Submission Details

The CFAP47 gene is located in chromosome Xp21.1 and encodes the cilia- and flagella-associated protein 47. The protein plays a role in flagellar formation and sperm motility. The protein is predominantly expressed in the testes, fallopian tubes, pituitary gland, and lungs, but it also shows weak expression in the kidneys.

Variants in CFAP47 have been reported in individuals with the following disease entities: X-linked spermatogenic failure-3, primary ciliary dyskinesia, and X-linked polycystic kidney disease. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in phenotypic variability. Therefore, we have split CFAP47 variants into two diseases: spermatogenic failure-3 (OMIM:301059) and X-linked polycystic kidney disease (PMID:39698362). The split curation for spermatogenic failure, X-linked, 3 has been curated separately.

CFAP47 was first reported in relation to polycystic kidney disease in 2024 (Mori et al., PMID: 39698362). The mechanism of pathogenicity proposed as loss of function. Patients with monoallelic CFAP47 missense variants presented with polycystic kidney disease without sperm flagellar defects. At least 3 variants (missense) reported in three probands in one publication (PMID: 39698362) are included in this curation. There was no functional evidence supporting the effect of these missense variants. One of these missense variants was reported in a patient without polycystic kidney disease in separate publication (PMID: 36401472). In addition, due to their frequencies in population databases and the possibility that the phenotypic findings reported in the cases could also be explained by potential variants in other genes, a score of zero was assigned to these variants (PMID: 39698362). Since no other publications or patient data associated with this phenotype were found in the literature, no points could be gathered from the genetic score.

This gene-disease relationship has been evaluated with expression studies, and animal models. The expression of CFAP47 in human kidney tubular cilia was demonstrated and knockout 40-week-old mice model showed larger kidneys, cyst-like histological changes in the kidneys, including tubular cell vacuolation and dilatation, and they had significantly shorter cilia compared to wild types (PMID: 36401472, 36571501). However, another study published later reported that 10-week-old knockout mice showed no apparent histological kidney problems (PMID: 40473901).

In summary, the evidence supporting the relationship between CFAP47 and X-linked polycystic kidney disease has been disputed and no valid evidence remains to support the claim. The absence of evidence supporting the impact of the reported variants, the presence of the same variants in individuals without reported disease symptoms, and the fact that knockout animal models are inconsistent have led to this conclusion. However, it is also possible that the gene may be associated with a susceptibility phenotype that could manifest with age-dependent incomplete penetrance. More evidence is needed to either support or entirely refute the role CFAP47 plays in this disease. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel GCEP on the meeting date [February 10, 2025] (SOP Version 11).