CFAP221

Inheritance Pattern: AR

Disease ID:MONDO:0016575

Submitter: ClinGen

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 presenting with typical features of PCD, including neonatal respiratory distress, chronic upper and lower airway disease, and bronchiectasis in two cases. 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 and 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. Since the initial report, three additional unrelated individuals with a clinical diagnosis of PCD and biallelic CFAP221 premature stop codon variants have been described (PMID: 39362668, 40250778, 38960684). These individuals show a consistent respiratory phenotype, including neonatal respiratory distress, chronic sino-pulmonary disease and bronchiectasis, without organ laterality defects. CFAP221 deficiency disrupts motile ciliary beating, consistent with its role in the C1d projection of the central apparatus, while nodal (9+0) ciliary function appears preserved, as evidenced by the absence of laterality defects. 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 localises 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). nm1054 mutant mice (400kbp deletion encompassing 6 genes, including *CFAP221)* have 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. Lastly, RNAi silencing of the *CFAP221* ortholog in Schmidtea mediterranea results in impaired ciliary-driven locomotion (~34% slower), with slower and asynchronous ciliary beating that mirrors functional defects seen in human respiratory epithelium. In summary, there is definitive evidence to support the relationship between *CFAP221* and autosomal recessive primary ciliary dyskinesia. This classification was approved by the ClinGen Motile Ciliopathy GCEP on November 13, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0016575

Submitter: Ambry Genetics