Submission Details

The CCDC40 gene was first reported in relation to primary ciliary dyskinesia in 2011 (Becker-Heck et al., PMID: 21131974). The specific disease entity, primary ciliary dyskinesia 15, is one of at least 40 different primary ciliary dyskinesias distinguished by a single monogenic cause. Affected patients frequently present as neonates with respiratory distress, recurrent chest infections, cough and/or pneumonia (PMID: 23255504). Recurrent upper and lower respiratory infections are highly prevalent and include sinusitis, rhinorrhea, chronic cough, pneumonia, and bronchitis. Patients frequently exhibit chronic cough, age-dependent bronchiectasis, and/or otitis media. Heterotaxy is present with approximately 50% penetrance, most often in the form of situs inversus totalis. Immotile sperm and female infertility are also reported for some affected patients. Biopsies of the airway epithelium show a variable motility defect including static cilia and rigid cilia with variable fast, flicking movements but reduced beating amplitudes. Defects in axonemal morphology include shifting or absence of central pairs, disorganization of peripheral microtubular doublets, abnormalities in both radial spokes and nexin links, and usually complete but sometimes partial absence of inner dynein arms. Outer dynein arms appear to be normal/intact. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the molecular mechanism (biallelic loss of function) and mode of inheritance (autosomal recessive) was found 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 CCDC40 variants have been lumped into a single disease entity, referred to as primary ciliary dyskinesia 15 (MONDO:0013435, OMIM #613808). Seventeen suspected pathogenic variants were scored as part of this curation (eight nonsense, seven frameshift, and two predicted to trigger frameshift by affecting splicing), which have been collectively reported in thirty-six probands in two publications (PMID: 21131974, PMID: 23255504). More case-level evidence is available in the literature (PMID: 22499950, PMID: 25619595, PMID: 32502479), 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 variants likely to trigger the absence of a gene product (PMID: 21131974, PMID: 23255504). All probands scored in this curation harbored two variant alleles within the CCDC40 locus. This gene-disease association is also supported by experimental evidence that CCDC40 localizes specifically to tissue types relevant to disease and known to have motile cilia, including the ovary (PMID: 10997877) and Kupffer’s vesicle in the developing zebrafish embryo (PMID: 21131974). Biochemical and immunoprecipitation studies from Chlamydomonas reinhardtii indicate that the orthologs of CCDC40 and CCDC39 form a complex that functions as an axonemal molecular ruler, defining the length of the cilia, radial spoke periodicity, and both the presence and orientation of components of the inner dynein arms and nexin-dynein regulatory complex (PMID: 25395538). Phenotypes of affected human patients are recapitulated by various model organisms with CCDC40 loss-of-function, including defective structure and motility in Chlamydomonas reinhardtii (PMID: 26348919), left-right patterning defects and defective ciliary ultrastructure in zebrafish (PMID: 21131974), and situs inversus and defective ciliary ultrastructure in mice (PMID: 21131974). Restoring wild-type CCDC40 expression successfully rescues these phenotypes in both Chlamydomonas (PMID: 26348919) and zebrafish (PMID: 21131974) models. Additional evidence is available in the literature (PMID: 10997877, PMID: 28182636) but its inclusion in this curation was not necessary to reach the maximum score for experimental evidence (6 points). In summary, CCDC40 is definitively associated with primary ciliary dyskinesia 15. This has been repeatedly demonstrated in both research and diagnostic 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 November 11, 2021 (SOP Version 8).