TCTN3 – Orofaciodigital Syndrome IV

TCTN3 encodes a primary cilium transition zone protein essential for ciliogenesis and Hedgehog signaling. A single patient with orofaciodigital syndrome IV–type features including orofacial dysmorphism, digital anomalies, intellectual disability, and a molar tooth sign was found to carry a homozygous canonical splice‐donor variant c.1203+1G>C (p.?) in TCTN3, predicted to cause in‐frame skipping of exon 7 and loss of function ([PMID:25118024]). No additional affected relatives have been reported, and segregation data are limited.

Mouse knockout of Tctn3 results in reduced ciliogenesis, impaired Hedgehog pathway activity, holoprosencephaly, and neural tube patterning defects; overexpression of Tctn3 rescues ciliogenesis in mutant cells, supporting haploinsufficiency as the pathogenic mechanism in human disease ([PMID:28800946]).

Key take-home: Biallelic loss‐of‐function variants in TCTN3 cause orofaciodigital syndrome IV via defective ciliogenesis, with direct implications for genetic diagnosis and management.

References

• European Journal of Human Genetics • 2015 • Tectonic gene mutations in patients with Joubert syndrome [PMID:25118024]
• 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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