Submission Details

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).