Wide phenotypic variability in RSPH9-associated primary ciliary dyskinesia: review of a case-series from Cyprus

Primary ciliary dyskinesia (PCD) is an inherited ciliary motility disorder caused by mutations in at least 40 genes. RSPH9 gene mutations encoding aberrant radial spoke head proteins have been linked with PCD. The clinical spectrum extent of RSPH9 gene mutations remains to date largely unknown. We aimed to describe the diagnostic and clinical phenotype in a case-series of RSPH9-associated PCD.

We performed whole exome sequencing in suspect patients from Cyprus who on repeated cilia biopsies demonstrated loss of the central pair apparatus on Transmission Electron Microscopy (TEM) and rotary beating patterns on High Speed Video Microscopy (HSVM), compatible to findings described previously in PCD patients bearing pathogenic RSPH9 mutations. In cases confirmed by genetic testing, we reviewed diagnostic, demographic and clinical data, as well as anthropometric and spirometric measurements.

We diagnosed 7 individuals (5 females) homozygous for the novel RSPH9 splice site mutation c.670+2T>C in intron 4, who originated from two families. Despite bearing the same genetic variant, patients presented a highly variable age (median 47.9 years; range, 6.6 to 51.4 years) and with a diverse clinical picture, all reporting a history of chronic or recurrent wet cough (100%), and at varying frequencies neonatal respiratory distress (43%), chronic rhinosinusitis (71%), and wheezing (43%). Complications such as bronchiectasis (71%), history of pneumonia(s) (57%) and surgical interventions (43%) clustered in some patients displaying typical PCD, but not in others with milder phenotypes. BMI-z scores (median: 0.53; range, -0.69 to 1.52), FEV1-z scores (median: -0.37; range: -1.79 to 0.22) and FVC z-scores (median: -0.80; range: -2.01 to 0.36) were on average within the normal range, although slightly reduced.

In conclusion, RSPH9-associated PCD disease demonstrates wide phenotypic variability. In some cases, mild clinical presentation is difficult to justify diagnostic work-up, highlighting the importance of wider adoption of genetic diagnostics. Larger studies are needed to assess variability of clinical spectrum associated to alterations of PCD genes.