Pathogenic variants in , , and cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.

BACKGROUND

Primary ciliary dyskinesia is a rare genetic disorder caused by insufficient mucociliary clearance leading to chronic airway infections. The diagnostic guideline of the European Respiratory Society primarily recommends an evaluation of the clinical history ( by the PICADAR prediction tool), nasal nitric oxide production rate measurements, high-speed videomicroscopy analysis of ciliary beating and an assessment of ciliary axonemes transmission electron microscopy. Genetic testing can be implemented as a last step.

AIMS

In this study, we aimed to characterise primary ciliary dyskinesia with a defective C1d projection of the ciliary central apparatus and we evaluated the applicability of the European Respiratory Society diagnostic guideline to this primary ciliary dyskinesia type.

METHODS

Using a high-throughput sequencing approach of genes encoding C1d components, we identified pathogenic variants in the novel primary ciliary dyskinesia genes and , and the known primary ciliary dyskinesia gene . To fully assess this primary ciliary dyskinesia type, we also analysed individuals with pathogenic variants in .

RESULTS

Careful evaluation revealed that C1d-defective primary ciliary dyskinesia is associated with normal situs composition, normal nasal nitric oxide production rates, normal ciliary ultrastructure by transmission electron microscopy and normal ciliary beating by high-speed videomicroscopy analysis. Despite chronic respiratory disease, PICADAR does not reliably detect this primary ciliary dyskinesia type. However, we could show by ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.

CONCLUSIONS

Overall, this study extends the spectrum of primary ciliary dyskinesia genes and highlights that individuals with C1d-defective primary ciliary dyskinesia elude diagnosis when using the current diagnostic algorithm. To enable diagnosis, genetic testing should be prioritised in future diagnostic guidelines.