The CFAP57 gene was first reported in relation to primary ciliary dyskinesia (PCD) in 2020 (Bustamante-Marin et al., PMID: 32764743). A homozygous nonsense variant, c.1762C>T (p.Arg588*), was identified in a proband with a classic PCD phenotype including neonatal respiratory distress, otitis media, sinusitis, bronchiectasis, and low nasal nitric oxide. Biopsies from nasal epithelia showed normal axonemal ultrastructure. Ciliary beat frequency was reduced, and most cilia exhibited abnormal waveforms with no clear effective and recovery strokes. Functional studies showed that the variant results in the skipping of exon 11 and a shorter protein that does not assemble into the axoneme. The genetic evidence for this curation is scarce, therefore, the maximum score was not reached (3/12 pts.). This gene-disease association is also supported by experimental evidence that human tissues exhibiting the highest levels of CFAP57 expression include tissue types relevant to disease and known to have motile cilia, including the lung, fallopian tube, brain, and testis (PMID: 23715323), biochemical function as a component that localises throughout the ciliary axoneme, functional alterations in patient cells consistent with a critical role in motile cilia function, altered expression in PCD patient tissue, and silencing of CFAP57 in control cells exhibiting cilia beat frequency and pattern defects (PMID: 32764743). More experimental evidence includes a Chlamydomonas model: the ortholog FAP57 has been shown to form an extended structure that interconnects multiple IDAs and regulatory complexes, and mutant FAP57 Chlamydomonas strains show reduced swimming velocity and altered waveforms (reduced bend amplitude and increased average curvature) (PMID: 32764743, PMID: 31483737). In summary, biallelic loss of CFAP57 is likely to cause PCD due to a failure to assemble a subset of IDAs. However, there is limited evidence to support this gene-disease 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 Motile Ciliopathy GCEP on June 9, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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