Submission Details

The RSPH4A gene was first reported in relation to primary ciliary dyskinesia in 2009 (Castleman et al., PMID: 19200523). The specific disease entity, Primary Ciliary Dyskinesia 11, is one of at least 50 different primary ciliary dyskinesias distinguished by a specific monogenetic cause. Affected patients frequently present as neonates or in early childhood with recurrent respiratory infections including sinusitis, as well as decreased nasal nitric oxide, otitis media, and/or bronchiectasis. Laterality defects were not observed for any of the reported patients. Biopsies of the airway epithelium ranged from exhibiting normal ciliary ultrastructure to central pair complex defects (PMID: 23798057, PMID: 25789548, PMID: 19200523). Ciliary motility is abnormal, characterized by a stiff ciliary appearance and beating, in some cases with a rotatory rather than planar pattern (PMID: 23798057, PMID: 25789548, PMID: 19200523). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and mode of inheritance (autosomal recessive) to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited RSPH4A variants have been lumped into a single disease entity, referred to as Primary Ciliary Dyskinesia 11 (MONDO:0012978, OMIM #612649). Eleven suspected pathogenic variants were scored as part of this curation (five nonsense, two frameshift, two missense, and two splicing), which have been collectively reported in thirty-three probands (as well as affected family members) in three publications (PMID: 19200523, PMID: 23798057, PMID: 25789548). More case-level evidence is available in the literature (PMID: 23993197, PMID: 22448264, PMID: 24824133, PMID: 27637300, PMID: 25186273) but its inclusion in this curation was not necessary to reach the maximum score for genetic evidence (12 points). This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level. The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by the absence of a gene product (PMID: 33852348). All probands scored in this curation harbored two variant alleles within the RSPH4A locus. This gene-disease association is also supported by experimental evidence that human tissues exhibiting the highest levels of RSPH4A expression include tissue types relevant to disease and known to have motile cilia, including the lung, fallopian tube, brain, and testis (PMID: 23715323). More experimental evidence includes biochemical function as a core component of the radial spoke head, functional alterations in patient cells consistent with a critical role in motile cilia structure/function and altered expression in PCD patient tissue. Model organisms (Chlamydomonas and mouse) show ciliary ultrastructural and motility defects similar to those observed in patients (PMID: 25789548, PIMD: 16507594, PMID: 32203505, PMID: 32694165). Electron tomography can detect central complex defects and absence of RS1 and RS2 head proteins in motile cilia from patient respiratory epithelial cells, and absence of the three RS head proteins (RS1, RS2 and RS3) in KO mice (PMID: 33852348, PMID: 32203505). In summary, RSPH4A is definitively associated with autosomal recessive primary ciliary dyskinesia 11. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on March 10th, 2022 (SOP Version 8).