Submission Details

The CCNO gene was first reported in relation to primary ciliary dyskinesia in 2014 (Wallmeier et al., PMID: 24747639). The specific disease entity, Primary Ciliary Dyskinesia 29, is one of at least 50 different primary ciliary dyskinesias distinguished by a specific monogenetic cause. Affected patients frequently present as neonates or in early childhood with recurrent respiratory infections including sinusitis, as well as decreased nasal nitric oxide, otitis media, and/or bronchiectasis. The reported cases presented with a severe clinical phenotype, including severe lung disease, and rarely hydrocephalus and ventriculomegaly. Laterality defects were not observed for any of the reported patients. Biopsies of upper and bronchial respiratory epithelial cells showed a complete absence or markedly reduced numbers of cilia, and in vitro ciliogenesis culture experiments demonstrated a severe defect in multiple motile cilia (MMC) generation, associated with insufficient centriole numbers and decreased basal bodies. Ciliary ultrastructure in the few expressed cilia was normal but beating was uncoordinated (PMID: 24747639, PMID: 24824133, PMID: 34102041). Due to this, Primary Ciliary Dyskinesia caused by pathogenic variants in CCNO belong to a group of disorders known as “reduced generation of multiple motile cilia” or RGMMC, associated with hydrocephalus in humans. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and mode of inheritance (autosomal recessive) to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited CCNO variants have been lumped into a single disease entity, referred to as Primary Ciliary Dyskinesia 29 (MONDO:0014378, OMIM #615872). Nine suspected pathogenic variants were scored as part of this curation (six frameshift, one nonsense and two missense), which have been collectively reported in fifteen probands (as well as affected family members) in four publications (PMID: 24747639, PMID: 24824133, PMID: 34102041, PMID: 26777464). More case-level evidence is available in the literature (PMID: 26139845) but its inclusion in this curation was not necessary to reach the maximum score for genetic evidence (12 points). This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level. The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by the absence of a gene product (PMID: 24747639). All probands scored in this curation harbored two variant alleles within the CCNO locus.

This gene-disease association is also supported by experimental evidence that human tissues exhibiting the highest levels of CCNO expression include tissue types relevant to disease and known to have motile cilia, including the lung, fallopian tube, brain, and testis (PMID: 23715323). More experimental evidence includes that CCNO normally localizes to the apical cytoplasm and is an essential component for generation of MMC, functional alterations in patient cells consistent with a critical role in MMC generation, and mislocalization in the cytoplasm and altered expression in PCD patient tissue. Model organisms (mouse and frog) show reduced numbers of MMC and characteristic phenotypes of MMC dysfunction, similar to those observed in patients (PMID: 25712475, PMID: 24747639, PIMD: 29245899). In summary, CCNO is definitively associated with autosomal recessive primary ciliary dyskinesia 29. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 19, 2022 (SOP Version 9).