CEP104 – Joubert syndrome

The association between CEP104 and Joubert syndrome has been supported by multiple independent case reports and multi‐patient studies, which provide strong evidence for a pathogenic link. At least one report identified a Chinese patient with Joubert syndrome harboring biallelic CEP104 mutations, including the recurrent frameshift variant c.414del (p.Asn138LysfsTer11) (PMID:31625690), consistent with an autosomal recessive inheritance pattern. In addition, other studies have reported CEP104 variants in patients displaying hallmark features of Joubert syndrome such as cerebellar vermis hypoplasia, as well as additional symptoms like hypotonia and intellectual disability.

Genetic evidence is bolstered by the observation of loss‐of‐function and splice site alterations across independent cohorts, with segregation of these biallelic variants in families (PMID:26477546). The recurrent identification of disruptive variants including c.414del (p.Asn138LysfsTer11) across distinct populations further corroborates the gene–disease association.

Functional studies provide additional support: in vitro assays and animal models have demonstrated that knockdown or loss‐of‐function of CEP104 leads to defects in ciliogenesis and impaired Hedgehog signaling, key processes implicated in Joubert syndrome pathology (PMID:31412255; PMID:32453716). Such experiments indicate that CEP104 plays a critical role in primary cilia formation and function.

These genetic and experimental findings converge on a coherent narrative. Biallelic loss‐of‐function mutations in CEP104 are consistently detected in patients with Joubert syndrome, supporting a strong ClinGen gene–disease association. The diversity of variant types (including frameshift and splice variants) seen in multiple unrelated probands further strengthens the diagnosis.

While some reports have hinted at phenotypic heterogeneity associated with CEP104 mutations, the bulk of the evidence, including well‐characterized family segregation and functional analyses, firmly supports its role in Joubert syndrome. Overall, the data exceed the maximum scoring thresholds for ClinGen, leaving little doubt regarding the clinical relevance of CEP104 in this ciliopathy.

Key take‑home: CEP104 mutations represent a highly reliable diagnostic marker for Joubert syndrome, and their identification should critically inform clinical decision‐making and patient management in the setting of suspected ciliopathies.

References

• Molecular genetics & genomic medicine • 2019 • Whole exome sequencing reveals novel CEP104 mutations in a Chinese patient with Joubert syndrome PMID:31625690
• The Journal of clinical investigation • 2020 • Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome PMID:32453716
• Cell reports • 2019 • A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling PMID:31412255
• Molecular biology reports • 2022 • CEP104 gene may involve in the pathogenesis of a new developmental disorder other than joubert syndrome PMID:35359234

Evidence Based Scoring (AI generated)