Submission Details

The first report of ciliopathy-CEP164 was in 2012 by Chaki M et al. (PMID: 22863007). Individuals with ciliopathy-CEP164 present with a broad range of phenotypes, including various combinations of nephronophthisis, respiratory system impact, retinal degeneration, developmental delay, CNS malformations, polydactyly, bronchiectasis and obesity. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. The spectrum of reported phenotypes encompassed various signs and symptoms associated with defects of both the primary and motile cilium, in line with the known roles of CEP164. Therefore, the following disease entities have been lumped into one disease entity: nephronophthisis 15 (MONDO:0013917) and Senior-Loken syndrome (MONDO:0017842).

Seven different variants (2 missense, 3 nonsense, 1 frameshift and 1 stop loss) that have been reported in 6 probands in 4 publications (PMIDs: 22863007, 34132027, 27708425, 36273371) are included in this curation. The mechanism of pathogenicity is reported to be loss-of-function. Genetic variants have been associated with reduced protein interactions, ciliary defects and DNA damage.

This gene-disease association is also supported by expression studies, multiple animal models (zebrafish and mouse) as well as in vitro functional assays (PMIDs: 31990917, 22863007, 23150559, 29244804, 31248650). Ablation of cep164 protein in foxj1-positive mice tissues resulted in loss of airway multicilia and hydrocephalus, indicating its essential roles in airway multiciliated cell differentiation. A similar effect was also detected in ependymal cells, seminiferous tubules, and oviducts of the knockout mice (PMID: 29244804). The Zebrafish cep164 knockout model could recapitulate various aspects of the ciliopathy-disease spectrum, exhibiting ventral body axis curvature, laterality defects, hydrocephalus, kidney cysts, and retinal dysplasia (PMID: 22863007). One nonsense variant (p.Gln525Ter/p.Gln525Ter) has been associated with a dominant negative effect on cell growth (PMID: 22863007). The proband had bronchiectasis along with nephronophthisis and retinal affection. Delvin LA et al investigated the motile ciliopathy affection in a compound heterozygous patient carrying the aforementioned variant and a stop gain in the penultimate exon (NM_014956.5 c.4228C > T p.(Gln1410Ter) (PMID:36273371). The male fertile patient had a predominantly respiratory phenotype (bronchiectasis, recurrent lower respiratory tract infection, recurrent ear infection and low nasal nitric oxide) and loss of CEP164 in the centriolar region in his nasal brushing (NB) and ALI‐cultured cells. High‐speed video microscopy of the patient's NB epithelium detected uncoordinated cilia with reduced ciliary beat amplitude, and lack of mucociliary clearance.

In summary, CEP164 is definitively associated with autosomal recessive ciliopathy-CEP164. 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 Kidney Cystic and Ciliopathy Disorders GCEP on 10/27/21 (SOP Version 8).