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The diagnostic guideline of the European Respiratory Society primarily recommends an evaluation of the clinical history (\n                      <jats:italic>e.g.<\/jats:italic>\n                      by the PICADAR prediction tool), nasal nitric oxide production rate measurements, high-speed videomicroscopy analysis of ciliary beating and an assessment of ciliary axonemes\n                      <jats:italic>via<\/jats:italic>\n                      transmission electron microscopy. Genetic testing can be implemented as a last step.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>In this study, we aimed to characterise primary ciliary dyskinesia with a defective C1d projection of the ciliary central apparatus and we evaluated the applicability of the European Respiratory Society diagnostic guideline to this primary ciliary dyskinesia type.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using a high-throughput sequencing approach of genes encoding C1d components, we identified pathogenic variants in the novel primary ciliary dyskinesia genes\n                      <jats:italic>CFAP46<\/jats:italic>\n                      and\n                      <jats:italic>CFAP54<\/jats:italic>\n                      , and the known primary ciliary dyskinesia gene\n                      <jats:italic>CFAP221<\/jats:italic>\n                      . To fully assess this primary ciliary dyskinesia type, we also analysed individuals with pathogenic variants in\n                      <jats:italic>CFAP74<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Careful evaluation revealed that C1d-defective primary ciliary dyskinesia is associated with normal situs composition, normal nasal nitric oxide production rates, normal ciliary ultrastructure by transmission electron microscopy and normal ciliary beating by high-speed videomicroscopy analysis. Despite chronic respiratory disease, PICADAR does not reliably detect this primary ciliary dyskinesia type. However, we could show by\n                      <jats:italic>in vitro<\/jats:italic>\n                      ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Overall, this study extends the spectrum of primary ciliary dyskinesia genes and highlights that individuals with C1d-defective primary ciliary dyskinesia elude diagnosis when using the current diagnostic algorithm. To enable diagnosis, genetic testing should be prioritised in future diagnostic guidelines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.00790-2024","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T11:25:16Z","timestamp":1727954716000},"page":"2400790","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Pathogenic variants in\n                    <i>CFAP46<\/i>\n                    ,\n                    <i>CFAP54<\/i>\n                    ,\n                    <i>CFAP74<\/i>\n                    and\n                    <i>CFAP221<\/i>\n                    cause primary ciliary dyskinesia with a defective C1d projection of the central 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