CFAP300 – Primary Ciliary Dyskinesia

CFAP300 encodes a dynein assembly and transport factor essential for motile cilia function. Autosomal recessive biallelic variants in CFAP300 cause primary ciliary dyskinesia by disrupting dynein arm assembly. Eight unrelated probands have been reported across multiple populations: three affected children from two families (PMID:29727692), one Chinese patient (PMID:39254424), two Polish patients (PMID:30916986), and two Finnish patients (PMID:36246608). Segregation of CFAP300 variants with PCD was observed in two affected siblings within one pedigree (PMID:29727692). Concordant functional data from patient cells and model organisms further support pathogenicity. Based on these data, the gene–disease association is classified as Strong.

Biallelic CFAP300 variants follow an autosomal recessive inheritance pattern. A recurrent Slavic/Finnish loss-of-function allele, c.198_200delinsCC, accounts for population-specific cases (PMID:30916986, PMID:36246608). A novel nonsense allele, c.466G>T (p.Glu156Ter), was identified in a Chinese patient and confirmed by whole-exome sequencing (PMID:39254424). Genetic segregation and absence of CFAP300 protein in patient cilia demonstrate loss-of-function. Two additional Polish patients carrying CFAP300 frameshift and splice-region variants expand the mutational spectrum (PMID:30916986).

The CFAP300 variant spectrum is dominated by loss-of-function alleles, including seven nonsense, one frameshift, and one splice-region variant. The recurrent c.198_200delinsCC variant displays a 3.6% allele frequency in the Polish PCD cohort (PMID:30916986). A founder effect in Slavic populations is supported by haplotype analysis. Chinese patients harbor a private nonsense variant, underscoring allelic heterogeneity (PMID:39254424). No pure missense phenotypes have been reported, suggesting that complete loss of CFAP300 function underlies PCD.

Functional studies delineate a loss-of-function mechanism disrupting dynein arm assembly and transport. Immunofluorescence and transmission electron microscopy of patient respiratory epithelia reveal absent inner and outer dynein arms (PMID:30916986, PMID:36246608). Super-resolution microscopy localizes CFAP300 along ciliary axonemes in healthy cells, indicating a role in dynein trafficking (PMID:36246608). Paramecium and flatworm model knockdown of C11orf70 orthologues recapitulates dynein arm loss and reduced ciliary motility (PMID:29727692).

No conflicting evidence has been reported. Integration of robust genetic segregation, recurrent population-specific alleles, and convergent functional data establishes CFAP300 as a definitive autosomal recessive PCD gene. This knowledge enhances molecular diagnostics, informs carrier screening, and guides reproductive counseling, including intracytoplasmic sperm injection for affected couples (PMID:39254424).

Key Take-home: Biallelic CFAP300 loss-of-function variants cause autosomal recessive PCD by disrupting dynein arm assembly and transport, supporting its clinical utility for genetic diagnosis and management.

References

• American Journal of Human Genetics • 2018 • C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia PMID:29727692
• American Journal of Respiratory Cell and Molecular Biology • 2019 • CFAP300: Mutations in Slavic Patients with Primary Ciliary Dyskinesia and a Role in Ciliary Dynein Arms Trafficking. PMID:30916986
• Frontiers in Genetics • 2022 • CFAP300 mutation causing primary ciliary dyskinesia in Finland. PMID:36246608
• Asian Journal of Andrology • 2025 • A novel homozygous mutation of CFAP300 identified in a Chinese patient with primary ciliary dyskinesia and infertility. PMID:39254424

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