Renal ciliopathies

Gene: GLIS2

Green List (high evidence)

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

Created: 24 Feb 2025, 5:45 p.m. | Last Modified: 24 Feb 2025, 5:45 p.m.

Panel Version: 3.18

Comment on list classification: There are three unrelated cases reported with biallelic GLIS2 variants and with nephronophthisis (MIM #611498). There is also functional evidence and mouse model available in support of the disease association. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 23 Jul 2024, 10:05 a.m. | Last Modified: 23 Jul 2024, 10:05 a.m.

Panel Version: 3.8

PMID:17618285 reported the identification of a homozygous splice site GLIS2 variant in three members of a consanguineous Canadian Oji-Cree family and they presented with nephronophthisis. All developed end-stage kidney disease by age 8 years and underwent renal transplantation. Experimental studies in Glis2 mutant mouse model showed severe renal atrophy and fibrosis starting at 8 weeks of age. Differential gene expression studies on Glis2 mutant kidneys demonstrate that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2.

PMID:23559409 reported the identification of a homozygous GLIS2 variant (p.Cys175Arg) in a patient of Turkish descent that was ascertained from a larger cohort of 1,056 individuals with nephronophthisis-related disorders who underwent genetic analysis. This patient had end stage renal disease at 15 years of age. PMID:26374130 provided functional evidence for the reported C175R variant, which showed that affects both localization and function of GLIS2.

PMID:31676329 reported the identification of a novel homozygous in-frame deletion (p.H188_Y192del) of GLIS2 in a female from a consanguineous family. She presented at 9 years of age with echogenic kidneys with loss of cortico-medullary differentiation and progressive chronic kidney disease reaching kidney failure by 10 years of age.

Created: 23 Jul 2024, 8:15 a.m. | Last Modified: 23 Jul 2024, 8:18 a.m.

Panel Version: 3.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nephronophthisis 7, OMIM:611498

Publications

• 17618285
• 23559409
• 26374130
• 31676329

Kept rating as Amber following Red reviews from Penny Clouston and Andrea Nemeth- insufficient evidence for inclusion of GLIS2 on this Ciliopathy panel.

Created: 17 Jun 2019, 8:12 a.m.

Transferring text over from Publications field: PMID:26374130 (functional study); PMIDs:23559409;18227149 Glis2 mutant (Glis2(mut)) mice exhibit significantly shorter life spans compared to wild-type (WT) mice, due to the development of progressive chronic kidney disease with features resembling nephronophthisis; PMID:17618285 - Canadian Oji-Cree kindred.

Created: 17 Jun 2019, 8:09 a.m.

Red List (low evidence)

Insufficient evidence in the literature to classify as a green gene.
2 cases (23559409 and 17618285) in the literature lack phenotype and/or functional data.

This gene is currently on our diagnostic panel, however, no cases have been identified to date (of 185 Joubert/Ciliopathy cases).

Created: 17 Sep 2018, 12:21 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 23559409
• 17618285, 26374130

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

Red List (low evidence)

The first paper reports a single splice mutation in a consanguineous family with NPHP, there is no detailed phenotyping. There is immunofluorescence data suggesting localisation to cilia, no other functional data.

The second paper reports a second family with a missense mutation, C175R, that might also affect splicing. Again the patient was reported to have NPHP, again there is no detailed phenotype data.

The third paper reports that the missense mutation C175R is likely to be pathogenic, and is involved in transcription, therefore questioning its role in cilial function.

The gene warrants being included in unexplained renal failure, but the evidence to support being in the cilial panel is weak.

Created: 5 Sep 2018, 11:39 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
nephronopthisis (NPHP)

Publications

• 17618285
• 23559409
• 26374130

Comment on list classification: A family report and a case report.

Created: 13 Dec 2016, 2:42 p.m.