Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes.

Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV₁)) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV₁.

The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47–100%) and laterality defects (mean 42%, range 28–69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV₁ z-score (–1.66). Median FEV₁ z-scores were significantly lower in CCNO (–3.26), CCDC39 (–2.49) and CCDC40 (–2.96) variant groups, while the FEV₁ z-score reductions were significantly milder in DNAH11 (–0.83) and ODAD1 (–0.85) variant groups compared to the whole PCD cohort.

This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function.

原发性纤毛运动障碍 (PCD) 是一组罕见的遗传性疾病，其特征是纤毛气道间隙不足，可能与偏侧性缺陷有关。我们的目的是描述潜在的基因缺陷、基因型的地理差异及其与诊断结果和临床表型的关系。

使用欧洲参考网络的 ERN-LUNG 国际 PCD 登记系统从 19 个国家收集遗传变异和临床结果（年龄、性别、体重指数、侧向缺陷、1 秒用力呼气量 (FEV ₁ )）。遗传数据根据美国医学遗传学和基因组学学院指南进行评估。我们评估了相关基因和遗传变异的区域分布以及基因型与偏侧性缺陷和 FEV _{1 的}相关性。

该研究纳入了 1236 名个体，其中 46 个 PCD 基因携带 908 个不同的致病性 DNA 变异。我们发现，由于存在不同的创始人变异，PCD 基因型在不同国家的分布存在相当大的差异。与特征性超微结构缺陷（平均 72%，范围 47-100%）和偏侧性缺陷（平均 42%，范围 28-69%）相关的 PCD 基因型患病率在各国之间差异很大。在没有特征性纤毛超微结构缺陷的 PCD 个体中，侧向缺陷的发生率显着较低 (18%)。 PCD 队列的_FEV1 z 分数中位数降低 (–1.66)。 CCNO (–3.26)、 CCDC39 (–2.49) 和CCDC40 (–2.96) 变异组的中位 FEV ₁ z 分数显着较低，而DNAH11 (–0.83) 和ODAD1中 FEV ₁ z 分数的降低明显较轻。 –0.85) 变异组与整个 PCD 队列相比。

这个前所未有的DNA变异多国数据集及其在各国的分布信息有助于解释PCD的遗传流行病学，并表明遗传变异可以预测诊断和表型特征，例如肺功能的过程。