Submission Details

Cilia and flagella associated protein 298 (CFAP298), also known as C21orf59, was first reported in relation to primary ciliary dyskinesia in 2013 (PMID: 24094744). Four unrelated individuals were reported with biallelic CFAP298 truncating variants and a classical PCD phenotype with reduced nasal nitric oxide, recurrent chest infections and both outer and inner dynein arm defects. Situs inversus was detected in all 3 patients carrying the homozygous c.735C>G (p.Tyr245Ter) nonsense variant. Haplotype analysis of these patients indicated that this mutation is located within a shared haplotype and strongly suggested a founder effect, consistent with the high allele frequency of 0.001736 observed in among control individuals in the Ashkenazi Jewish population. The fourth published patient was compound heterozygous for the truncating variants c.292C>T (p.Arg98Ter), and c.792_795delTTTA (p.Tyr264Ter). Injection of human C21orf59 mRNA bearing the c.792_795delTTTA (p.Tyr264Ter) mutation failed to rescue cilia motility in zebrafish (PMID: 24094744). This curation identified but did not score an additional published proband from a cohort with laterality defects, due to the absence of additional clinical details to evaluate the full phenotype (PMID: 34215651). This curation was also informed by the identification of an additional proband within a French PCD cohort with biallelic variants in CFAP298 and a phenotype matching the published cases. The mechanism of disease appears to be biallelic loss-of-function in CFAP298, however, there is an urgent need for publication of additional cases to better understand the spectrum of disease-causing variants and clinical features.

This gene-disease relationship is also supported by experimental evidence that the C21orf59 transcript is strongly expressed in ciliated tissues of the zebrafish trunk, including the pronephric ducts and spinal canal (PMID: 24094744). Morpholino knockdown of the C21orf59 gene in zebrafish resulted in loss of dynein arms and a strong ciliopathy phenotype, including those involving pronephric cysts, axis curvature, left-right asymmetry defects, and hydrocephalus. Moreover, C21orf59 mRNA expression in ciliated tissues is eliminated by Foxj1a knockdown, indicating that C21orf59 expression is controlled by this ciliogenic transcription factor. C21orf59/Kurly (Kur) was also required for proper cilia polarization needed for the movement of the ECF in the zebrafish kidney and the larval skin of Xenopus laevis (PMID: 26904945). Motility- impaired Chlamydomonas mutants showed increased abundance of C21orf59/FBB18 protein suggesting that it is induced or stabilized when cilia motility is impaired (PMID: 24094744).

In summary, there is moderate evidence to support the gene-disease relationship of CFAP298 with primary ciliary dyskinesia 26 (MONDO:0014211). While more evidence is needed to establish this relationship more definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 10th, 2023 (SOP Version 9).