TCTN1

Inheritance Pattern: AR

Disease ID:MONDO:0013608

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013608

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

The Tectonic Family, Member 1 (TCTN1) gene is located on chromosome 12 at 12q24.11, spans 13 exons, and consists of 592 amino acids. It encodes encodes a protein involved in ciliogenesis and Hedgehog signaling. TCTN1 is a component of the ciliary transition zone complex, interacting with other ciliopathy-related proteins such as TCTN2, TCTN3, MKS1, TMEM67, and CEP290. It plays a critical role in regulating ciliary membrane composition and signaling pathways, particularly the Hedgehog (Hh) pathway, which is essential for embryonic development. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism or inheritance pattern, and phenotypic variability was associated with a spectrum, rather than isolated disease entities. Therefore, the following disease entities have been lumped into one disease entity: Joubert Syndrome 13 (JBTS13), Meckel-Gruber Syndrome (MKS), and Varadi syndrome (Orofaciodigital syndrome type VI). The lumped disease entity is autosomal recessive ciliopathy. Joubert Syndrome is a rare neurodevelopmental disorder characterized by cerebellar vermis hypoplasia, “Molar tooth sign” on MRI, hypotonia, ataxia, developmental delay, variable involvement of the kidney (nephronophthisis), liver, and retina. The first case of Joubert Syndrome 13, in association with TCTN1, was first reported in 2011 (Garcia-Gonzalo et al., PMID 21725307). Meckel–Gruber Syndrome is a severe, often lethal ciliopathy with occipital encephalocele, polycystic kidneys, polydactyly. Additional features include liver fibrosis, cardiac anomalies, and pulmonary hypoplasia. Varadi Syndrome is a subtype of orofaciodigital syndrome with craniofacial abnormalities, polydactyly and cerebellar malformations (overlapping with Joubert syndrome). A total of 16 variants, (splice acceptor, slice donor, missense, frameshift, nonsense, inframe deletion, intron variant) have been reported in over 12 probands in 12 publications (PMIDs: 21725307, 22693042, 26123494, 26477546, 26489806, 28593008, 28631893, 31302911, 32139166, 34980503, 39097279, 39731278) were included in this curation. The first publication is from 2011, while the most recent one is from 2025. The maximum score for genetic evidence (12 pts.) has been reached, considering case-level data and segregation data. This gene-disease relationship is also supported by experimental studies (including a mouse model, rescue evidence, biochemical functional data, expression-level evidence, and interaction evidence; PMIDs: 12723291, 16357211, 21725307). Mouse and human TCTN1 were first identified in the 2006. TCTN1 (also known as tectonic) is first expressed during gastrulation stages in the ventral node in in the gut endoderm, limb buds, notochord, somites, neural tube, and floorplate. Tectonic was shown to be required for Hh-mediated patterning of the ventral neural tube. Tectonic mutants lacking a histologically distinct floorplate and died, displaying holoprosencephaly, a defect associated with reduced Hh signaling. Tectonic acts in neural patterning by positively regulating the Hh pathway and also acts downstream of Ptch and Rab23, negatively regulating the Hedgehog signaling pathway, and its function is required for their effects to be seen. TCTN1 was later identified as a novel disease gene in ciliopathies in 2011 through comprehensive genetic, structural, and functional analyses. At the molecular level, TCTN1 forms part of a ciliopathy-associated protein complex and interacts with multiple transition zone proteins, including TCTN2, TCTN3, B9D1, MKS1, TMEM67, TMEM216, CEP290, and CC2D2A, with strong evidence that TCTN1, TCTN2, and TCTN3 function together within the same complex. Localization studies demonstrate that TCTN1 and its interactors are enriched at the ciliary transition zone, where they regulate the composition and organization of ciliary proteins. Functional experiments further show that loss of TCTN1 disrupts the localization of key transition zone components, such as MKS1 and TMEM67, indicating a role in maintaining transition zone integrity. Together, these findings support that TCTN1 is an essential structural and functional component of the ciliary transition zone complex, required for proper ciliogenesis and ciliary signaling. Another previous study investigated the physiological role of TCTN1 in Chlamydomonas reinhardtii, showing that full-length TCTN1 could rescue the tctn1 cell line, which is a TCTN1-null mutant. In summary, there is definitive evidence supporting the relationship between TCTN1 and autosomal recessive ciliopathy. This has been demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders Gene Curation Expert Panel GCEP on the meeting date Febbruary 25th, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0013608

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0018921

Submitter: Orphanet