Variable expressivity of TCTEX1D2 mutations and a possible pathogenic link of molar-incisor malformation to ciliary dysfunction

- Our study expands the spectrum of clinical features associated with mutations linked to Jeune syndrome, and highlights the need to assess dental phenotypes in affected individuals.
- Our study confirms TCTEX1D2 mutations as a cause of short-rib dysplasia with variable expressivity.
- TCTEX 1 domain-containing protein 2 might have an unknown role in odontogenesis.

ObjectiveClarification of the molecular basis of a ciliopathy associated with molar-incisor malformation in a consanguineous Turkish family.DesignFull dental and clinical examinations, histologic analysis, comprehensive genetic analyses including exome sequencing, ciliary function tests and transmission electron microscopy of ciliary biopsies in the surviving patient.ResultsTwo siblings had situs inversus and complex heart defects suggestive of ciliary dysfunction. The affected girl who died in utero showed severe chest abnormalities compatible with Jeune syndrome which were not present in the affected boy. Dental investigations in the boy showed typical signs of molar-incisor-malformation. Exome sequencing identified a homozygous intragenic deletion in TCTEX1D2 which is predicted to completely remove protein function. Ciliary function tests and electron microscopy showed mild irregularities of motile cilia such as compound cilia and loss of membranes.ConclusionsOur findings support the suggestion that TCTEX1D2 mutations have variable expressivity and may be associated with disturbances of embryonic development caused by both, ciliary signaling and motile dysfunction. The presence of molar-incisor-malformation in the living patient raises the possibility of a pathogenetic link of this rare dental anomaly to ciliary dysfunction during tooth development at least in some individuals.