CFAP47

Inheritance Pattern: XL

Disease ID:MONDO:0025354

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0025354

Submitter: ClinGen

The *CFAP47* gene was first reported in relation to X-linked spermatogenic failure in 2021 (Liu et al, PMID: 33472045). The specific disease entity, X-linked spermatogenic failure 3 (MONDO:0025354, MIM #301059), is one of at least 3 different forms of X-linked spermatogenic failure distinguished by a single monogenic cause. Consistent features among the reported male patients are infertility, reduced sperm motility, and multiple morphological abnormalities of the sperm flagellum. Flagella can be abnormally short, coiled, or absent, and can exhibit abnormal axoneme morphology. While the number of patients published so far is quite small, all of them have been noted for the lack of phenotypes typically associated with primary ciliary dyskinesia, including absence of sinusitis, bronchitis, otitis media, and pneumonia (PMID: 33472045). This curation has scored three suspected disease-causing *CFAP47* variants (all missense), which were collectively reported in three male probands in one publication (PMID: 33472045). None of the probands were reported to be from consanguineous parents, and all of them harbored a single *CFAP47* variant in the hemizygous state. Although a fourth male proband with a matching phenotype harbored a deletion of the entire *CFAP47* locus, the variant could not be scored as the exact coordinates of the deletion could not be defined (PMID: 33472045). Nevertheless, the molecular mechanism appears to be hemizygous loss-of-function with an X-linked mode of inheritance, characterized in at least some cases by variants predicted to trigger the absence of a gene product. An urgent need remains for additional published data to more directly evaluate the mechanism of pathogenicity by which missense variants affect CFAP47 function. A second article has become available online reporting additional probands with a compatible phenotype harboring a missense variant in *CFAP47*, but had not yet been published at the time of this curation and could not be included among the genetic evidence scored (https://www.authorea.com/users/354197/articles/571930-a-novel-recurrent-mutation-in-cfap47-causes-male-infertility-with-asthenoteratozoospermia#annotations:BvkA_GhvEe2wiJ-G-1Q61A). This gene-disease relationship is also supported by experimental evidence that high levels of *CFAP47* expression in humans are specific to tissues known to harbor multi-ciliated cells (PMID: 23715323). *CFAP47* encodes a protein that localizes to the base of sperm flagella (PMID: 33472045). CFAP47 protein physically interacts with CFAP65, which is encoded by the gene that harbors variants associated with spermatogenic failure 40. CFAP47 levels are severely reduced in sperm flagella from affected patients harboring CFAP65 variants (PMID: 33472045). A mouse model of *Cfap47* loss-of-function recapitulates additional human patient phenotypes such as male infertility, multiple abnormalities of sperm morphology, and reduced sperm motility (PMID: 33472045). In summary, *CFAP47* has limited evidence of association with X-linked spermatogenic failure 3. This has been demonstrated in both research and diagnostic settings, but has so far reached only a Limited classification. Additional genetic evidence and replication over a longer period of time will be required to reach a stronger gene-disease association. This classification has been approved by the ClinGen Motile Ciliopathy GCEP on February 9th, 2023 (SOP Version 9).

Inheritance Pattern: XL

Disease ID:MONDO:0020642

Submitter: ClinGen

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).

Inheritance Pattern: XL

Disease ID:MONDO:0020642

Submitter: University of Washington Center for Rare Disease Research (UW-CRDR)