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 (e.g. by the PICADAR prediction tool), nasal nitric oxide production rate measurements, high-speed videomicroscopy analysis of ciliary beating and an assessment of ciliary axonemes via transmission electron microscopy. Genetic testing can be implemented as a last step.

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.

Using a high-throughput sequencing approach of genes encoding C1d components, we identified pathogenic variants in the novel primary ciliary dyskinesia genes CFAP46 and CFAP54, and the known primary ciliary dyskinesia gene CFAP221. To fully assess this primary ciliary dyskinesia type, we also analysed individuals with pathogenic variants in CFAP74.

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 in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.

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.

原发性纤毛运动障碍是一种罕见的遗传性疾病，由粘液纤毛清除不足引起慢性气道感染。欧洲呼吸学会的诊断指南主要建议评估临床病史（例如通过 PICADAR 预测工具）、鼻腔一氧化氮生成速率测量、纤毛跳动的高速视频显微镜分析以及通过透射电子显微镜评估睫状轴丝。基因检测可以作为最后一步实施。

在这项研究中，我们旨在表征睫状中枢装置 C1d 投影缺陷的原发性纤毛运动障碍，并评估了欧洲呼吸学会诊断指南对这种原发性纤毛运动障碍类型的适用性。

使用编码 C1d 成分的基因的高通量测序方法，我们鉴定了新的原发性纤毛运动障碍基因 CFAP46 和 CFAP54 中的致病性变异，以及已知的原发性纤毛运动障碍基因 CFAP221。为了全面评估这种原发性纤毛运动障碍类型，我们还分析了具有 CFAP74 致病性变异的个体。

仔细评估显示，C1d 缺陷的原发性纤毛运动障碍与正常的井口组成、正常的鼻腔一氧化氮生成速率、透射电子显微镜显示的纤毛超微结构正常和高速视频显微镜分析的正常纤毛跳动有关。尽管患有慢性呼吸系统疾病，但 PICADAR 并不能可靠地检测到这种原发性纤毛运动障碍类型。然而，我们可以通过体外纤毛转运试验表明，受影响的个体表现出纤毛清除不足。

总体而言，这项研究扩展了原发性纤毛运动障碍基因的范围，并强调 C1d 缺陷原发性纤毛运动障碍的个体在使用当前的诊断算法时无法逃避诊断。为了便于诊断，未来的诊断指南应优先考虑基因检测。