TCTN3 – Ciliopathy

TCTN3 encodes a transition zone membrane protein essential for primary cilia integrity and Hedgehog signaling. Ciliopathies (Ciliopathy) are a spectrum of autosomal recessive disorders featuring neural tube defects, polydactyly, and renal cysts. To date, two unrelated fetuses with biallelic TCTN3 loss-of-function variants have been reported. The first case presented occipital encephalocele and orofaciodigital type IV due to compound heterozygous c.1423_1429del (p.Arg475SerfsTer10) and c.3G>A (p.Met1Ile) variants (PMID:35170189). A second fetus diagnosed with Meckel–Gruber syndrome harbored a homozygous c.530del (p.Lys177ArgfsTer47) variant in exon 4 of TCTN3 (PMID:34096792). These reports support an autosomal recessive inheritance with loss-of-function mechanism.

Loss of Tctn3 in knockout mice causes decreased ciliogenesis, impaired Hedgehog signaling, holoprosencephaly, and randomized heart looping, with rescue of ciliogenesis upon Tctn3, but not Tctn1 or Tctn2, overexpression (PMID:28800946). In human cardiomyocytes carrying heterozygous p.Gly423Glu, contractile rate and force are reduced and cardiac developmental pathways are dysregulated, consistent with ciliary dysfunction (PMID:33098376). These experimental models confirm that TCTN3 deficiency disrupts cilia-mediated signaling. Under ClinGen criteria, the current genetic and functional evidence is categorized as Limited. Further segregation and familial studies are needed to strengthen the association. Key Take-home: Biallelic truncating variants in TCTN3 cause autosomal recessive ciliopathies and should be included in diagnostic gene panels.

References

• American Journal of Medical Genetics Part A • 2022 • Prenatally detected encephalocele associated with a novel pathogenic TCTN3 variant: A case report and literature review. PMID:35170189
• Genetic Testing and Molecular Biomarkers • 2021 • Meckel-Gruber Syndrome: Clinical and Molecular Genetic Profiles in Two Fetuses and Review of the Current Literature. PMID:34096792
• 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
• Journal of Cellular and Molecular Medicine • 2020 • Novel mutations of TCTN3/LTBP2 with cellular function changes in congenital heart disease associated with polydactyly. PMID:33098376

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