CFAP300 (C11orf70) was first characterized as an evolutionarily conserved protein essential for assembly of dynein arms with the gene variants reported in a cohort of PCD affected children in 2018 (PMID: 29727692). Reported cases showed a consistent PCD phenotype with recurrent respiratory tract infection, neonatal respiratory distress and reduced nasal nitric oxide along with immotile respiratory cilia displaying combined loss of inner and outer dynein arms (IDA+ODA). Laterality defects were observed in some of the investigated PCD-affected individuals with biallelic CFAP300 mutations (PMIDs:29727692, 29727693 and 30916986). Fertility defects are also reported in both male and female patients (PMID: 29727693).
Seven (missense, splice site, and frameshift) variants that have been reported in 3 publications are used in this curation (PMIDs: 29727692, 29727693 and 30916986). Mechanism of pathogenicity appears to be loss of function resulting in defects in the dynein-arm assembly machinery (PMID: 29727693).
Phylogenetic analysis shows that C11orf70 is expressed in species that require dynein arms for cilia motility (PMID:29727692). RNAi knockdown of the Paramecium C11orf70 ortholog led to combined loss of ciliary IDA+ODA with reduced cilia beating and swim velocity (PMID:29727692). C11orf70 shows a similar RNA expression profile to genes involved in dynein arm assembly, and to those coding for structural dynein arm proteins (PMID: 30916986). High resolution immunofluorescence revealed that the ODA components DNAH5, DNAH9, DNAI1, and DNAI2 as well as IDA components (DNALI1 and DNAH6) were absent or severely reduced from the respiratory ciliary axonemes of the affected individuals (PMIDs:29727693 and 30916986). The identification of FBB5, the Chlamydomonas CFAP300 ortholog, as a member of a group of flagellar basal body genes and the cytoplasmic apical localization of the dynein arm components (DNAH5, DNAI2, and DNALI1) by IF in patients carrying biallelic CFAP300 mutations, suggest a role of CFAP300 in dynein arm transport within the axoneme (PMID: 30916986).
In summary, CFAP300 is definitively associated with primary ciliary dyskinesia 38. This has been repeatedly demonstrated in both clinical diagnostic and research settings and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification.This classification was approved by the ClinGen Motile Ciliopathy GCEP on September 8, 2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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