Submission Details

The CFAP221 gene was first reported in relation to autosomal recessive primary ciliary dyskinesia (PCD) in humans in 2020 (Bustamante-Marin et al., PMID: 31636325). Compound heterozygous loss of function variants in CFAP221 were identified in three French-Canadian siblings with a clinical diagnosis of PCD. All three patients had neonatal respiratory distress, rhinosinusitis, otitis media and wet cough, and two had bronchiectasis. Nasal nitric oxide levels were normal and laterality defects were not observed for any of the reported patients. Biopsies from nasal epithelia also showed normal ciliary ultrastructure. Ciliary beat from nasal epithelial cells was investigated in one patient and demonstrated slightly reduced beat frequency; however, the cilia exhibited an abnormal circular pattern with no clear effective recovery strokes. Functional studies showed that one of the variants results in a frameshift and a subsequent premature truncation of the protein, and the other variant results in an in-frame deletion of exon 22. CFAP221 was not expressed in patient cilia. This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level. The mechanism of pathogenicity appears to be biallelic loss of function, characterized in the reported cases by the absence of a gene product (PMID: 31636325). All 3 probands scored in this curation harbored two variant alleles within the CFAP221 locus. This curation was also informed by two additional unpublished probands harboring biallelic CFAP221 variants identified within French and Polish PCD cohorts. Please note that there remains an urgent need for additional published probands to better establish the spectrum of disease-causing variants and clinical features associated with this gene-disease relationship.

This gene-disease association is also supported by experimental evidence that human tissues exhibiting the highest levels of CFAP221 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 in human control cells as a component that localizes to the ciliary axoneme and is not expressed in undifferentiated airways cells while expression is increased in ciliated cell differentiation, functional alterations in patient cells consistent with a critical role in motile cilia function, and altered expression in PCD patient tissue (PMID: 31636325). More experimental evidence includes a Chlamydomonas model: the ortholog FAP221 has been shown to be a key component in the assembly of central pair projection C1d and be essential for control of ciliary motility. Mutant FAP221 Chlamydomonas strains show significant impairment of motility including uncoordinated bends, severely reduced beat frequency, and altered waveforms (PMID: 20421426). Lastly, nm1054 mutant mice (harboring a 400kbp deletion encompassing 6 genes, including Cfap221) exhibit a PCD phenotype (severe hydrocephalus, accumulation of mucus in sinus cavity and male infertility), with complete absence of mature flagella in testis, present respiratory cilia with normal ultrastructure but reduced ciliary beat frequency. Transgenic rescue of Cfap221 in nm1054 mutant mice shows PCD is solely caused by the loss of Cfap221.

In summary, there is moderate evidence to support the relationship between CFAP221 and autosomal recessive primary ciliary dyskinesia. This classification was approved by the ClinGen Motile Ciliopathy GCEP on January 12, 2023 (SOP Version 9).