Submission Details

TCTN2 is located on chromosome 12 at 12q24.31 and encodes the Tectonic family member 2 type I membrane protein. The TCTN2 protein is a component of the tectonic-like complex which is localized at the transition zone of primary cilia and acts as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. TCTN2 was first reported in relation to Joubert Syndrome 24 in 2011 (Sang et al., PMID: 21565611). Joubert Syndrome is an autosomal recessive ciliopathy characterized by delays in psychomotor development in addition to congenital malformations of the brainstem appearing as agenesis or hypoplasia of the cerebellar vermis on brain imaging. TCTN2 has been noted to be associated with the following disease entities: Joubert Syndrome and Meckel Syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. We additionally found that observed phenotypic variability was representative of Meckel syndrome presenting as a severe manifestation on the phenotypic spectrum of Joubert Syndrome. Therefore, the following disease entities have been lumped into one disease entity, Joubert Syndrome 24 (OMIM:616654). A total of 6 variants (splice site, nonsense, and frameshift) that have been reported in 6 probands in 4 publications (PMID: Shaheen et al., 2011, PMID: 21462283; PMID: 21565611; Huppke et al., 2015, PMID: 25118024; Zhang et al., 2020, PMID: 32655147) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by expression studies, protein interaction studies and mouse models (Garcia-Gonzalo et al., 2011, PMID: 21725307; PMID: 21462283; PMID: 21565611). TCTN2 was shown to have significant levels of expression in mice in tissues commonly affected in Meckel Syndrome. Additionally, TCTN2 was shown to interact with another component of the tectonic-like complex and also implicated in Joubert Syndrome, TCTN1. The gene-disease relationship is supported by two mouse models, with a ciliopathy phenotype shown in one TCTN2 null mouse and further recapitulation of the human phenotype in another. In summary, TCTN2 is definitively associated with autosomal recessive Joubert Syndrome 24. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 02.01.2023 (SOP Version 9.0).