020, 11 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations

Publications

• 32631816

Variants in this GENE are reported as part of current diagnostic practice