The tetratricopeptide repeat domain 12 (TTC12) gene encodes a cytoplasmic protein of the tetratricopeptide repeat gene family. The gene was first shown to function in dynein assembly in motile cilia and flagella and was first implicated in primary ciliary dyskinesia in 2020 (Thomas et al., PMID: 31978331). Common patient phenotypes included recurrent upper and lower respiratory infections, bronchiectasis, and respiratory ciliary axonemes characterized by absence of inner dynein arms and varying degrees of disorganization detected by transmission electron microscopy, and male infertility due to asthenospermia (PMID: 31978331). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism and autosomal recessive mode of inheritance to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, the asserted cases associated with *TTC12 *variants, were curated for a single disease entity, primary ciliary dyskinesia, 45 (MONDO: 0032924).
This curation includes 11 variants (splice site, nonsense, frameshift and missense) reported in four publications (PMID: 31978331, PMID: 36273201, PMID: 37325566, PMID: 38992144). Absence of TTC12 immunofluorescence signal from proband samples was consistent with a loss-of-function mechanism of pathogenicity.
Experimental evidence supporting this gene disease relationship includes transmission electron microscopic analysis of sperm cells from patients carrying biallelic TTC12 variants, revealing total lack of both inner and outer dynein arms and diminished TTC12 and DNAH17 signals in the patient spermatozoa relative to controls (PMID: 31978331, PMID: 37325566). Knockdown of TTC12a+b in Paramecia recapitulated the sperm phenotype and led to loss of both ODAs and IDAs. The swimming velocity and cell death observed in TTC12a-depleted cells were successfully rescued by the expression of an RNAi-resistant version of the gene (PMID: 31978331).
In summary, TTC12 is definitively associated with autosomal recessive primary ciliary dyskinesia 45. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Motile Ciliopathy GCEP on May 8th, 2025 (SOP version 11).
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