Mucociliary and cough clearance in primary ciliary dyskinesia as affected by mutations in RSPH1 or DNAH5

Primary ciliary dyskinesia (PCD) is a rare disease caused by mutations in >50 genes that impair the function of motile cilia. The clinical phenotype is heterogeneous and recent studies have begun to investigate genotype-phenotype relationships to better understand disease pathogenesis and develop improved treatments. The major cause of morbidity and mortality among individuals with PCD is the lack of mucociliary clearance (MCC) that results in chronic respiratory infections and leads to bronchiectasis. Here we examine the relationship between MCC and genotype in two groups of PCD individuals; one with mutations in a gene (DNAH5) that causes PCD with mostly immotile cilia and one with mutations in a gene (RSPH1) that cause PCD with cilia that beat with a near-normal frequency, but an abnormal, sometimes circular waveform.

Patients with known pathogenic variants in DNAH5 (n=8) or RSPH1 (n=7), along with healthy controls (n=8), were assessed for clearance of an inhaled radioactive tracer by mucociliary and cough clearance as measured by gamma scintigraphy.

Neither DNAH5 nor RSPH1 subjects showed clear evidence of MCC under either baseline or albuterol stimulated conditions. Unexpectedly, subjects with RSPH1 mutations demonstrated cough clearance (median 9.7%, IQR 6.2-17%) that was significantly higher than subjects with DNAH5 mutations (4.2% (0.94-5.1%); p=0.015) and was not significantly different from healthy control subjects (8.3% (4.2-16%); p=0.88).

The results confirm impaired MCC in people with PCD of both genotypes. However, in this small cohort, the results suggest cough clearance may differ between these two genotypes.