Biallelic variants in CEP164 cause a motile ciliopathy-like syndrome

Abstract

Ciliopathies may be classed as primary or motile depending on the underlying ciliary defect and are usually considered distinct clinical entities. Primary ciliopathies are associated with multisystem syndromes typically affecting the brain, kidney, and eye, as well as other organ systems such as the liver, skeleton, auditory system, and metabolism. Motile ciliopathies are a heterogenous group of disorders with defects in specialised motile ciliated tissues found within the lung, brain, and reproductive system, and are associated with primary ciliary dyskinesia, bronchiectasis, infertility and rarely hydrocephalus. Primary and motile cilia share defined core ultra-structures with an overlapping proteome, and human disease phenotypes can reflect both primary and motile ciliopathies. CEP164 encodes a centrosomal distal appendage protein vital for primary ciliogenesis. Human CEP164 mutations are typically described in patients with nephronophthisis-related primary ciliopathies but have also been implicated in motile ciliary dysfunction. Here we describe a patient with an atypical motile ciliopathy phenotype and biallelic CEP164 variants. This work provides further evidence that CEP164 mutations can contribute to both primary and motile ciliopathy syndromes, supporting their functional and clinical overlap, and informs the investigation and management of CEP164 ciliopathy patients.

Keywords: CEP164; ciliopathy; genetics; mutation; primary ciliary dyskinesia.

FIGURE 1

Non‐CF bronciectasis patient with CEP164 compound heterozygous variants, motile ciliary defects and loss of CEP164 from the ciliary brush border. (A) Pedigree diagram showing the single affected male patient (arrow) with non‐CF bronchiectasis. Compound heterozygous stop gain CEP164 variants, segregating from each parent were identified. The patient had phenotypes shown. RTI, respiratory tract infection. (B) Immunofluorescence labelling of NB and ALI cultured epithelial cells, showing expression of the centriolar marker gamma tubulin (red), CEP164 (green) and DAPI nuclear counterstain. In the healthy controls, CEP164 colocalises with gamma tubulin, marking the centriolar region. The patient's NB and ALI‐cultured cells show loss of CEP164 in the centriolar region (arrows), but some aggregate CEP164 staining remains in the cell cytoplasm. (C) Still images from high‐speed video microscopy showing the patient's NB epithelium which had uncoordinated cilia with reduced ciliary beat amplitude, and lack of mucociliary clearance. There is variable cilia length, with some long cilia (arrows). (D) TEM of patient's ALI cells show that motile cilia have a mostly normal microtubule structure. (E) Analysis of TEM images of motile cilia show that only a few cilia have microtubule defects, mainly disarranged microtubules (MT), but the ultrastructure is largely normal. The 108 cilia were counted. MT, microtubule; MTD, microtubular defect; IDA, inner dynein arm defect; ODA, outer dynein arm defect. [Colour figure can be viewed at wileyonlinelibrary.com]