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Raidt, Johanna; Riepenhausen, Sarah; Pennekamp, Petra; Olbrich, Heike; Amirav, Israel; Athanazio, Rodrigo A; Aviram, Micha; Balinotti, Juan E; Bar-On, Ophir; Bode, Sebastian FN; Boon, Mieke; Borrelli, Melissa; Carr, Siobhan B; Crowley, Suzanne; Dehlink, Eleonora; Diepenhorst, Sandra; Durdik, Peter; Dworniczak, Bernd; Emiralioğlu, Nagehan; Erdem, Ela; Fonnesu, Rossella; Gracci, Serena; Große-Onnebrink, Jörg; Gwozdziewicz, Karolina; [...]

Analyses of 1,236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations

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  • Medientyp: E-Artikel
  • Titel: Analyses of 1,236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations
  • Beteiligte: Raidt, Johanna; Riepenhausen, Sarah; Pennekamp, Petra; Olbrich, Heike; Amirav, Israel; Athanazio, Rodrigo A; Aviram, Micha; Balinotti, Juan E; Bar-On, Ophir; Bode, Sebastian FN; Boon, Mieke; Borrelli, Melissa; Carr, Siobhan B; Crowley, Suzanne; Dehlink, Eleonora; Diepenhorst, Sandra; Durdik, Peter; Dworniczak, Bernd; Emiralioğlu, Nagehan; Erdem, Ela; Fonnesu, Rossella; Gracci, Serena; Große-Onnebrink, Jörg; Gwozdziewicz, Karolina; [...]
  • Erschienen: European Respiratory Society (ERS), 2024
  • Erschienen in: European Respiratory Journal (2024), Seite 2301769
  • Sprache: Englisch
  • DOI: 10.1183/13993003.01769-2023
  • ISSN: 0903-1936; 1399-3003
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: BackgroundPrimary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterized 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.MethodsGenetic variants and clinical findings (age, sex, body mass index, laterality defects, FEV1) were collected from 19 countries using the ERN LUNG International PCD Registry. Genetic data were evaluated according to ACMG guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1.Results1236 individuals carried 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%; 47–100%) and laterality defects (mean 42%; 28–69%) varied widely among the 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 FEV1z-score (−1.66). In the group of individuals withCCNO(−3.26),CCDC39(−2.49), andCCDC40(−2.96) variants, FEV1z-scores were significantly lower, while the group ofDNAH11(−0.83) andODAD1(−0.85) variant individuals had significantly milder FEV1z-score reductions compared to the whole PCD cohort.ConclusionThis unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of genetic epidemiology of PCD and provides prediction of diagnostic and phenotypic features such as the course of lung function.