Submission Details

RSPH3 was first described as a primary ciliary dyskinesia (PCD)-causing gene in 2015 (Jeanson et al. 2015, PMID: 26073779). The specific disease entity, primary ciliary dyskinesia 32 (MONDO:0014657, OMIM:616481), is one of at least 45 different primary ciliary dyskinesias distinguished by a single monogenic cause. Some of the common clinical phenotypes are: neonatal respiratory distress syndrome, bronchiectasis, male/female infertility, chronic rhinosinusitis, otitis media, reduced nasal nitric oxide, and reduced or absent ciliary motility.

RSPH3 encodes a protein of the radial spoke of the ciliary axoneme. This curation includes six variants (3 nonsense, 1 frameshift, 1 missense and 1 canonical splice site) that have been reported in 6 unrelated probands in 2 publications (PMIDs: 26073779 and 32124190). Overall, the pattern of variants observed in the probands indicated that the mechanism of pathogenicity appears to be loss of RSPH3 function. However, it is important to note that missense variants contribute to the gene-disease relationship through mechanisms that have not yet been well-studied.

This gene-disease relationship is supported by multiple kinds of experimental evidence ranging from gene expression and biochemical studies to non-human model organisms (PMID: 23715323, PMID: 16607017, PMID: 28915070). High levels of expression of RSPH3 are found in human tissues associated with motile cilia (testis, lungs, and brain/hypothalamus, PMID: 23715323). An RSPH3 ortholog knockout in Trypanosoma brucei recapitulated phenotypes displayed by patients carrying pathogenic variants in RSPH3, including reduced ciliary beat frequency (PMID: 16607017). RSPH3 localizes to radial spoke heads (PMID: 28915070), matching the RSPH9 protein previously shown to be associated with PCD 12 (19200523). A zebrafish model lacking the orthologous gene encoding lrrc23, a component of the radial spoke neck, showed otolith defects (an ear problem which indicates an underlying problem with ciliary movement, PMID: 29475374). Lastly, a naturally occurring Chlamydomonas mutant “pf14” lacks the RSPH3 ortholog and shows abnormal flagellar morphology and movement as well as central pair defects when examined by electron microscopy (PMID: 24283352).

In conclusion, RSPH3 is definitively associated with autosomal recessive primary ciliary dyskinesia 32. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Motile Ciliopathy GCEP on August 8th, 2024 (SOP Version 10).