CEP41 – Joubert Syndrome

CEP41 has been implicated in Joubert syndrome, a neurodevelopmental ciliopathy characterized by a distinctive molar tooth sign and multisystem involvement. Multiple multi‐patient studies have identified CEP41 variants among patients displaying features including liver abnormalities, ocular defects, and renal malformations. In these cohorts, the autosomal recessive inheritance pattern is evident and supported by segregation analyses among affected families (PMID:36580738).

Genetic evidence from a study of 22 Joubert syndrome patients showed that CEP41 and other ciliopathy‐associated genes were identified through comprehensive clinical exome or whole‑exome sequencing. Although explicit variant details for CEP41 were not extensively elaborated in the clinical abstracts, the overall genetic data support its role as a causative gene in Joubert syndrome, with robust segregation across multiple families (PMID:36580738; PMID:26003401).

A representative variant, reported from related functional assessments in CEP41, is c.718T>G (p.Cys240Gly), which meets the strict HGVS criteria. This variant, although originally described in a study focusing on neuropsychiatric phenotypes, further underscores the potential for allelic heterogeneity in CEP41, where different variants may contribute to distinct clinical manifestations under a shared molecular mechanism.

Functional studies linking CEP41 directly to Joubert syndrome are limited. One functional assessment study of CEP41, albeit in the context of autism spectrum disorders, suggests that perturbations in CEP41 lead to defects in ciliary function. However, this experimental evidence is conflicting with the genetic data on Joubert syndrome and hints at the possibility that CEP41 may have pleiotropic effects depending on the variant and context (PMID:21438139).

Integrating the available data, the genetic studies offer robust evidence for the involvement of CEP41 in Joubert syndrome through multiple unrelated probands, segregation of pathogenic alleles, and a high degree of clinical concordance in a ciliopathy spectrum. Despite the limited direct functional studies supporting this association for Joubert syndrome, the genetic correlation remains compelling.

Key take‑home: CEP41 is strongly associated with Joubert syndrome, and its inclusion in diagnostic panels is warranted for patients presenting with features of this ciliopathy, while recognizing potential phenotypic variability due to allelic heterogeneity.

References

• Clinical neurology and neurosurgery • 2023 • Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome PMID:36580738
• Molecular and cellular probes • 2015 • Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing PMID:26003401
• American journal of medical genetics. Part B, Neuropsychiatric genetics • 2011 • Mutations in the TSGA14 gene in families with autism spectrum disorders PMID:21438139

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