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TCTN3
tectonic family member 3
TCTN3 is located on the long (q) arm of chromosome 10, at band 10q24.1. Arm ratio per GRCh38 - banding schematic.
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Overview
TCTN3 belongs to the tectonic protein family, a group of molecules that contribute to the structural organisation of transition zones at the base of cilia. Cilia are present on most human cell types and serve diverse functions, from sensing chemical signals to moving fluid across epithelial surfaces. During embryonic development, cilia coordinate tissue patterning and left-right body axis determination. The TCTN3 protein localises to a specialised region called the ciliary transition zone, which acts as a gatekeeper controlling what molecules can enter or exit the cilium. Disruption of this regulatory barrier can impair multiple developmental pathways, leading to a spectrum of clinical features collectively termed ciliopathies.
What the gene does
The tectonic family member 3 protein functions as a structural component of the ciliary transition zone, a cylindrical region positioned between the basal body and the ciliary axoneme. This transition zone contains an intricate protein network that forms diffusion barriers and anchoring points, ensuring selective transport into the ciliary compartment. TCTN3 appears to stabilise these membrane-associated protein complexes, thereby maintaining the integrity of ciliary architecture. Proper transition zone assembly is required for the cilium to transduce extracellular signals through pathways such as Hedgehog and Wnt signalling, both of which are critical for embryonic patterning and tissue differentiation. When TCTN3 function is compromised, the ciliary gate becomes permeable or structurally defective, resulting in aberrant signal transduction and defective developmental programmes in multiple organ systems.
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Chromosome location
TCTN3 is located on the long arm of chromosome 10 at position 10q24.1. The gene spans genomic DNA and encodes a transcript that is translated into a 607-amino-acid protein. The chromosomal region 10q24 contains several genes involved in developmental processes, and deletions or rearrangements in this region can contribute to syndromic presentations.
Protein structure
The TCTN3 protein comprises 607 amino acids. Structural prediction indicates a disordered region spanning amino acids 21-60, which may confer flexibility or serve as a binding interface for regulatory partners. Beyond this disordered segment, the protein is predicted to contain transmembrane or membrane-associated domains that anchor it within the ciliary transition zone. Detailed experimental characterisation of additional functional domains remains an area of ongoing research.
Key variants
Pathogenic variants in TCTN3 are typically inherited in an autosomal recessive manner, meaning that affected individuals carry two altered copies of the gene. Loss-of-function changes, including nonsense and frameshift variants, are commonly observed and result in absent or severely truncated protein. Missense variants affecting conserved residues may also impair protein folding or interaction with transition zone partners. Carrier screening can identify individuals who harbour one pathogenic variant and are at risk of having affected children if their partner is also a carrier.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1164dup | p.Lys389fs | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome 18 |
c.276_277del | p.Cys92_Asp93delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | TCTN3-related disorder |
c.338_341del | p.His113fs | Pathogenic/Likely pathogenic | ★★☆☆ | TCTN3-related disorder |
c.622dup | p.Tyr208fs | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome 18 |
c.650_653del | p.Tyr217fs | Pathogenic/Likely pathogenic | ★★☆☆ | TCTN3-related disorder |
c.710del | p.Gly237fs | Pathogenic/Likely pathogenic | ★★☆☆ | Joubert syndrome 18 |
c.717_718del | p.Cys239_Ala240insTer | Pathogenic/Likely pathogenic | ★★☆☆ | TCTN3-related disorder |
c.776dup | p.Lys260fs | Pathogenic/Likely pathogenic | ★★☆☆ | TCTN3-related disorder |
c.910dup | p.Thr304fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.940G>T | p.Gly314Ter | Pathogenic/Likely pathogenic | ★★☆☆ | TCTN3-related disorder |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in TCTN3 are associated with a spectrum of ciliopathy phenotypes, ranging from isolated congenital anomalies to multisystem syndromic conditions. Clinical features can include craniofacial anomalies such as cleft lip and palate, structural brain malformations, renal cystic disease, skeletal abnormalities, and ocular defects. Some affected individuals present with intellectual disability or developmental delay. The severity and combination of features vary widely, reflecting the pleiotropic roles of cilia during development. The range of presentations underscores the importance of comprehensive genetic evaluation in families with suggestive clinical findings.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TCTN3 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
TCTN3 is included on multiple NHS Genomic Medicine Service gene panels, reflecting its clinical relevance for diverse developmental disorders. It holds green (high-evidence) status on the Clefting, DDG2P, Fetal anomalies (R21), Intellectual disability (R29), Neurological ciliopathies, Ophthalmological ciliopathies, Rare multisystem ciliopathy disorders, Renal ciliopathies, and Skeletal dysplasia (R104) panels. This broad panel representation indicates that TCTN3 testing is recommended for individuals presenting with ciliopathy-related phenotypes across paediatric and prenatal diagnostic pathways in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is a ciliopathy?
A ciliopathy is a group of genetic disorders caused by defects in the structure or function of cilia, the hair-like projections on cell surfaces. Because cilia play roles in many organs during development, ciliopathies often affect multiple systems, including the brain, kidneys, eyes, and skeleton.
How is TCTN3-related ciliopathy inherited?
TCTN3-related conditions follow an autosomal recessive inheritance pattern. An affected individual inherits one pathogenic variant from each parent, both of whom are typically unaffected carriers. Two carrier parents have a 25% chance with each pregnancy of having an affected child.
Can carrier screening detect TCTN3 variants?
Yes, carrier screening can identify individuals who carry one pathogenic TCTN3 variant. Knowing carrier status allows prospective parents to understand their reproductive risks and make informed decisions about family planning, including options such as prenatal diagnosis or preimplantation genetic testing.