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

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.

Pulmonary Function in Paediatric Patients with Inflammatory Bowel Disease.

BACKGROUND: Among the extraintestinal manifestations of inflammatory bowel disease (IBD), those involving the lungs are relatively rare and often overlooked. There are only scarce data on the prevalence of IBD-associated lung involvement in children. OBJECTIVES: The aim of our study was to assess pulmonary function in IBD children by different methods and to evaluate the influence of immunosuppressive therapy on disease severity. METHODS: Seventy-two children with IBD (mean age of 14.45 ± 2.27 years) and 40 age-matched healthy controls (mean age of 14.17 ± 2.82) were included in the study. Pulmonary function tests (PFTs) were carried out by means of spirometry, oscillometry (IOS) and fractional exhaled nitric oxide (FeNO) to assess the pulmonary involvement. RESULTS: Certain differences were observed between the study group and the control group, regarding the spirometric and oscillometry parameters. The fractions of exhaled nitric oxide did not differ between the group with IBD patients and the control group with regards to disease activity, the duration of illness and the administered immunosuppressive treatment. CONCLUSIONS: The mean spirometry results were significantly different in the study group compared to the controls, although they were still within the normal limits. The pulmonary function abnormalities did not depend on either the disease activity or the immunosuppressive therapy. Oscillometry could be a supplementary method to assess pulmonary resistance. In turn, FeNO does not appear to be useful either in screening IBD children for pulmonary involvement or for the evaluation of disease activity. It appears then that only general screening of asymptomatic patients is a suitable method and a necessary recommendation in this population, prompting a revision of the current diagnostic approach.