TEKT1

Inheritance Pattern: AR

Disease ID:MONDO:0016575

Submitter: ClinGen

Executive Summary TEKT1: **TEKT1, Primary Ciliary Dyskinesia (MONDO:0016575), autosomal recessive** TEKT1 was first described in relation to PCD (MONDO:0016575), OMIM:603336) in 2018 (PMID: 29121203, Ryan et al. 2018). Currently, there are no published monogenic probands in the literature that display respiratory features characteristic of primary ciliary dyskinesia. Per the recommendations of the ClinGen Lumping and Splitting Working Group, the GCEP decided to dispute the current assertions for the gene-diseases entities. This curation is focused on the relationship between TEKT1 and Primary Ciliary Dyskinesia. The only asserted proband in the literature was a proband with two TEKT1 variants: NM_053285.2:c.730C>T (p.Arg244Ter) and NM_053285.2:c.933G>T (p.Lys311Asn). NM_053285.2:c.933G>T (p.Lys311Asn) was found to have high frequency in the East Asian population. However, the proband also carried two WDR19 variants: NM_025132.4:c.3533G>A (p.Arg1178Gln) and a large deletion of the 5’ region encompassing the 4 first exons of the gene (PMID: 29121203). The proband received a diagnosis of Mainzer-Saldino syndrome with PCD-like airway disease and Leber congenital amaurosis. The PCD-like airway disease was attributed to TEKT1 and the Mainzer-Saldino syndrome was attributed to WDR19. Phenotypes included: intellectual disability/intellectual disability associated with brain ventricle dilatation, cardiomegaly, recurrent infections, pneumothorax/lung collapse, respiratory tract infection/respiratory syncytial virus infections, immotile cilia, mispositioned ciliary basal bodies, misaligned cilia, cystic liver and pancreas, bone dysplasia with cone-shaped epiphyses, thoracic distension, kidney cysts and end-stage renal disease. However, there was a noted lack of sinusitis, otitis media and situs inversus. The proband was an only child of French (Caucasian; mother) and Japanese (father) origin. Two variants: (2 types of genetic mutations: missense (1) and nonsense (1)) that have been reported in 1 proband in 1 publication (PMID: 29121203) are included in this curation. The proband included in this curation was not scored. This gene-disease relationship is also supported by multiple forms of experimental evidence such as expression A (Quantity: 1), model system: Zebrafish (Quantity: 1) and biochemical function B (Quantity: 1). First, GTEx data showed that TEKT1 is primarily expressed in fallopian tube, liver and testis. This evidence is recapitulated within ProteinAtlas where the gene was shown to be primarily expressed in female tissues, respiratory system, brain and male tissues, which is consistent with PCD phenotypes (PMID: 23715323). Ryan et al. 2018 (PMID: 29121203) included a Zebrafish model where the model recapitulated the abnormal ciliary motility found in the human proband. The model also had additional phenotypes typically associated with PCD that were not found in the human probands: very mild body curvature (scoliosis), heart looping (laterality defects), and tekt1 morphants which presented incorrect formation and positioning of the otoliths in the otic vesicle which requires motile cilia function. 54% of the tekt1 morphants presented fused, misshapen or supernumerary otoliths (affected ciliary morphology and motility). Next, Gui el al. 2022 showed the localization of TEKT1 within human respiratory doublet microtubules, which are a part of the microtubule inner protein family (MIPs). Lastly, human patients with PCD caused by defects in CCDC39 or CCDC40 show ciliary structural defects that include reduced signal from tektins (Walton et al, 2023, PMID: 37258679). In conclusion, TEKT1 has a disputed association with Primary Ciliary Dyskinesia. While the published experimental evidence demonstrates phenotypes that are consistent with a PCD diagnosis, it is currently unclear how the disease expression translates to a monogenic disease presentation within human probands. This classification was approved by the Motile Ciliopathy GCEP on March 13th, 2025 (SOP Version 10).