CYS1

Inheritance Pattern: AR

Disease ID:MONDO:0020642

Submitter: ClinGen

The relationship between CYS1 (Cystin 1 or cilia-associated protein 1) and autosomal recessive polycystic kidney disease (ARPKD) was evaluated using the ClinGen Clinical Validity Framework. The CYS1 gene encodes a small protein that is expressed in the primary apical cilia of renal ductal epithelial cells. This gene was suspected to be affected in polycystic kidney disease because two deletions in the corresponding mouse gene result in a model of ARPKD, which has been characterized extensively and resembles the human disease (Hou et al 2002: PMID: 11854326). CYS1 was reported in relation to ARPKD by Yang et al in 2021, PMID: 34521872. This is the only disease associated with pathogenic variants in this gene. The kidney cysts arise from the collecting duct epithelium, and there is also biliary dysgenesis and portal tract fibrosis. The disease onset is usually in childhood. Only two pathogenic variants have been reported in CYS1 associated with human disease; a homozygous splice region variant proven to be pathogenic in a minigene construct, and a homozygous missense variant. The lack of reported pathogenic variants is probably because of the protein’s small size and difficulties with sequencing due to the gene’s GC-rich nature. The mechanism of pathogenicity is loss of function. This gene-disease pair is supported by experimental expression, protein interaction data, and a non-human model organism. In summary, there is Limited evidence supporting the relationship between CYS1 and ARPKD. This has been demonstrated in both the clinical diagnostic and research setting. The classification was originally approved by the ClinGen Kidney Cystic GCEP on 04/27/22. This gene-disease relationship was re-evaluated on 03/11/24 and as a result, the classification did not change. This assessment was approved by the ClinGen KCCD GCEP on the meeting date 03/11/2024 (SOP Version 10).