CEP290 – Joubert syndrome with oculorenal defect

Centrosomal protein 290 kDa (CEP290) is a cilia–basal body component essential for ciliogenesis and centrosome integrity. Biallelic pathogenic variants in CEP290 underlie an autosomal recessive ciliopathy spectrum, including Joubert syndrome with oculorenal defect ([PMID:29217415]).

Clinical validity: The CEP290–Joubert syndrome with oculorenal defect association is classified as Strong based on six probands across four unrelated families harboring homozygous or compound heterozygous loss-of-function and splice variants, segregation of variants in affected siblings, and concordant ciliary dysfunction assays.

Genetic evidence: Inheritance is autosomal recessive. Six probands—including two siblings—presented with the molar tooth sign, hypotonia, nystagmus, psychomotor retardation, and bilateral renal cysts while retaining normal renal function. Variants include the recurrent intronic splice mutation c.6012-12T>A and splice-site and frameshift alleles (c.1711+1G>A; c.5924delT) that segregate with disease ([PMID:35642300], [PMID:29217415]). One additional affected sibling demonstrated segregation beyond probands.

Functional evidence: Patient-derived fibroblasts exhibit reduced CEP290-positive cilia, elongated axonemes protruding into the cytoplasm, and decreased ciliation, indicating centrosome disruption and impaired ciliogenesis consistent with a loss-of-function mechanism ([PMID:29217415]).

Conflicting evidence: No studies dispute the CEP290 association with Joubert syndrome with oculorenal defect.

Conclusion: Biallelic CEP290 LoF and splice variants cause autosomal recessive Joubert syndrome with oculorenal defect through disrupted ciliogenesis. CEP290 genetic testing is recommended for diagnostic confirmation, family counseling, and guiding management of ciliary manifestations.

Key take-home: CEP290 sequencing provides definitive diagnosis of Joubert syndrome with oculorenal defect and informs surveillance of neurologic and renal complications.

References

• Brain & development • 2018 • Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases. PMID:29217415
• Neuropediatrics • 2023 • Two Siblings Showing a Mild Phenotype of Joubert Syndrome with a Specific CEP290 Variant. PMID:35642300

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