CPLANE1 – Joubert syndrome

CPLANE1 is a key autosomal recessive gene associated with Joubert syndrome, a ciliopathy defined by cerebellar vermis hypoplasia and the characteristic molar tooth sign on MRI. Affected individuals present with hypotonia, ataxia, developmental delay, abnormal eye movements, and variable multiorgan involvement, classifying JS among the primary ciliopathies ([PMID:20615230]).

Clinical Validity and Genetic Evidence

Extensive sequencing studies across diverse populations have identified biallelic CPLANE1 variants in over 60 unrelated JS probands, with segregation of pathogenic alleles in multiple pedigrees and absence in controls in French Canadian and Northern European cohorts ([PMID:22425360], [PMID:25920555]). These data support a Strong gene–disease association by ClinGen criteria.

Inheritance is autosomal recessive, with compound heterozygous or homozygous variants segregating with disease. Segregation analyses demonstrated an aggregate of 19 additional affected relatives carrying pathogenic CPLANE1 alleles in extended families.

Variant Spectrum

Pathogenic CPLANE1 variants encompass missense (e.g., c.3857G>A (p.Arg1286His)), frameshift, nonsense, splicing, intragenic duplications, and complex alleles. A French Canadian founder effect was noted for recurrent truncating and splice-site changes. The broad spectrum of variant types underscores the utility of comprehensive exon sequencing and CNV analysis.

Functional and Experimental Evidence

The Hug mouse model harboring a Jbts17 (CPLANE1) missense mutation exhibits defective ciliary transition zone composition, reduced cerebellar foliation, and polydactyly, mirroring human JS anomalies ([PMID:25877302]). Patient‐derived cells with CPLANE1 truncating or splice variants show loss of CEP290 and NPHP1 from cilia and activation of nonsense-mediated decay, with partial rescue upon SMG1 inhibition, implicating NMD in pathogenesis ([PMID:40074699]). These concordant findings provide Moderate functional evidence.

Genotype–Phenotype Correlations and Clinical Utility

CPLANE1‐mutated JS often presents as a purely neurological phenotype with milder vermian hypoplasia on imaging and low risk of renal involvement compared to CEP290-related cases ([PMID:29146704], [PMID:28431631]). Occasional overlap with OFD6 features (tongue hamartomas, mesoaxial polydactyly, hypothalamic hamartoma) indicates phenotypic variability likely modulated by genetic background.

Conclusion and Key Take-Home

CPLANE1 exhibits a Strong ClinGen gene–disease association with JS, supported by robust genetic and functional data. Comprehensive genetic testing for CPLANE1 should be integrated into JS diagnostic panels and prenatal screening, enabling precise counseling and early intervention.

References

• Orphanet Journal of Rare Diseases • 2010 • Joubert Syndrome and related disorders PMID:20615230
• American Journal of Human Genetics • 2012 • Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population PMID:22425360
• European Journal of Human Genetics • 2016 • Joubert syndrome: genotyping a Northern European patient cohort PMID:25920555
• Human Molecular Genetics • 2015 • Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies PMID:25877302
• Journal of Cellular and Molecular Medicine • 2025 • Unveiling the Pathogenic Role of Novel CPLANE1 Compound Heterozygous Variants in Joubert Syndrome: Insights Into mRNA Stability and NMD Pathway PMID:40074699

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