Submission Details

Variants in the RSPH9 gene were first described as a cause of primary ciliary dyskinesia (PCD) in 2009 (Castleman et al., PMID: 19200523). Some of the most common phenotypes observed among patients in this curation are neonatal respiratory distress, bronchitis, bronchiectasis, rhinorrhea, recurrent wet cough, otitis media and rotational ciliary movement rather than planar whiplash ciliary movement. Male and female infertility have been reported, while nasal nitric oxide levels could be either low or near the low end of the normal range. All of the probands found had normal abdominal situs. Electron microscopy findings sometimes included central complex defects but rarely showed inner or outer dynein arm abnormalities.

This curation has included eight variants (3 missense, 1 splice site, 2 nonsense, 1 start-loss and 1 in-frame deletion) that have been reported in 12 probands in 7 publications (PMIDs: 35046476, 33577779, 31285900, 36873931, 36059358, 19200523, 25789548). The in-frame deletion was a potential founder variant observed among a number of probands of Middle Eastern or Mediterranean origin (PMID: 35046476, PMID: 20070851). RSPH9 variants co-segregated with PCD in at least two affected families (PMID:36059358, PMID: 19200523). The mechanism of pathogenicity appears to be loss of function as shown by the presence of null variants and the absence of RSPH9 staining in the cells of some of the probands (PMID: 36873931).

This gene-disease relationship is also supported by multiple forms of experimental evidence. High levels of expression of RSPH9 were observed in human tissues associated with PCD (fallopian tube, testis and lung, PMID:23715323) and has been confirmed in mouse tissues (PMID:30383886). RSPH9 encodes a component of the ‘head’ structure of ciliary radial spoke complexes (PMID: 36873931), a role shared by the RSPH1 gene that has previously been linked to PCD 24. RSPH9 localizes to the kinocilia in zebrafish, indicating that the protein may affect ciliary formation and function in this organism (PMID: 27687975). Depleting Rsph9 from multiciliated mouse ependymal cells (mEPCs) by RNAi found that the ciliary beat pattern became rotational, similar to the PCD patients (PMID: 19200523). Two different mouse knockouts of Rsph9 both resulted in hydrocephalus and sinusitis (PMID: 27626380, PMID: 32709945).

In conclusion, RSPH9 is definitively associated with autosomal recessive primary ciliary dyskinesia 12. This classification has been clearly demonstrated through both experimental and genetic evidence in a combination of clinical and laboratory settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Motile Ciliopathy GCEP on October 12th, 2023 (SOP Version 9).