GLIS2

Inheritance Pattern: AR

Disease ID:MONDO:0012680

Submitter: ClinGen

Variants in the *GLIS2* gene have been observed in individuals with nephronophthisis, an autosomal recessive inherited disease presenting in childhood with polyuria, polydipsia, progressive chronic kidney disease, a bland urinary sediment, and progression to kidney failure before the age of 30. Affected children may have growth restriction. Their kidneys are small or normal-sized and hyperechoic with corticomedullary cysts and tubular basement membrane abnormalities. *GLIS2* was first reported in association with nephronophthisis in 2007 (Attanasio M et al., 2007 PMID 17618285). At least 3 unique variants, c.775+1G>T ; p.Cys175Arg, and (NM_032,575.3: c.560_574del, p.H188_Y192del) have been reported in humans (PMIDs: 17618285; 23559409; 34917135). The disease mechanism is reported to be a loss-of-function. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found there is only one molecular mechanism underlying nephronophthisis 7 (MIM: 611498). Evidence supporting this *GLIS2*-nephronophthisis 7 relationship includes case-level data and experimental data. Genetic evidence on case-level data contributes 4.2 points. Variants in GLIS2 have been reported in at least three probands in three publications (PMIDs: 17618285; 23559409; 34917135). Variants in this gene segregated with disease in two additional family members in one of these publications (PMID 17618285). This gene-disease relationship has not been studied in any case-control studies at the single or aggregate variant level. This gene-disease association is supported by experimental evidence. Zhang et al. cloned GLIS2 from mouse kidney RNA (PMID 11741991), and the deduced 521-amino acid protein has a calculated molecular mass of 55.8 kD. Northern blot analysis and RT-PCR detected highest expression in the kidney. Immunohistochemical staining in a mouse model has revealed GLIS2 expression throughout all renal tubule segments and epithelial cells of Bowman’s capsule (PMIDs: 17618285; 23559409). Zhang et al. concluded that GLIS2 behaves as a bifunctional transcriptional regulator (PMID: 11741991). In a zebrafish model, knockdown of the zebrafish isoform nphp7.2 resulted in cyst formation, which was rescued by zebrafish nphp7.2 mRNA. However, forced nuclear import did not rescue the transcriptional defects of GLIS2 p.Cys175Arg, indicating additional defects of the DNA-binding protein (PMID: 26374130). New experimental data shows that GLIS2 is a key effector of this cilia dependent cyst growth pathway and a potential target for therapy in autosomal dominant polycystic kidney disease (PMID: 38693102). Furthermore, a novel Nphp7/GLIS2-deficient mouse model reveals that GLIS2 is essential for the DNA damage response within kidney tubular epithelial cells (PMID: 40713016). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was originally approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 05/22/2024 (SOP Version 10). It was re-evaluated on 04/22/2026 where additional functional studies were included (PMIDs: 38693102, 40713016) (SOP Version 12). As a result of this re-evaluation, the classification did not change.

Inheritance Pattern: AR

Disease ID:MONDO:0012680

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012680

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009728

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012680

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012680

Submitter: Ambry Genetics