Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype

Whole-exome sequencing has expedited the diagnostic work-up of primary ciliary dyskinesia (PCD), when used in addition to clinical phenotype and nasal nitric oxide. However, it reveals variants of uncertain significance (VUS) in established PCD genes or (likely) pathogenic variants in genes of uncertain significance in approximately 30% of tested individuals. We aimed to assess genotype-phenotype correlations in adults with bronchiectasis, clinical suspicion of PCD, and inconclusive whole-exome sequencing results using transmission electron microscopy (TEM) and ciliary image averaging by the PCD Detect software. We recruited 16 patients with VUS in , , , , / , / , , and as well as variants in the PCD candidate genes , , , and . We found normal ciliary ultrastructure in eight patients with VUS in , , , / , , and . In six patients with VUS in , , , and , we identified a corresponding ultrastructural hallmark defect. In one patient with homozygous variant in , we detected a central complex defect supporting clinical relevance. Using TEM as a targeted approach, we established important genotype-phenotype correlations and definite PCD in a considerable proportion of patients. Overall, the PCD Detect software proved feasible in support of TEM.