Centrosomal protein (CEP) 78 is composed of five putative leucine rich repeats and one coiled-coil domain. It has been shown to localize at the distal end of both the mother and daughter centrioles, even though it has been reported that, through electron microscopy observations, CEP78 could localize at the centriolar satellite. CEP78 is found only in ciliated organisms, indicating a role in cilia biogenesis/function. Inactivation of CEP78 results in impaired ciliogenesis both in planarians and human retinal pigment epithelium (RPE) 1 cells. Additionally,CEP78 has been suggested to orchestrate important roles in centriolar anchoring and stability in planarians. The mechanism of disease is not yet understood. However, it seems clear that, due to the existence of genotype/phenotype correlation, CEP78 plays a specific and unique role in the visual and hearing system. Mutation in CEP78 result in abnormally long primary cilia in patient derived skin fibroblasts. Long primary cilia could structurally affect the finely organized structure of the outer retina, including photoreceptor stability and neural retina-RPE contact. Molecularly, CEP78 interacts with centriolar duplication master regulator Polo-Like Kinase (PLK) 4, affecting its function and centrosomal localization. Moreover, CEP78 associates with and restrains the function of E3-ubiquitin ligase EDD-DYRK2-DDB1VprBP preventing ubiquitylation and centrosomal removal of the endogenous ciliogenesis inhibitor CP110. Mutations in CEP78 are scattered throughout the gene (NM_001098802) and are represented by nonsense and frame-shift variants and nucleotide aberrations interfering with the canonical splicing of CEP78 primary transcripts.
Possible molecular diagnostic approaches to confirm the diagnosis in a proband include:
- Performing a NGS multi-gene panel that includes CEP78 or performing exome sequencing, if multiple differential diagnoses exist.
- Performing CEP78 Sanger sequencing (single-gene testing), if the clinical suspicion of CEP78 related syndrome is high.
Clinical evaluation and targeted genetic testing of identified variants in CEP78 is recommended in parents of probands in case the phase of mutations has to be determined.