Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations

Abstract

Background 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. 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. Conclusion 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. © 2024 European Respiratory Society. All rights reserved.

• author: Raidt, J. ; Hansen, C.R. and Omran, H.
• author collaboration: et al.
• organization: Paediatrics (Lund)
• publishing date: 2024
• type: Contribution to journal
• publication status: published
• subject: Medical Genetics and Genomics (including Gene Therapy)
• keywords: Adolescent, Adult, Aged, Axonemal Dyneins, Child, Child, Preschool, Cytoskeletal Proteins, Europe, Female, Forced Expiratory Volume, Genetic Association Studies, Genetic Variation, Genotype, Humans, Infant, Kartagener Syndrome, Male, Middle Aged, Mutation, Phenotype, Proteins, Registries, Young Adult, nitric oxide, axonemal dynein, CCDC39 protein, human, CCDC40 protein, human, cytoskeleton protein, DNAH11 protein, human, protein, age, Article, body composition, body mass, child, ciliary dyskinesia, cohort analysis, correlational study, cystic fibrosis, diagnostic accuracy, disease severity, dyskinesia, female, forced expiratory volume, gene, genetic screening, genetic variability, genotype, high throughput sequencing, human, hydrocephalus, immunofluorescence, immunofluorescence microscopy, lung clearance, lung function, major clinical study, male, phenotype, preschool child, prevalence, Sanger sequencing, Schizosaccharomyces pombe, school child, statistical analysis, transmission electron microscopy, video microscopy, adolescent, adult, aged, genetic association study, genetic variation, genetics, infant, Kartagener syndrome, middle aged, mutation, pathophysiology, register, young adult
• in: European Respiratory Journal
• volume: 64
• issue: 2
• article number: 2301769
• publisher: European Respiratory Society
• external identifiers: scopus:85194899923; pmid:38871375
• ISSN: 0903-1936
• DOI: 10.1183/13993003.01769-2023
• language: English
• LU publication?: yes
• id: c7daebc6-070e-43ee-a9ef-eccc9dbe2338
• date added to LUP: 2025-10-16 11:25:48
• date last changed: 2025-10-17 03:00:15