RSPH9 – Primary Ciliary Dyskinesia

RSPH9 encodes a radial spoke head protein essential for motile 9+2 cilia function. Biallelic RSPH9 variants cause autosomal recessive primary ciliary dyskinesia (PCD), leading to impaired mucociliary clearance and recurrent respiratory infections.

Genetic Evidence

Autosomal recessive inheritance is supported by homozygous in-frame and loss-of-function variants identified in multiple consanguineous families. A homozygous deletion c.804_806del (p.Lys268del) was found in a neonate and her three affected siblings presenting with tachypnea and desaturation ([PMID:36059358]). A recurrent splice variant c.670+2T>C was identified in seven patients from two Cypriot families with variable age at diagnosis and chronic wet cough ([PMID:31285900]). Eleven additional PCD cases across six Kuwaiti families carried the same c.804_806del founder variant, confirmed by segregation analysis ([PMID:37892643]). Overall, >30 probands from at least six unrelated pedigrees harbor RSPH9 variants.

Segregation analysis demonstrated co-segregation in three additional siblings in one family ([PMID:22384920]) and six relatives in Cypriot pedigrees ([PMID:31285900]). The variant spectrum includes homozygous in-frame deletions (c.804_806del (p.Lys268del)), splice site mutations (c.670+2T>C), and nonsense alleles (c.799G>T (p.Glu267Ter)).

Functional Evidence

Knockdown of the Rsph9 ortholog in zebrafish recapitulates central pair defects and impaired motility, which are rescued by wild-type gene expression ([PMID:19200523]). High-resolution immunofluorescence of respiratory cilia from RSPH9-mutant individuals shows axonemal absence of RSPH9 without affecting RSPH1 or RSPH4A assembly, confirming radial spoke head disruption ([PMID:25789548]).

Conflicting Evidence

No studies have refuted the role of RSPH9 in PCD or described alternative phenotypes.

Conclusion

Extensive genetic and experimental data establish a definitive association between biallelic RSPH9 variants and autosomal recessive primary ciliary dyskinesia. Incorporation of RSPH9 into diagnostic gene panels and targeted screening for the c.804_806del founder allele enables early diagnosis and tailored management.

Key Take-home: RSPH9 testing is high-yield in PCD diagnostics, especially in consanguineous and Bedouin Arab populations.

References

• Cureus • 2022 • An Unusual Cause of Respiratory Distress in Term Neonate. PMID:36059358
• Journal of Thoracic Disease • 2019 • Wide phenotypic variability in RSPH9-associated primary ciliary dyskinesia: review of a case-series from Cyprus. PMID:31285900
• Journal of Clinical Medicine • 2023 • Mapping the Most Common Founder Variant in RSPH9 That Causes Primary Ciliary Dyskinesia in Multiple Consanguineous Families of Bedouin Arabs. PMID:37892643
• Annals of Human Genetics • 2012 • From a single whole exome read to notions of clinical screening: primary ciliary dyskinesia and RSPH9 p.Lys268del in the Arabian Peninsula. PMID:22384920
• Journal of Human Genetics • 2022 • Combining RSPH9 founder mutation screening and next-generation sequencing analysis is efficient for primary ciliary dyskinesia diagnosis in Saudi patients. PMID:35046476
• American Journal of Human Genetics • 2009 • Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. PMID:19200523
• American Journal of Respiratory Cell and Molecular Biology • 2015 • Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects. PMID:25789548

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