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TTC8
tetratricopeptide repeat domain 8
TTC8 is located on the long (q) arm of chromosome 14, at band 14q31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
TTC8 (tetratricopeptide repeat domain 8) is located on chromosome 14 and encodes a 541-amino-acid protein characterised by multiple tetratricopeptide repeat motifs. These structural elements facilitate protein-protein interactions crucial for assembling multiprotein complexes. The TTC8 protein functions within cilia, microscopic structures that extend from the cell surface and serve as sensory antennae and transport hubs. Proper ciliary function depends on coordinated movement of proteins and other molecules along the ciliary length, a process in which TTC8 participates. When both copies of the gene carry pathogenic variants, individuals may develop features of ciliopathy, a group of conditions caused by defective cilia.
What the gene does
The TTC8 protein contributes to the BBSome, a complex of proteins required for intraciliary transport and ciliary membrane protein trafficking. Cilia are present on most cell types and perform diverse roles, from detecting chemical signals in sensory neurons to moving fluid across epithelial surfaces. Within the cilium, the BBSome acts as an adaptor, recognising specific cargo proteins and facilitating their movement to and from the ciliary compartment. This sorting function ensures that the ciliary membrane maintains the correct composition of receptors and signalling molecules. The tetratricopeptide repeat domains in TTC8 mediate interactions with other BBSome components and cargo proteins, enabling the complex to assemble and function properly. Defects in TTC8 disrupt this transport system, leading to accumulation of proteins in inappropriate locations and impaired ciliary signalling. This molecular dysfunction underlies the multi-organ manifestations observed when TTC8 function is lost.
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Chromosome location
TTC8 is located at chromosomal band 14q31.3 on the long arm of chromosome 14. This region contains numerous genes involved in developmental processes and cellular maintenance. The precise genomic context of TTC8 places it among other genes with roles in cellular organisation and signalling pathways.
Protein structure
The TTC8 protein comprises 541 amino acids organised into a series of tetratricopeptide repeat (TPR) motifs. These include TPR 1 (amino acids 14-47), TPR 2 (amino acids 251-284), TPR 3 (amino acids 285-317), TPR 4 (amino acids 318-351), TPR 5 (amino acids 352-385), TPR 6 (amino acids 386-419), TPR 7 (amino acids 423-456), and TPR 8 (amino acids 457-490). A disordered region spans amino acids 118-137, likely providing flexibility for conformational changes. The TPR motifs form a scaffold that enables the protein to interact with multiple binding partners simultaneously, a property essential for its role in assembling and stabilising protein complexes within the cilium.
Key variants
Pathogenic variants in TTC8 are distributed across the gene and include missense changes, nonsense mutations, and small insertions or deletions. Loss-of-function variants that severely reduce or eliminate protein production typically result in more pronounced clinical features. Because TTC8-related conditions follow autosomal recessive inheritance, individuals require pathogenic variants in both gene copies to develop symptoms, whilst carriers with a single variant remain unaffected.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TTC8 cause Bardet-Biedl syndrome, a ciliopathy characterised by retinal degeneration, obesity, kidney abnormalities, polydactyly (extra fingers or toes), learning difficulties, and hypogonadism. The condition shows variable expression, meaning affected individuals may present with different combinations and severities of these features. Early signs often include vision problems due to progressive retinal dystrophy, which may lead to significant visual impairment. Other features such as developmental delay and renal anomalies contribute to the clinical complexity of this multi-system disorder.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TTC8 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
TTC8 appears on multiple NHS Genomic Medicine Service gene panels with green (diagnostic-grade) classification. These include the Bardet Biedl syndrome panel (R107), Retinal disorders panel (R32), Severe early-onset obesity panel (R149), Intellectual disability panel (R29), Fetal anomalies panel (R21), and Skeletal dysplasia panel (R104). The gene is also listed on panels for Ophthalmological ciliopathies, Rare multisystem ciliopathy disorders, Renal ciliopathies, and Limb disorders, reflecting the diverse organ systems affected by TTC8 dysfunction. This broad panel representation underscores the gene's relevance across multiple clinical specialties within the NHS diagnostic pathway.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a TTC8 variant?
Carriers have one pathogenic variant in TTC8 and one functioning copy. They typically remain healthy and do not develop symptoms. However, if both parents are carriers, each pregnancy has a 25% chance of inheriting two variants and being affected by Bardet-Biedl syndrome.
How are TTC8-related conditions diagnosed?
Diagnosis combines clinical evaluation of characteristic features such as retinal changes, obesity, and kidney abnormalities with genetic testing to identify biallelic pathogenic variants in TTC8. Molecular confirmation helps guide clinical management and family planning.
Can TTC8 variants affect only one organ system?
Whilst Bardet-Biedl syndrome is a multi-system disorder, the severity and combination of features vary considerably between affected individuals. Some people may have more prominent manifestations in certain organs, though multiple systems are typically involved to some degree over time.