METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
方法:遗传变异和临床表现(年龄,性别,身体质量指数,侧向缺陷,FEV1)是使用ERNLUNG国际PCD登记处从19个国家收集的。根据ACMG指南评估遗传数据。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侧向缺陷和FEV1的相关性。
结果:1236名个体在46个PCD基因中携带908种不同的致病DNA变异。我们发现,由于存在不同的创始人变体,各国之间的PCD基因型分布存在很大差异。与病理超微结构缺陷(平均72%;47-100%)和侧向缺陷(平均42%;28-69%)相关的PCD基因型的患病率在各国之间差异很大。在没有病理形态纤毛超微结构缺陷的PCD个体中,侧向缺陷的患病率显着降低(18%)。PCD队列的FEV1z评分中位数降低(-1.66)。在具有CCNO(-3.26)的个体组中,CCDC39(-2.49),和CCDC40(-2.96)变体,FEV1z-得分明显较低,而与整个PCD队列相比,DNAH11(-0.83)和ODAD1(-0.85)变异个体组的FEV1z评分降低程度显著。
结论:这种前所未有的多国DNA变异数据集及其在各国分布的信息有助于解释PCD的遗传流行病学,并提供诊断和表型特征的预测,例如肺功能的过程。