TTC25 – Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder of motile cilia characterized by chronic upper and lower respiratory tract infections, bronchiectasis, and randomization of left–right body asymmetry (situs inversus or heterotaxy) (HP:0002205, HP:0001998).

Biallelic loss‐of‐function variants in TTC25 (HGNC:25280) have been reported in multiple unrelated families with PCD. Whole‐exome sequencing in two families identified a homozygous splice‐site variant c.114+1G>T and a frameshift insertion c.425_426insT (p.Lys142fsTer) in three affected individuals from two families (PMID:27486780). A Turkish cohort study detected TTC25 pathogenic variants in one of 46 genetically diagnosed PCD patients (PMID:31765523).

A newborn with Kartagener syndrome was found to carry compound heterozygous TTC25 variants: the canonical splice donor c.1145+1G>A and a 50 kb heterozygous deletion encompassing TTC25, establishing gross deletion as a second mutational mechanism (PMID:33746037).

Mechanistic studies in CRISPR/Cas9 Ttc25‐knockout mice recapitulated PCD phenotypes, including laterality defects, immotile nodal cilia, and absence of outer dynein arms (ODAs) on transmission electron microscopy (TEM) (PMID:27486780). Patient ciliary analyses by TEM and immunofluorescence confirmed loss of ODAs and the ODA docking complex (ODA‐DC) components CCDC114, CCDC151, and ARMC4. Co‐immunoprecipitation demonstrated a direct interaction between TTC25 and CCDC114, supporting a role in ODA‐DC assembly.

No studies to date have disputed the TTC25–PCD association or reported alternative phenotypes for biallelic TTC25 variants.

Collectively, genetic and experimental evidence satisfy a Strong level of clinical validity: multiple unrelated probands with recessive TTC25 loss‐of‐function variants, segregation in families, and concordant murine and cellular assays. TTC25 should be included in diagnostic gene panels for PCD to enable precise molecular diagnosis and genetic counseling.

References

• American journal of human genetics • 2016 • TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization. PMID:27486780
• Pediatric pulmonology • 2020 • Genotype and phenotype evaluation of patients with primary ciliary dyskinesia: First results from Turkey. PMID:31765523
• European journal of medical genetics • 2021 • A splice site and copy number variant responsible for TTC25-related primary ciliary dyskinesia. PMID:33746037

Evidence Based Scoring (AI generated)