CFAP221 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal recessive disorder characterized by impaired motile cilia function leading to chronic airway disease. CFAP221 (Cilia and Flagella Associated Protein 221) was recently implicated in PCD based on whole-exome sequencing and functional studies (CFAP221; Primary Ciliary Dyskinesia).

In the initial report, three affected siblings from a single family presented with classical PCD symptoms but normal ciliary ultrastructure. Compound heterozygous loss-of-function variants c.2318+1G>A and c.2303_2307del (p.Leu768fs) were identified, and segregation analysis confirmed co-segregation with disease in two additional siblings ([PMID:31636325]). Nasal epithelial cells displayed slightly reduced beat frequency and an aberrant circular waveform, linking CFAP221 deficiency to motility defects.

A second case involved a 42-year-old man with bronchiectasis, sinusitis and obstructive azoospermia, initially suspected as Young’s syndrome. Electron microscopy and nasal nitric oxide were normal, but compound heterozygous CFAP221 variants were detected, revising the diagnosis to PCD and highlighting phenotypic overlap ([PMID:38960684]).

A third study described a Polish patient with a novel homozygous protein-truncating CFAP221 variant. Immunofluorescence and high-speed videomicroscopy of nasal epithelium revealed asynchronous circular ciliary motion and reduced beat frequency, while RNAi knockdown of the CFAP221 homolog in Schmidtea mediterranea reproduced motility impairment, confirming causality in an independent model ([PMID:40250778]).

Collectively, three unrelated probands and one multiplex family (total 5 individuals) with autosomal recessive CFAP221 variants demonstrate consistent genotype–phenotype correlation. Segregation in the sibship (2 additional affected relatives) and corroborative functional assays establish loss of CFAP221 as the pathogenic mechanism.

CFAP221 should be included in diagnostic panels for PCD, especially in patients with normal ciliary ultrastructure or Young’s syndrome phenotypes. Key take-home: CFAP221 loss-of-function variants impair ciliary motility and cause autosomal recessive PCD, warranting routine genetic testing for accurate diagnosis and management.

References

• Journal of human genetics • 2020 • Identification of genetic variants in CFAP221 as a cause of primary ciliary dyskinesia. PMID:31636325
• Internal medicine (Tokyo, Japan) • 2025 • Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia. PMID:38960684
• Biochimica et biophysica acta. Molecular basis of disease • 2025 • A novel pathogenic variant of CFAP221 is a cause of a mild form of primary ciliary dyskinesia. PMID:40250778

Evidence Based Scoring (AI generated)