Submission Details

The CFAP74 gene was first reported in relation to primary ciliary dyskinesia (PCD) in 2020 (Sha et al., PMID: 32555313), which identified compound heterozygous missense variants in 2 unrelated probands with suspected PCD and diagnosis of multiple morphological abnormalities of the sperm flagella (MMAF). Both patients presented with bronchiectasis, chronic sinusitis, chronic wet cough and male infertility with a spectrum of sperm tail defects including incomplete mitochondrial sheath and disorganised outer dense fibres and microtubules. Sperm samples from affected individuals showed absent CFAP74 expression in flagella compared to controls (PMID: 32555313). In respiratory multiciliated cells, immunofluorescence analysis has demonstrated absence of CFAP46, a component of the C1d projection, in patient cells, supporting a defect in the central apparatus (PMID: 39362668). However, direct localisation of CFAP74 in respiratory cilia by immunofluorescence remains unreported.

A second publication (PMID: 36047773) reported compound heterozygous frameshift variants leading to premature truncation in two siblings and one unrelated patient with suspected PCD (bronchiectasis, recurrent airway infections, chronic wet cough and recurrent sinusitis). One of these probands was also diagnosed with MMAF. In both studies, nasal nitric oxide levels were within normal range, and no laterality defects were observed. Transmission electron microscopy (TEM) of respiratory cilia showed normal ultrastructure. High-speed video microscopy demonstrated reduced ciliary beat frequency and slightly decreased beating amplitude, with a partially stiff and rotatory beat pattern. Neonatal respiratory distress was not reported in any patient, and PCD was diagnosed in adulthood in all cases except one (diagnosed at age 14). An additional proband with suspected PCD was submitted to ClinVar (SCV005326514.1, VCV003340495.2), carrying two frameshift variants in CFAP74 with unconfirmed phase, and presenting with recurrent respiratory infections and wheezing since childhood.

Experimental support for this gene-disease relationship includes the finding that human tissues with high CFAP74 expression include motile ciliated tissues such as the lung, fallopian tube, brain, and testis (PMID: 23715323). The Chlamydomonas reinhardtii ortholog FAP74 is a subunit of the C1d projection of the central apparatus. Knockout strains exhibit absent C1d projections and reduced ciliary beat frequency with abnormal waveforms characterized by uncoordinated motion with impaired propagation of bends and switching between effective and recovery strokes (PMID: 33809498, PMID: 20421426). Co-immunoprecipitation studies in wild-type Chlamydomonas demonstrate interaction between FAP74 and other C1d projection components including Fap54, Fap46, Fap74, and Fap221 (PMID: 33809498, PMID: 20421426). Additionally, a zebrafish model of cfap74 deficiency shows laterality defects, which were rescued by expression of wild-type cfap74, confirming the phenotype is CFAP74-specific (PMID: 36459505). It is important to note that zebrafish possess central pair microtubules in their left–right organiser (LRO), unlike humans, which provides functional context for the observed situs-related phenotype in this model.

In summary, there is Moderate evidence to support the relationship between CFAP74 and autosomal recessive primary ciliary dyskinesia 49, without situs inversus (MIM#: 620197). This has been demonstrated in both research and diagnostic settings without the emergence of conflicting evidence. Additional genetic evidence will be required to reach a more definitive classification for this gene-disease relationship. This classification was approved by the ClinGen Motile Ciliopathy GCEP on June 18th, 2025 (SOP Version 11).