TCTN1 and Joubert Syndrome

TCTN1 has emerged as an important gene in the etiology of Joubert syndrome, a ciliopathy characterized by cerebellar and brainstem malformations manifesting as the molar tooth sign on MRI, hypotonia, and global developmental delay (PMID:26489806). Several independent case reports have now implicated TCTN1 variants in patients with Joubert syndrome, reinforcing its clinical relevance and prompting further investigation into its biological role.

The genetic evidence supports an autosomal recessive inheritance model, with affected individuals harboring compound heterozygous variants including both missense and truncating mutations. For instance, one report documented the variant c.800A>G (p.Tyr267Cys) in a Saudi boy with classical Joubert syndrome features (PMID:34980503). Additional reported loss‑of‑function alleles further substantiate the causative link between TCTN1 and the disease phenotype.

Multi‐patient studies have contributed to the accumulation of genetic data, with independent probands showing segregation of pathogenic variants in TCTN1 across unrelated families. This combined evidence, derived from case reports and gene panel analyses, enhances confidence in the genetic association by demonstrating both allelic heterogeneity and consistent clinical presentations among affected patients (PMID:22693042).

Experimental assessments provide moderate functional evidence supporting the pathogenicity of TCTN1 mutations. Studies using murine models have shown that loss of Tctn1 disrupts neural tube patterning and Gli3 processing, underlying developmental mechanisms that are congruent with the neurological deficits observed in Joubert syndrome (PMID:28800946). These functional data, although divergent in aspects of ciliogenesis and Hedgehog signaling, corroborate the clinical and genetic findings.

The integration of robust genetic findings with supportive experimental evidence creates a coherent narrative for the role of TCTN1 in Joubert syndrome. Although additional evidence exists beyond the maximum ClinGen score, the current dataset strongly supports the diagnostic utility of TCTN1 variants in defining the clinical heterogeneity of Joubert syndrome.

Key take‑home: The convergence of multiple case reports, segregation data, and functional studies confirms that TCTN1 is a strong candidate gene for Joubert syndrome, offering a valuable marker for diagnostic decision‑making and clinical management.

References

• Research in developmental disabilities • 2015 • Cognitive rehabilitation in a child with Joubert Syndrome: Developmental trends and adaptive changes in a single case report PMID:26489806
• Brain & development • 2022 • Clinical and molecular characteristics of tectonic (TCTN1) gene‑related Joubert syndrome in a Saudi boy PMID:34980503
• Human mutation • 2012 • Molecular characterization of Joubert syndrome in Saudi Arabia PMID:22693042
• Developmental biology • 2017 • Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse PMID:28800946

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