Submission Details

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 (Attanasio M et al., 2007 PMID 17618285; Halbritter et al., 2013 PMID 23559409; Al Alawi et al. 2021 PMID 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 3 probands in 3 publications (Attanasio M et al., 2007 PMID 17618285; Halbritter et al., 2013 PMID 23559409; Al Alawi et al. 2021 PMID 34917135). Variants in this gene segregated with disease in 2 additional family members in one of these publications (Attanasio M et al., 2007 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 (Zhang et al., 2002 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 (Attanasio M et al., 2007 PMID 17618285; Halbritter et al., 2013 PMID 23559409). Zhang et al. concluded that Glis2 behaves as a bifunctional transcriptional regulator (Zhang et al., 2002 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 (Ramachandran H et al. 2016, PMID 26374130). Thus, the score for experimental evidence for a gene-disease association was 5.5 points.

In summary, there is Moderate evidence to support this GLIS2-nephronophthisis relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 05/22/2024 (SOP Version 10).