Submission Details

The CEP104 gene is located on chromosome 1 at 1p36.32 and encodes the centrosomal protein 104kDa. The protein contains an IFT25/APC10-like domain, two coiled-coil domains, a tumor overexpressed gene domain, four zinc finger domains, and an SxIP motif. This centrosomal protein is required for ciliogenesis and for ciliary tip structural integrity. Nagase et al. (1998) screened large proteins expressed in the brain with RT-PCR analysis and detected variable expression in all human tissues examined, with highest levels in kidney and skeletal muscle. Multiple disease entities have been reported in association with this gene, including autosomal recessive Joubert syndrome and autosomal recessive intellectual developmental disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism, inheritance pattern, or phenotypic spectrum. Therefore, these disease entities have been lumped into one disease entity: autosomal recessive ciliopathy: MONDO:0005308.

The CEP104 gene was first reported in relation to autosomal recessive Joubert syndrome in 2015 (Srour et al., PMID: 26477546). Patients with CEP104 gene variants have been reported to have a distinctive cerebellar and brain stem malformation (known as the molar tooth sign), hypotonia, and developmental delays which are the three primary features of Joubert syndrome. In addition, individuals with CEP104 variants have also been reported to have oculomotor apraxia and intellectual disability. At least 9 variants (nonsense, frameshift, splice site) have been reported in 9 probands across 4 publications (PMIDs: 26477546, 31625690, 34196201, 35359234 included in this curation). The mechanism of pathogenicity is known to be loss of function. A maximum score of 12 pts. genetic evidence was reached, considering case-level data and segregation data.

This gene-disease relationship is also supported by expression studies, functional studies, in vitro assays in non-patient cells, and animal models. The scored expression data include the detection of cloned CEP104 (known as Glybp) in rat cortex, hippocampus, cerebellum, and brainstem tissue (Kumar et al., PMID: 7488117). In addition, another expression study noted cloned human CEP104 (known as KIAA0562) in all human tissues examined, with highest levels in kidney and skeletal muscle (Nagase et al., PMID: 9628581). The scored functional evidence involves RNAi experiments with CEP104-depleted cultures of human RPE1 retinal pigment epithelial cells to demonstrate a loss of CEP104 staining at the tip of the primary cilium and daughter centriole, significant reduction in cilia formation, and significant reduction in length of cilia which supports the hypothesis that CEP104 is required for ciliogenesis (Satish Tammana, et al., PMID: 23970417). Frikstad et al. showed that CEP104 silencing in zebrafish causes cilia-related manifestations, including a shortened cilia in Kupffer's vesicle, heart laterality, and cranial nerve development defects. This study also completed in vivo and in vitro analyses of CEP104 and its interaction with another Joubert syndrome-associated cilia tip protein, CSPP1. The loss of CEP104 or CSPP1 in human cells leads to defective Hedgehog signaling in cilia (Frikstad et al., PMID: 31412255). A total of 4.5 pts. experimental evidence was reached.

In summary, there is definitive evidence supporting the relationship between CEP104 and autosomal recessive ciliopathy. 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 the meeting date May 13th, 2024 (SOP Version 11).