Submission Details

TCTN3 was first linked to autosomal recessive orofacialdigital syndrome IV (OFDS IV), Meckel-Gruber syndrome (MKS), and Joubert syndrome (JBTS) in 2012 by homozygosity mapping in several unrelated families with affected children diagnosed with these various ciliopathy conditions (PMID: 22883145). Since then, biallelic alterations in TCTN3 have been identified in patients presenting with abnormalities in several organ systems including kidneys (cystic), brain (corpus callosum agenesis, molar tooth sign, occipital encephalocele, hypotonia, ataxic gait, developmental delay, intellectual disability), limbs and digits (shortened limbs, polydactyly), liver (bile duct proliferation) and dysmorphic facies; many of which are part of the phenotypic spectrum of the above described ciliopathies (PMIDs: 22883145, 22118024, 34096782) . Given the heterogenous phenotypic manifestations of patients with biallelic variants in TCTN3, (highlighted in the first, Thomas et al., study (PMID: 22883145)), but no apparent differences in molecular mechanism of disease pathogenesis, the gene disease association of TCTN3 has been lumped to the ‘Ciliopathy’ term in adherence with criteria established by the Lumping and Splitting working group. Several other recent studies have also reported patients with biallelic TCTN3 variants who present with similar symptoms (PMIDs: 26092869, 30629328, 32139166, 34411415, 35170189). Within these reports, many probands present with renal symptoms including cystic kidneys and imaging abnormalities among other clinical findings (PMIDs: 22883145, 26092869, 32139166, 34096782, 34411415). Overall, the genetic evidence included in the curation has reached the maximum of 12 points. Evidence supporting gene-disease relationship not only includes genetic case-level data but also experimental data using mouse models and cell lines derived from patients harboring TCTN3 mutations. These animal models have recapitulated an array of defects observed in patients including cystic kidneys, skeletal, and neurological abnormalities (PMIDs: 28800946, 29725084). Further, the animal and cell-based studies have demonstrated that absence of Tctn3 results in aberrant Sonic Hedgehog (Shh) signaling via improper modulation of GLI3 protein levels, a key component of Shh pathway and leads to reduced cilia formation, both of which can be rescued by overexpressing wild-type Tctn3 (PMID: 22883145, 28800946, 29725084). The experimental evidence was scored at a total of 4 points. Hence, biallelic pathogenic variants in TCTN3 are “Definitely” associated with autosomal recessive ciliopathy. Importantly, the genetic and experimental evidence supporting gene-disease validity has been replicated over time in both research and clinical diagnostic settings. This classification was approved by the ClinGen Kideny Cystic and Ciliopathy Disorders Expert Panel on the meeting date 11/10/2022 (SOP Version 8).