Considerable variability in the clinical and ciliary features of primary ciliary dyskinesia in patients with DNAH5 mutations

Abstract Background: Primary ciliary dyskinesia (PCD) is a clinically and genetically heterogeneous disorder, but the relationship between genotype and phenotype is poorly established. We aimed to characterize the detailed clinical characteristics, ciliary phenotype and mutational spectrum of PCD patients with DNAH5 mutations.Methods: Whole exome sequencing followed by targeted copy number variation (CNV) analysis was used to screen 114 Chinese patients with highly suspected PCD. In cases with DNAH5 mutation, detailed demographic and clinical data, as well as ciliary beat pattern and ciliary ultrastructure, were comprehensively reviewed. Results: Thirty patients (median, 15.3 years; range, 0.6 to 43 years), who carried DNAH5 mutation, were identified. We characterized 38 novel and 7 known DNAH5 mutations (10 nonsense, 5 frameshift, 10 splicing, 16 missense mutations, 2 in-frame deletions and 2 large deletions). Despite bearing the same genotype, patients presented a highly variable phenotypic picture, including milder respiratory symptom, normal nasal nitric oxide levels (2/21, 9.5%) and “nontypical” ciliary beat pattern (4/21, 19.0%). Conclusions: DNAH5-associated PCD disease demonstrates dramatic phenotypic heterogeneity, contributing to the challenges of diagnosis. A composite work-up and cautious interpretation of the results are necessary during the PCD diagnosis process.