Novel Compound Heterozygous RSPH4A Variants in a Chinese Family with Primary Ciliary Dyskinesia: A Case Report and Literature Review

Novel Compound Heterozygous RSPH4A Variants in a Chinese Family with Primary Ciliary Dyskinesia: A Case Report and Literature Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Novel Compound Heterozygous RSPH4A Variants in a Chinese Family with Primary Ciliary Dyskinesia: A Case Report and Literature Review Jiali Huang, Fei Tong, Kaiyue Xiao, Xinyu Zhai, Xuyang Zheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8990118/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The Radius Spoke Head Protein 4 Homolog A (RSPH4A) gene is one of over 50 genes responsible for causing primary ciliary dyskinesia (PCD)(De Jesús-Rojas et al., 2023).Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder characterized by dysfunction of motile cilia, with or without detectable ultrastructural abnormalities(Chenling Shen et al., 2024).This study analyzed the clinical and genetic data of an index case suspected of having PCD based on her relevant test results. adolescent patients primary ciliary dyskinesia compound heterozygous mutation RSPH4A case report Figures Figure 1 Introduction Primary ciliary dyskinesia (PCD) is a rare inherited disorder caused by defective motile cilia, leading to chronic respiratory symptoms and progressive lung damage.(Leigh et al., 2019). Individuals with PCD are unable to clear accumulated mucus and typically experience recurrent upper and lower respiratory tract infections, chronic sinusitis, progressive bronchiectasis, and lung atelectasis(Lobo, Zariwala, & Noone, 2015).Diagnosis of PCD relies on a combination of gene sequencing tests, high-speed videomicroscopy assessing ciliary beat frequency and pattern, transmission electron microscopy (TEM), and nasal nitric oxide measurement (Muhonen et al., 2025).Its prevalence ranges from 1 in 15,000 to 1 in 30,000 live births, involving 50 genes and over 2,000 pathogenic mutations(Collison et al., 2025).Proteins constituting the functional ciliary structures of the upper and lower respiratory tracts are affected by genetic mutations. The RSPH4A gene encodes a structural protein essential for ciliary function.The RSPH4A gene (c.921 + 3921+6delAAGT) was first identified as a pathogenic variant in Puerto Rico in 2013 and is linked to its ancestral haplotype(Daniels et al., 2013),while fewer variants have been reported in China.Previous studies confirmed that the protein encoded by RSPH4A is a key component of the radial arm head of ciliary microtubules. The radial arm is a vital component of the ciliary “9 + 2” microtubule structure (9 peripheral microtubule doublets surrounding a central microtubule pair), responsible for connecting the central microtubule to peripheral microtubules. It regulates ciliary beating frequency and direction by transmitting mechanical signals, ensuring proper mucociliary clearance (MCC) function. Mutations in the RSPH4A gene cause inconsistent ciliary beating frequency and direction, ultimately leading to impaired mucus clearance.While most reported pathogenic variants are homozygous, compound heterozygous mutations are rare and less well understood.In this study, we report a novel RSPH4A compound heterozygous variant: the pathogenic c.658A > T p.Lys220Ter heterozygote and the c.1764G > T p.Gly588 = heterozygote, which caused primary ciliary dyskinesia in the patient. This configuration has not been previously described in the literature of RSPH4A-related disorders. Additionally, we conducted a literature review to elucidate the clinical features of this PCD and provide diagnostic insights for the early identification of this PCD gene. Method: The index patient is an 11-year-old girl who experienced recurrent upper respiratory tract infections since birth, with a history of allergic rhinitis,and progressively persistent recurrent coughing and became highly prone to wheezing.She had multiple episodes of wheezing and repeated hospitalizations for pneumonia. High-resolution computed tomography (HRCT) of the lungs revealed bronchiectasis. Two variants in the RSPH4A gene were identified in the proband.Sanger sequencing was employed to validate the RSPH4A variant in the proband, her father, her mother, and her brother. Finally, the patient's phenotypic characteristics were analyzed, and the current literature was reviewed to gain a better understanding of genetic variants associated with pulmonary infections in PCD and the clinical presentation of RSPH4A variants in PCD. Results: Her first variant: DNA sequencing revealed an A-to-T transition at position 658 in the first exon of RSPH4A. This variant had never been reported previously. The mutation resulted in the replacement of lysine at position 220 with a stop codon (p.Lys220Ter), causing a missense mutation. Such variants are typically classified as pathogenic. Her second variant: DNA sequencing revealed a G-to-T transition at position 1764 in the fourth exon of RSPH4A. This variant has also never been reported before. The mutation causes a synonymous substitution at position 588 (Gly588S). However, synonymous mutations are not necessarily harmless; they may be pathogenic by affecting mRNA splicing, stability, or translation efficiency. The same variant was detected in the proband's brother, who exhibited similar clinical manifestations and ancillary test results, further confirming the pathogenicity of this synonymous mutation. A heterozygous variant was identified in the proband's parents, who are carriers of the RSPH4A mutation gene but remain clinically unaffected. Discussion: Literature review indicates that most reported pathogenic RSPH4A variants are homozygous, with compound heterozygous variants being relatively rare. Case Report An 11-year-old girl was admitted to the Pediatrics Department of Hangzhou First People's Hospital with a 2-year history of cough worsening over the past week. Family history indicated she was from a non-biological family; her parents showed no symptoms, but her brother presented with similar symptoms. The patient was born at term and experienced recurrent upper respiratory infections since birth, with a high susceptibility to wheezing. She had multiple hospitalizations for pneumonia. She had no history of long-term oxygen dependence or visceral transposition. Since age 9, she experienced recurrent coughing and persistent allergic rhinitis. She had been continuously inhaling budesonide powder for one year, but her cough symptoms showed no significant improvement. On physical examination, the adolescent patient did not exhibit tachypnea, but pectus excavatum was visible, and moist rales were audible on auscultation.. Figure 1 presents an overview of proband’s family history and radiographic findings. Figure 1 Figure 1 Family history and clinical features of the patient. A This PCD patient comes from a non-consanguineous family; her parents show no clinical symptoms, but her brother exhibits similar clinical features. The adolescent female proband inherited a compound heterozygous mutation from two heterozygous carrier parents. The proband is indicated by the arrow. (B) Chest radiograph reveals bilateral pleural thickening, inflammation in the lower fields of both lungs, and no ectopic heart. The arrow indicates an image of inflammatory infiltration. (C) Transmission electron microscopy shows microvilli on the epithelial surface. D-F: Lung CT scan demonstrates pulmonary infection, bilateral pneumonia, and mild bronchial dilatation in both lungs. Supporting Tests: HRCT reveals bronchitis with scattered infectious lesions in both lungs, more prominent in the left lung, accompanied by localized bronchiectasis and thickened bronchial walls. Multiplex respiratory pathogen detection in BALF: Pseudomonas aeruginosa and Streptococcus pneumoniae DNA negative; Mycobacterium tuberculosis DNA negative. Due to poor pulmonary condition upon admission, pulmonary function testing was not performed; only exhaled nitric oxide (FeNO) was measured. Nasal FeNO level was 8 ppb, oral NO level was 5 ppb. Bronchoscopy revealed mucosal hyperemia and edema, with copious white viscous secretions and mucus plugs filling the bilateral bronchial lumens. Transmission electron microscopy showed cilia on the surface of ciliated epithelium: sparse, irregularly arranged, intermingled with microvilli. Localized epithelial cell loss was observed, with focal areas showing minimal inflammatory cell infiltration.The above investigations supported the diagnosis of primary ciliary dyskinesia (PCD). No significant abnormalities were detected in electrocardiogram, echocardiogram, cardiac enzymes, liver and kidney function tests, plasma electrolytes, serum mycoplasma and chlamydia antibodies, or immunoglobulin levels. After receiving intravenous ceftriaxone for 10 days, inhaled corticosteroids for 10 days, and undergoing bronchoscopy with treatment, the patient's cough improved and was discharged. However, recurrent respiratory infections and cough persisted. Despite ongoing use of budesonide powder, the patient's pulmonary function showed no significant improvement. Diagnosis Given the history of full-term birth, allergic rhinitis, multiple episodes of pneumonia, bronchiectasis, and extremely low FENO results, a suspected diagnosis of primary ciliary dyskinesia (PCD) is made. Follow-up PCD is fundamentally a genetic disorder. Whole-exome sequencing identified two novel heterozygous variants in the RSPH4A gene:c.658A > T (p.Lys220Ter), a premature stop codon, classified as likely pathogenic.c.1764G > T (p.Gly588=), a synonymous variant of uncertain significance.Both variants were confirmed by Sanger sequencing. The siblings inherited one variant each from their unaffected parents, confirming compound heterozygosity.The patient's history, bronchiectasis, extremely low FENO results, transmission electron microscopy (TEM), and WES findings confirmed the definitive diagnosis of PCD. Bronchoscopy, alveolar lavage for airway clearance, and intravenous ceftriaxone with expectorants improved her recurrent wet cough. Follow-up chest X-ray one month after discharge showed multiple bronchiectasis with infection in both lungs, representing significant improvement compared to initial findings.However, compared to previous imaging, the small patchy ground-glass opacities in the left lower lobe showed minimal change. At the one-month follow-up after discharge, pulmonary function (PF) testing revealed moderate obstructive changes in conventional lung ventilation with mild impairment of ventilation capacity and small airway disease. The forced vital capacity (FVC) was 68.4% of predicted, peak expiratory flow rate at 61% of predicted, forced vital capacity at 66.8% of predicted, forced expiratory volume in one second at 59.2% of predicted, and FEV1/FVC ratio at 71.95%. At the 3-month follow-up post-discharge, pulmonary function (PF) revealed moderate obstructive changes in conventional lung ventilation with moderate reduction in ventilatory capacity and small airway disease. The forced vital capacity (FVC) was 68.25% of predicted, peak expiratory flow rate was 49.8% of predicted, forced vital capacity was 67.0% of predicted, forced expiratory volume in one second was 56.4% of predicted, and forced expiratory ratio was 68.68%. Her nasal exhaled FeNO level was 9 ppb, and oral exhaled NO level was 14 ppb. No significant improvement was noted. However, the patient's cough symptoms improved, with no recurrence of fever or wheezing. Body mass index was appropriate for age and gender. The patient adhered to daily administration of prescribed inhaled corticosteroids and ciliary motility enhancers. No liver function abnormalities, emotional changes, or behavioral alterations were observed.Table 1is a generation verification diagram of proband,her parents,and siblings. Table 1 Table 1: Sanger Sequencing Analysis of RSPH4A Variant Families Sample Generation Verification Diagram Proband - Heterozygous Proband's father - Wild-type Proband's mother - Heterozygous Proband's brother - Heterozygous RSPH4A Location:chr6：116950831 mutation site:c.1764G>T Sample Generation Verification Diagram Proband - Heterozygous Proband's father - Heterozygous Proband's mother - Wild-type Proband's brother - Heterozygous Discussion Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliary motility disorder characterized by progressive pulmonary disease manifesting as neonatal respiratory distress, recurrent upper and lower respiratory tract infections, poor fertility, and unilateral defects. Diagnosis relies on confirmation through a series of tests, including nasal nitric oxide measurement, high-speed videomicroscopy analysis, immunofluorescence staining, ultrastructural analysis of cilia via transmission electron microscopy (TEM), and genetic testing(Despotes, Zariwala, Davis, & Ferkol, 2024).To date, 54 disease-causing genes have been identified that can lead to related pathological conditions(Barber et al., 2025).In the cross-section of cilia, nine sets of outer microtubule dyads typically surround a central pair, forming a 9 + 2 ultrastructure. T-shaped radial spokes connect the central pair of microtubules to the outer dyads. RSPH4A is a fundamental component as it constitutes the central portion of the radial spoke head(C. Shen et al., 2024).The RSPH4A variant primarily disrupts ciliary ultrastructure and causes loss of radial head function, thereby impairing mucus clearance(Zhao et al., 2021).In this study, we report a case of an 11-year-old girl who presented with recurrent upper respiratory tract infections since birth, a history of allergic rhinitis, and progressively developed persistent recurrent cough with a high susceptibility to wheezing. She had multiple hospitalizations for pneumonia. Chest CT scans revealed bronchiectasis. She was diagnosed with PCD following whole-exome sequencing, transmission electron microscopy (TEM), and nasal nitric oxide testing. A novel compound heterozygous mutation in RSPH4A was identified. The pathogenic c.658A > T p.Lys220Ter compound heterozygote is a missense mutation classified as likely pathogenic according to ACMG guidelines. The c.1764G > T/p.Gly588 = mutation is a missense variant classified as of uncertain significance (OUI) per ACMG guidelines. This specific genetic alteration has not been previously reported in the literature among patients with RSPH4A-related disorders. Details are summarized in Table 2 . Clinicians should therefore be aware of this condition, particularly when young patients present with bronchiectasis. Table 2 RSPH4A variants identified in this family through exome sequencing. Gene Chromosomal&RS number HGVS Genetic Pattern Carrier Status for Mutations ACMG Standards ACMG Classification RSPH4A chr6: 116938444 NM_001010892.3 Exon1/6 c.658A > T/p.Lys220Ter AR heterozygous (67/138) PVS1 + PM2 Likely pathogenic chr6: 116950831 M_001010892.3 Exon4/6 c.1764G > T/p.Gly588= AR heterozygous(69/135) PM2 + PP3+PM3 Uncertain significance Unlike homozygous mutations, compound heterozygous mutations involve two distinct pathogenic mutations on a single gene pair, whereas homozygous mutations carry identical pathogenic mutations on the same gene pair. Compound heterozygosity is one of the primary mechanisms underlying autosomal recessive disorders, though it remains clinically uncommon. Herein, unlike other patients with homozygous mutations,this is only the second reported case of compound heterozygous RSPH4A mutations causing PCD. The first case involved compound heterozygosity for c.2T > C, p.(Met1Thr) and c.1774_1775del, p.(Leu592Aspfs*5)(Wang et al., 2022). Synonymous mutations have long been considered harmless or silent in humans(Bin, Wang, Zhao, Wen, & Xia, 2019).However, this concept has now changed, as synonymous mutations may potentially induce clinically significant alterations in protein expression, conformation, and function(Sauna & Kimchi-Sarfaty, 2011).Due to the degeneracy of genetic codons, synonymous mutations do not alter the encoded amino acid but can induce changes at the RNA level. Increasing evidence indicates that synonymous mutations significantly impact RNA splicing, stability, and folding, as well as translation or co-translational protein folding(Gorivale et al., 2024),such as synonymous mutations promote tumorigenesis by disrupting m 6 A-dependent mRNA metabolism(Lan et al., 2025).In practice, many synonymous mutations are initially classified as “variants of uncertain significance.” Only through functional experiments and robust genetic evidence can they be upgraded to “likely pathogenic” or “pathogenic” variants.The synonymous variant, though initially considered benign, likely disrupts mRNA processing or protein function, as evidenced by the shared phenotype in both siblings.These findings expand the genetic spectrum of RSPH4A-related PCD and highlight the need for functional validation of synonymous variants. The pathological basis of PCD is ciliary dyskinesia. Since patients lack normal ciliary movement, clearing airway secretions is a critical component of PCD treatment. Patients should receive personalized airway clearance techniques from respiratory physicians with PCD expertise. If mucus expectoration proves challenging, mucolytic therapies such as hypertonic saline nebulization and carbocysteine may be provided(Bush et al., 2006).Using a handheld positive airway pressure device can effectively eliminate coughing(Schofield, Duff, & Brennan, 2018).Preventive measures such as vaccination against influenza, COVID-19, and pneumonia are crucial(Lee, 2020).For sinus disorders and recurrent otitis media, regular examinations by an otolaryngologist are required(Collison et al., 2025).Patients with PCD face significant challenges to their quality of life due to the complexity of treatment and multisystem involvement. Current symptomatic therapies, such as airway clearance, only provide relief from symptoms(Ewen et al., 2024).The combination of idefloirid and hypertonic saline offers a novel approach to improving lung function, while mRNA therapy represents a potential direction for curing PCD at the genetic level, though technical bottlenecks must be overcome(Ringshausen et al., 2024).Future research requires more long-term studies to validate efficacy and safety, while strengthening multidisciplinary management to reduce the burden on patients(Paff, Omran, Nielsen, & Haarman, 2021).Additionally, long-term monitoring of lung function, exercise assessment, hearing evaluation, rehabilitation training, and psychological therapy feedback are all essential for improving the quality of life for patients with primary ciliary dyskinesia. In this study, we analyzed the genetic sequence of an adolescent patient with primary ciliary dyskinesia (PCD) who presented with recurrent cough, recurrent pneumonia, bronchiectasis, and extremely low FENO results. WES results revealed a novel compound heterozygous mutation in the RSPH4A gene: c.658A > T p.Lys220Ter heterozygous and c.1764G > T p.Gly588 = heterozygous. This mutation in the proband was inherited from her parents, each carrying a single heterozygous mutation, resulting in compound heterozygosity in the patient. This mutation in RSPH4A identified in the adolescent patient has not been previously reported in databases or the literature, including ClinVar ( https://www.ncbi.nlm.nih.gov/ClinVar ), LOVD3 ( https://databases.lovd.nl/shared/genes/RSPH4A ), and gnomAD ( https://gnomad.broadinstitute.org/ ). All information was retrieved on October 16, 2025. This indicates that the variant in RSPH4A is a rare novel variant, reported for the first time in a patient with PCD. Conclusion We describe a novel compound heterozygous RSPH4A mutation in two siblings with PCD. These variants have not been previously reported, underscoring the importance of comprehensive genetic testing in patients with unexplained bronchiectasis and recurrent respiratory infections. Declarations Author Contributions : Jiali Huang(First Author): Data Curation, Chart Creation, Writing-Original Draft, Investigation, Writing-Review & Editing. Xuyang Zheng(Corresponding Author): Supervision, Writing-Review & Editing. Kaiyue Xiao: Data Curation, Chart Creation. Fei Tong: Data Curation, Chart Creation. Xinyu Zhai:Data Curation, Chart Creation. Data Curation, Chart Creation. All authors have read and agreed to the published version of the manuscript. Funding support: The authors received no funding support for the research. Data Availability Statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Conflicts of Interest: The authors declare no conflict of interest, financial or otherwise. Acknowledgments ：We thank the patients and their families who participated in this study. Consent to participate declaration: not applicable. Consent to publish declaration: Written informed consent for publication of their clinical details and clinical images was obtained from the patient of the patient. Ethics declaration:The study involving human participants have obtained informed consent from the patient and their families. References Barber, A. T., Davis, S. D., Ferkol, T. W., Shapiro, A. J., Atkinson, J., Sagel, S. D., . . . Leigh, M. W. (2025). The Association of Neonatal Respiratory Distress With Ciliary Ultrastructure and Genotype in Primary Ciliary Dyskinesia. Pediatr Pulmonol, 60 (5), e71091. doi:10.1002/ppul.71091 Bin, Y., Wang, X., Zhao, L., Wen, P., & Xia, J. (2019). An analysis of mutational signatures of synonymous mutations across 15 cancer types. BMC Med Genet, 20 (Suppl 2), 190. doi:10.1186/s12881-019-0926-4 Bush, A., Payne, D., Pike, S., Jenkins, G., Henke, M. O., & Rubin, B. K. (2006). Mucus properties in children with primary ciliary dyskinesia: comparison with cystic fibrosis. Chest, 129 (1), 118-123. doi:10.1378/chest.129.1.118 Collison, R., Hyatali, S. A., Kamenova, A., Rashed, A., Riley, D., Kumar, K., . . . Loebinger, M. R. (2025). Primary ciliary dyskinesia: Aetiology, diagnosis and clinical management. Clin Med (Lond), 25 (3), 100319. doi:10.1016/j.clinme.2025.100319 Daniels, M. L., Leigh, M. W., Davis, S. D., Armstrong, M. C., Carson, J. L., Hazucha, M., . . . Zariwala, M. A. (2013). Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. Hum Mutat, 34 (10), 1352-1356. doi:10.1002/humu.22371 De Jesús-Rojas, W., Meléndez-Montañez, J., Muñiz-Hernández, J., Marra-Nazario, A., Alvarado-Huerta, F., Santos-López, A., . . . Mosquera, R. A. (2023). The RSPH4A Gene in Primary Ciliary Dyskinesia. International Journal of Molecular Sciences, 24 (3). doi:10.3390/ijms24031936 Despotes, K. A., Zariwala, M. A., Davis, S. D., & Ferkol, T. W. (2024). Primary Ciliary Dyskinesia: A Clinical Review. Cells, 13 (11). doi:10.3390/cells13110974 Ewen, R., Pink, I., Sutharsan, S., Aries, S. P., Grünewaldt, A., Shoemark, A., . . . Ringshausen, F. C. (2024). Primary Ciliary Dyskinesia in Adult Bronchiectasis: Data from the German Bronchiectasis Registry PROGNOSIS. Chest, 166 (5), 938-950. doi:10.1016/j.chest.2024.05.023 Gorivale, M., Sawant, P., Kargutkar, N., Hariharan, P., Thaker, P., Chiddarwar, A., & Nadkarni, A. (2024). When a synonymous mutation breaks the silence in a thalassaemia patient. Br J Haematol, 204 (2), 677-682. doi:10.1111/bjh.19115 Lan, Y., Xia, Z., Shao, Q., Lin, P., Lu, J., Xiao, X., . . . Xie, Q. (2025). Synonymous mutations promote tumorigenesis by disrupting m(6)A-dependent mRNA metabolism. Cell, 188 (7), 1828-1841 e1815. doi:10.1016/j.cell.2025.01.026 Lee, G. M. (2020). Preventing infections in children and adults with asplenia. Hematology Am Soc Hematol Educ Program, 2020 (1), 328-335. doi:10.1182/hematology.2020000117 Leigh, M. W., Horani, A., Kinghorn, B., O'Connor, M. G., Zariwala, M. A., & Knowles, M. R. (2019). Primary Ciliary Dyskinesia (PCD): A genetic disorder of motile cilia. Transl Sci Rare Dis, 4 (1-2), 51-75. doi:10.3233/trd-190036 Lobo, J., Zariwala, M. A., & Noone, P. G. (2015). Primary ciliary dyskinesia. Semin Respir Crit Care Med, 36 (2), 169-179. doi:10.1055/s-0035-1546748 Muhonen, E. G., Zhu, A., Sempson, S., Bothwell, S., Sagel, S. D., & Chan, K. H. (2025). Management of middle ear disease in pediatric primary ciliary dyskinesia. Int J Pediatr Otorhinolaryngol, 192 , 112297. doi:10.1016/j.ijporl.2025.112297 Paff, T., Omran, H., Nielsen, K. G., & Haarman, E. G. (2021). Current and Future Treatments in Primary Ciliary Dyskinesia. Int J Mol Sci, 22 (18). doi:10.3390/ijms22189834 Ringshausen, F. C., Shapiro, A. J., Nielsen, K. G., Mazurek, H., Pifferi, M., Donn, K. H., . . . Ferkol, T. W. (2024). Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial. Lancet Respir Med, 12 (1), 21-33. doi:10.1016/s2213-2600(23)00226-6 Sauna, Z. E., & Kimchi-Sarfaty, C. (2011). Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet, 12 (10), 683-691. doi:10.1038/nrg3051 Schofield, L. M., Duff, A., & Brennan, C. (2018). Airway Clearance Techniques for Primary Ciliary Dyskinesia; is the Cystic Fibrosis literature portable? Paediatr Respir Rev, 25 , 73-77. doi:10.1016/j.prrv.2017.03.011 Shen, C., Shen, Y., Huang, W., Zhang, A., Zou, T., Guo, D., . . . Ye, B. (2024). A novel homozygous RSPH4A variant in a family with primary ciliary dyskinesia and literature review. Frontiers in Genetics, 15 . doi:10.3389/fgene.2024.1364476 Shen, C., Shen, Y., Huang, W., Zhang, A., Zou, T., Guo, D., . . . Ye, B. (2024). A novel homozygous RSPH4A variant in a family with primary ciliary dyskinesia and literature review. Front Genet, 15 , 1364476. doi:10.3389/fgene.2024.1364476 Wang, L., Wang, R., Yang, D., Lu, C., Xu, Y., Liu, Y., . . . Luo, H. (2022). Novel RSPH4A Variants Associated With Primary Ciliary Dyskinesia-Related Infertility in Three Chinese Families. Front Genet, 13 , 922287. doi:10.3389/fgene.2022.922287 Zhao, Y., Pinskey, J., Lin, J., Yin, W., Sears, P. R., Daniels, L. A., . . . Nicastro, D. (2021). Structural insights into the cause of human RSPH4A primary ciliary dyskinesia. Mol Biol Cell, 32 (12), 1202-1209. doi:10.1091/mbc.E20-12-0806 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8990118","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":603376575,"identity":"3cd4e99d-addb-4b81-98b1-c5ed68b088a4","order_by":0,"name":"Jiali Huang","email":"","orcid":"","institution":"Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiali","middleName":"","lastName":"Huang","suffix":""},{"id":603376576,"identity":"5d5fa6ce-1630-49e8-bcd0-2849a3a610f3","order_by":1,"name":"Fei Tong","email":"","orcid":"","institution":"Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Tong","suffix":""},{"id":603376577,"identity":"ec2bae12-233a-4741-8044-6193b9ce1265","order_by":2,"name":"Kaiyue Xiao","email":"","orcid":"","institution":"Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kaiyue","middleName":"","lastName":"Xiao","suffix":""},{"id":603376578,"identity":"5ba0f832-4d3e-4090-a6cc-d37a17067a83","order_by":3,"name":"Xinyu Zhai","email":"","orcid":"","institution":"Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xinyu","middleName":"","lastName":"Zhai","suffix":""},{"id":603376579,"identity":"b9b71522-0a71-4c05-bb2a-7f2ff8ffdcb7","order_by":4,"name":"Xuyang Zheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIie3RsUoEMRCA4QkDOYvotrMoPsOIcFiI9yoJC1cpXCUprthDSQrXfn0LwcZO5GCr2K/d3iNcZyPnWtpstjwwXxeYnyEMQJLsoVkJ2BFfXok7fO+0XcYTUYLkCzsv0LuCu9CMSoBsWAtfhWm+ucd4gnTN/OkQD2s9taaUkPkHPZhIFXjz5ORRXut5a15PgMLH82CiJhWf507hWa2b1gQJTDfDCaHi429H4q01bmEcxhPutxAFFqtqLWFcoppbJqsL4R2SDo2K/mVWFy/9KXf9KbPt9ssuTzP/OJwAHPCfp4qM/5p0I4aSJEn+tR/bxEq8IRQLWAAAAABJRU5ErkJggg==","orcid":"","institution":"Westlake University","correspondingAuthor":true,"prefix":"","firstName":"Xuyang","middleName":"","lastName":"Zheng","suffix":""}],"badges":[],"createdAt":"2026-02-27 16:23:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8990118/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8990118/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104470551,"identity":"cb7b3bd7-43ef-4ad8-820c-281ecd505812","added_by":"auto","created_at":"2026-03-12 07:22:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":89879,"visible":true,"origin":"","legend":"\u003cp\u003eFamily history and clinical features of the patient. A This PCD patient comes from a non-consanguineous family; her parents show no clinical symptoms, but her brother exhibits similar clinical features. The adolescent female proband inherited a compound heterozygous mutation from two heterozygous carrier parents. The proband is indicated by the arrow. (B) Chest radiograph reveals bilateral pleural thickening, inflammation in the lower fields of both lungs, and no ectopic heart. The arrow indicates an image of inflammatory infiltration. (C) Transmission electron microscopy shows microvilli on the epithelial surface. D-F: Lung CT scan demonstrates pulmonary infection, bilateral pneumonia, and mild bronchial dilatation in both lungs.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8990118/v1/728320e6a517280047ec575f.jpg"},{"id":109245748,"identity":"38168e31-7f21-4010-b737-fecbee50b83d","added_by":"auto","created_at":"2026-05-14 07:55:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":599595,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8990118/v1/3d5c8a0b-dd80-483c-ba63-08524fac0448.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Novel Compound Heterozygous RSPH4A Variants in a Chinese Family with Primary Ciliary Dyskinesia: A Case Report and Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrimary ciliary dyskinesia (PCD) is a rare inherited disorder caused by defective motile cilia, leading to chronic respiratory symptoms and progressive lung damage.(Leigh et al., 2019). Individuals with PCD are unable to clear accumulated mucus and typically experience recurrent upper and lower respiratory tract infections, chronic sinusitis, progressive bronchiectasis, and lung atelectasis(Lobo, Zariwala, \u0026amp; Noone, 2015).Diagnosis of PCD relies on a combination of gene sequencing tests, high-speed videomicroscopy assessing ciliary beat frequency and pattern, transmission electron microscopy (TEM), and nasal nitric oxide measurement (Muhonen et al., 2025).Its prevalence ranges from 1 in 15,000 to 1 in 30,000 live births, involving 50 genes and over 2,000 pathogenic mutations(Collison et al., 2025).Proteins constituting the functional ciliary structures of the upper and lower respiratory tracts are affected by genetic mutations. The RSPH4A gene encodes a structural protein essential for ciliary function.The RSPH4A gene (c.921\u0026thinsp;+\u0026thinsp;3921+6delAAGT) was first identified as a pathogenic variant in Puerto Rico in 2013 and is linked to its ancestral haplotype(Daniels et al., 2013),while fewer variants have been reported in China.Previous studies confirmed that the protein encoded by RSPH4A is a key component of the radial arm head of ciliary microtubules. The radial arm is a vital component of the ciliary \u0026ldquo;9\u0026thinsp;+\u0026thinsp;2\u0026rdquo; microtubule structure (9 peripheral microtubule doublets surrounding a central microtubule pair), responsible for connecting the central microtubule to peripheral microtubules. It regulates ciliary beating frequency and direction by transmitting mechanical signals, ensuring proper mucociliary clearance (MCC) function. Mutations in the RSPH4A gene cause inconsistent ciliary beating frequency and direction, ultimately leading to impaired mucus clearance.While most reported pathogenic variants are homozygous, compound heterozygous mutations are rare and less well understood.In this study, we report a novel RSPH4A compound heterozygous variant: the pathogenic c.658A\u0026thinsp;\u0026gt;\u0026thinsp;T p.Lys220Ter heterozygote and the c.1764G\u0026thinsp;\u0026gt;\u0026thinsp;T p.Gly588\u0026thinsp;=\u0026thinsp;heterozygote, which caused primary ciliary dyskinesia in the patient. This configuration has not been previously described in the literature of RSPH4A-related disorders. Additionally, we conducted a literature review to elucidate the clinical features of this PCD and provide diagnostic insights for the early identification of this PCD gene.\u003c/p\u003e \u003cp\u003eMethod: The index patient is an 11-year-old girl who experienced recurrent upper respiratory tract infections since birth, with a history of allergic rhinitis,and progressively persistent recurrent coughing and became highly prone to wheezing.She had multiple episodes of wheezing and repeated hospitalizations for pneumonia. High-resolution computed tomography (HRCT) of the lungs revealed bronchiectasis. Two variants in the RSPH4A gene were identified in the proband.Sanger sequencing was employed to validate the RSPH4A variant in the proband, her father, her mother, and her brother. Finally, the patient's phenotypic characteristics were analyzed, and the current literature was reviewed to gain a better understanding of genetic variants associated with pulmonary infections in PCD and the clinical presentation of RSPH4A variants in PCD.\u003c/p\u003e \u003cp\u003eResults: Her first variant: DNA sequencing revealed an A-to-T transition at position 658 in the first exon of RSPH4A. This variant had never been reported previously. The mutation resulted in the replacement of lysine at position 220 with a stop codon (p.Lys220Ter), causing a missense mutation. Such variants are typically classified as pathogenic. Her second variant: DNA sequencing revealed a G-to-T transition at position 1764 in the fourth exon of RSPH4A. This variant has also never been reported before. The mutation causes a synonymous substitution at position 588 (Gly588S). However, synonymous mutations are not necessarily harmless; they may be pathogenic by affecting mRNA splicing, stability, or translation efficiency. The same variant was detected in the proband's brother, who exhibited similar clinical manifestations and ancillary test results, further confirming the pathogenicity of this synonymous mutation. A heterozygous variant was identified in the proband's parents, who are carriers of the RSPH4A mutation gene but remain clinically unaffected.\u003c/p\u003e \u003cp\u003eDiscussion: Literature review indicates that most reported pathogenic RSPH4A variants are homozygous, with compound heterozygous variants being relatively rare.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eAn 11-year-old girl was admitted to the Pediatrics Department of Hangzhou First People\u0026apos;s Hospital with a 2-year history of cough worsening over the past week. Family history indicated she was from a non-biological family; her parents showed no symptoms, but her brother presented with similar symptoms. The patient was born at term and experienced recurrent upper respiratory infections since birth, with a high susceptibility to wheezing. She had multiple hospitalizations for pneumonia. She had no history of long-term oxygen dependence or visceral transposition. Since age 9, she experienced recurrent coughing and persistent allergic rhinitis. She had been continuously inhaling budesonide powder for one year, but her cough symptoms showed no significant improvement. On physical examination, the adolescent patient did not exhibit tachypnea, but pectus excavatum was visible, and moist rales were audible on auscultation.. Figure\u0026nbsp;1 presents an overview of proband\u0026rsquo;s family history and radiographic findings.\u003c/p\u003e\n\u003cp\u003eFigure 1\u003c/p\u003e\n\u003cp\u003eFigure 1\u003c/p\u003e\n\u003cp\u003eFamily history and clinical features of the patient. A This PCD patient comes from a non-consanguineous family; her parents show no clinical symptoms, but her brother exhibits similar clinical features. The adolescent female proband inherited a compound heterozygous mutation from two heterozygous carrier parents. The proband is indicated by the arrow. (B) Chest radiograph reveals bilateral pleural thickening, inflammation in the lower fields of both lungs, and no ectopic heart. The arrow indicates an image of inflammatory infiltration. (C) Transmission electron microscopy shows microvilli on the epithelial surface. D-F: Lung CT scan demonstrates pulmonary infection, bilateral pneumonia, and mild bronchial dilatation in both lungs.\u003c/p\u003e\n\u003cdiv id=\"Sec3\"\u003e\n \u003ch2\u003eSupporting Tests:\u003c/h2\u003e\n \u003cp\u003eHRCT reveals bronchitis with scattered infectious lesions in both lungs, more prominent in the left lung, accompanied by localized bronchiectasis and thickened bronchial walls. Multiplex respiratory pathogen detection in BALF: Pseudomonas aeruginosa and Streptococcus pneumoniae DNA negative; Mycobacterium tuberculosis DNA negative. Due to poor pulmonary condition upon admission, pulmonary function testing was not performed; only exhaled nitric oxide (FeNO) was measured. Nasal FeNO level was 8 ppb, oral NO level was 5 ppb. Bronchoscopy revealed mucosal hyperemia and edema, with copious white viscous secretions and mucus plugs filling the bilateral bronchial lumens. Transmission electron microscopy showed cilia on the surface of ciliated epithelium: sparse, irregularly arranged, intermingled with microvilli. Localized epithelial cell loss was observed, with focal areas showing minimal inflammatory cell infiltration.The above investigations supported the diagnosis of primary ciliary dyskinesia (PCD). No significant abnormalities were detected in electrocardiogram, echocardiogram, cardiac enzymes, liver and kidney function tests, plasma electrolytes, serum mycoplasma and chlamydia antibodies, or immunoglobulin levels. After receiving intravenous ceftriaxone for 10 days, inhaled corticosteroids for 10 days, and undergoing bronchoscopy with treatment, the patient\u0026apos;s cough improved and was discharged. However, recurrent respiratory infections and cough persisted. Despite ongoing use of budesonide powder, the patient\u0026apos;s pulmonary function showed no significant improvement.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eDiagnosis\u003c/h3\u003e\n\u003cp\u003eGiven the history of full-term birth, allergic rhinitis, multiple episodes of pneumonia, bronchiectasis, and extremely low FENO results, a suspected diagnosis of primary ciliary dyskinesia (PCD) is made.\u003c/p\u003e\n\u003ch3\u003eFollow-up\u003c/h3\u003e\n\u003cp\u003ePCD is fundamentally a genetic disorder. Whole-exome sequencing identified two novel heterozygous variants in the RSPH4A gene:c.658A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Lys220Ter), a premature stop codon, classified as likely pathogenic.c.1764G\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Gly588=), a synonymous variant of uncertain significance.Both variants were confirmed by Sanger sequencing. The siblings inherited one variant each from their unaffected parents, confirming compound heterozygosity.The patient\u0026apos;s history, bronchiectasis, extremely low FENO results, transmission electron microscopy (TEM), and WES findings confirmed the definitive diagnosis of PCD. Bronchoscopy, alveolar lavage for airway clearance, and intravenous ceftriaxone with expectorants improved her recurrent wet cough. Follow-up chest X-ray one month after discharge showed multiple bronchiectasis with infection in both lungs, representing significant improvement compared to initial findings.However, compared to previous imaging, the small patchy ground-glass opacities in the left lower lobe showed minimal change. At the one-month follow-up after discharge, pulmonary function (PF) testing revealed moderate obstructive changes in conventional lung ventilation with mild impairment of ventilation capacity and small airway disease. The forced vital capacity (FVC) was 68.4% of predicted, peak expiratory flow rate at 61% of predicted, forced vital capacity at 66.8% of predicted, forced expiratory volume in one second at 59.2% of predicted, and FEV1/FVC ratio at 71.95%. At the 3-month follow-up post-discharge, pulmonary function (PF) revealed moderate obstructive changes in conventional lung ventilation with moderate reduction in ventilatory capacity and small airway disease. The forced vital capacity (FVC) was 68.25% of predicted, peak expiratory flow rate was 49.8% of predicted, forced vital capacity was 67.0% of predicted, forced expiratory volume in one second was 56.4% of predicted, and forced expiratory ratio was 68.68%. Her nasal exhaled FeNO level was 9 ppb, and oral exhaled NO level was 14 ppb. No significant improvement was noted. However, the patient\u0026apos;s cough symptoms improved, with no recurrence of fever or wheezing. Body mass index was appropriate for age and gender. The patient adhered to daily administration of prescribed inhaled corticosteroids and ciliary motility enhancers. No liver function abnormalities, emotional changes, or behavioral alterations were observed.Table\u0026nbsp;1is a generation verification diagram of proband,her parents,and siblings.\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;1\u003c/p\u003e\n\u003cp\u003eTable 1: Sanger Sequencing Analysis of RSPH4A Variant Families\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"557\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 137px;\"\u003e\n \u003cp\u003eSample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eGeneration Verification Diagram\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eProband - Heterozygous\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1773232137.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003eProband\u0026apos;s father - Wild-type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1773232142.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003eProband\u0026apos;s mother - Heterozygous\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1773232147.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003eProband\u0026apos;s brother - Heterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1773232152.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eRSPH4A \u0026nbsp; \u0026nbsp;Location:chr6：116950831 \u0026nbsp; mutation site:c.1764G\u0026gt;T\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eSample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003eGeneration Verification Diagram\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eProband - Heterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1773232158.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eProband\u0026apos;s father - Heterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1773232163.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eProband\u0026apos;s mother - Wild-type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1773232168.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003eProband\u0026apos;s brother - Heterozygous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 429px;\"\u003e\n \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/69519_bce2c0439cd956a6/69519_custom_files/img1773232172.png\"\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrimary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliary motility disorder characterized by progressive pulmonary disease manifesting as neonatal respiratory distress, recurrent upper and lower respiratory tract infections, poor fertility, and unilateral defects. Diagnosis relies on confirmation through a series of tests, including nasal nitric oxide measurement, high-speed videomicroscopy analysis, immunofluorescence staining, ultrastructural analysis of cilia via transmission electron microscopy (TEM), and genetic testing(Despotes, Zariwala, Davis, \u0026amp; Ferkol, 2024).To date, 54 disease-causing genes have been identified that can lead to related pathological conditions(Barber et al., 2025).In the cross-section of cilia, nine sets of outer microtubule dyads typically surround a central pair, forming a 9\u0026thinsp;+\u0026thinsp;2 ultrastructure. T-shaped radial spokes connect the central pair of microtubules to the outer dyads. RSPH4A is a fundamental component as it constitutes the central portion of the radial spoke head(C. Shen et al., 2024).The RSPH4A variant primarily disrupts ciliary ultrastructure and causes loss of radial head function, thereby impairing mucus clearance(Zhao et al., 2021).In this study, we report a case of an 11-year-old girl who presented with recurrent upper respiratory tract infections since birth, a history of allergic rhinitis, and progressively developed persistent recurrent cough with a high susceptibility to wheezing. She had multiple hospitalizations for pneumonia. Chest CT scans revealed bronchiectasis. She was diagnosed with PCD following whole-exome sequencing, transmission electron microscopy (TEM), and nasal nitric oxide testing. A novel compound heterozygous mutation in RSPH4A was identified. The pathogenic c.658A\u0026thinsp;\u0026gt;\u0026thinsp;T p.Lys220Ter compound heterozygote is a missense mutation classified as likely pathogenic according to ACMG guidelines. The c.1764G\u0026thinsp;\u0026gt;\u0026thinsp;T/p.Gly588\u0026thinsp;=\u0026thinsp;mutation is a missense variant classified as of uncertain significance (OUI) per ACMG guidelines. This specific genetic alteration has not been previously reported in the literature among patients with RSPH4A-related disorders. Details are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Clinicians should therefore be aware of this condition, particularly when young patients present with bronchiectasis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRSPH4A variants identified in this family through exome sequencing.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChromosomal\u0026amp;RS number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHGVS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGenetic Pattern\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCarrier Status for Mutations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eACMG Standards\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eACMG Classification\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRSPH4A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003echr6: 116938444\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNM_001010892.3\u003c/p\u003e \u003cp\u003eExon1/6\u003c/p\u003e \u003cp\u003ec.658A\u0026thinsp;\u0026gt;\u0026thinsp;T/p.Lys220Ter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eheterozygous\u003c/p\u003e \u003cp\u003e(67/138)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePVS1\u0026thinsp;+\u0026thinsp;PM2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLikely pathogenic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003echr6: 116950831\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM_001010892.3\u003c/p\u003e \u003cp\u003eExon4/6\u003c/p\u003e \u003cp\u003ec.1764G\u0026thinsp;\u0026gt;\u0026thinsp;T/p.Gly588=\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eheterozygous(69/135)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePM2\u0026thinsp;+\u0026thinsp;PP3+PM3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUncertain\u003c/p\u003e \u003cp\u003esignificance\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eUnlike homozygous mutations, compound heterozygous mutations involve two distinct pathogenic mutations on a single gene pair, whereas homozygous mutations carry identical pathogenic mutations on the same gene pair. Compound heterozygosity is one of the primary mechanisms underlying autosomal recessive disorders, though it remains clinically uncommon. Herein, unlike other patients with homozygous mutations,this is only the second reported case of compound heterozygous RSPH4A mutations causing PCD. The first case involved compound heterozygosity for c.2T\u0026thinsp;\u0026gt;\u0026thinsp;C, p.(Met1Thr) and c.1774_1775del, p.(Leu592Aspfs*5)(Wang et al., 2022).\u003c/p\u003e \u003cp\u003eSynonymous mutations have long been considered harmless or silent in humans(Bin, Wang, Zhao, Wen, \u0026amp; Xia, 2019).However, this concept has now changed, as synonymous mutations may potentially induce clinically significant alterations in protein expression, conformation, and function(Sauna \u0026amp; Kimchi-Sarfaty, 2011).Due to the degeneracy of genetic codons, synonymous mutations do not alter the encoded amino acid but can induce changes at the RNA level. Increasing evidence indicates that synonymous mutations significantly impact RNA splicing, stability, and folding, as well as translation or co-translational protein folding(Gorivale et al., 2024),such as synonymous mutations promote tumorigenesis by disrupting m\u003csup\u003e6\u003c/sup\u003eA-dependent mRNA metabolism(Lan et al., 2025).In practice, many synonymous mutations are initially classified as \u0026ldquo;variants of uncertain significance.\u0026rdquo; Only through functional experiments and robust genetic evidence can they be upgraded to \u0026ldquo;likely pathogenic\u0026rdquo; or \u0026ldquo;pathogenic\u0026rdquo; variants.The synonymous variant, though initially considered benign, likely disrupts mRNA processing or protein function, as evidenced by the shared phenotype in both siblings.These findings expand the genetic spectrum of RSPH4A-related PCD and highlight the need for functional validation of synonymous variants.\u003c/p\u003e \u003cp\u003eThe pathological basis of PCD is ciliary dyskinesia. Since patients lack normal ciliary movement, clearing airway secretions is a critical component of PCD treatment. Patients should receive personalized airway clearance techniques from respiratory physicians with PCD expertise. If mucus expectoration proves challenging, mucolytic therapies such as hypertonic saline nebulization and carbocysteine may be provided(Bush et al., 2006).Using a handheld positive airway pressure device can effectively eliminate coughing(Schofield, Duff, \u0026amp; Brennan, 2018).Preventive measures such as vaccination against influenza, COVID-19, and pneumonia are crucial(Lee, 2020).For sinus disorders and recurrent otitis media, regular examinations by an otolaryngologist are required(Collison et al., 2025).Patients with PCD face significant challenges to their quality of life due to the complexity of treatment and multisystem involvement. Current symptomatic therapies, such as airway clearance, only provide relief from symptoms(Ewen et al., 2024).The combination of idefloirid and hypertonic saline offers a novel approach to improving lung function, while mRNA therapy represents a potential direction for curing PCD at the genetic level, though technical bottlenecks must be overcome(Ringshausen et al., 2024).Future research requires more long-term studies to validate efficacy and safety, while strengthening multidisciplinary management to reduce the burden on patients(Paff, Omran, Nielsen, \u0026amp; Haarman, 2021).Additionally, long-term monitoring of lung function, exercise assessment, hearing evaluation, rehabilitation training, and psychological therapy feedback are all essential for improving the quality of life for patients with primary ciliary dyskinesia.\u003c/p\u003e \u003cp\u003eIn this study, we analyzed the genetic sequence of an adolescent patient with primary ciliary dyskinesia (PCD) who presented with recurrent cough, recurrent pneumonia, bronchiectasis, and extremely low FENO results. WES results revealed a novel compound heterozygous mutation in the RSPH4A gene: c.658A\u0026thinsp;\u0026gt;\u0026thinsp;T p.Lys220Ter heterozygous and c.1764G\u0026thinsp;\u0026gt;\u0026thinsp;T p.Gly588\u0026thinsp;=\u0026thinsp;heterozygous. This mutation in the proband was inherited from her parents, each carrying a single heterozygous mutation, resulting in compound heterozygosity in the patient. This mutation in RSPH4A identified in the adolescent patient has not been previously reported in databases or the literature, including ClinVar (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/ClinVar\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/ClinVar\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), LOVD3 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://databases.lovd.nl/shared/genes/RSPH4A\u003c/span\u003e\u003cspan address=\"https://databases.lovd.nl/shared/genes/RSPH4A\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and gnomAD (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gnomad.broadinstitute.org/\u003c/span\u003e\u003cspan address=\"https://gnomad.broadinstitute.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). All information was retrieved on October 16, 2025. This indicates that the variant in RSPH4A is a rare novel variant, reported for the first time in a patient with PCD.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe describe a novel compound heterozygous RSPH4A mutation in two siblings with PCD. These variants have not been previously reported, underscoring the importance of comprehensive genetic testing in patients with unexplained bronchiectasis and recurrent respiratory infections.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJiali Huang(First Author): Data Curation, Chart Creation, Writing-Original Draft, Investigation, Writing-Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eXuyang Zheng(Corresponding Author): Supervision, Writing-Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eKaiyue Xiao: Data Curation, Chart Creation.\u003c/p\u003e\n\u003cp\u003eFei Tong: Data Curation, Chart Creation.\u003c/p\u003e\n\u003cp\u003eXinyu Zhai:Data Curation, Chart Creation.\u003c/p\u003e\n\u003cp\u003eData Curation, Chart Creation.\u003c/p\u003e\n\u003cp\u003eAll authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003eFunding support: The authors received no funding support for the research.\u003c/p\u003e\n\u003cp\u003eData Availability Statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eConflicts of Interest: The authors declare no conflict of interest, financial or otherwise.\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u0026nbsp;：We thank the patients and their families who participated in this study.\u003c/p\u003e\n\u003cp\u003eConsent to participate declaration: not applicable.\u003c/p\u003e\n\u003cp\u003eConsent to publish declaration: Written informed consent for publication of their clinical details and clinical images was obtained from the patient of the patient.\u003c/p\u003e\n\u003cp\u003eEthics declaration:The study involving human participants have obtained informed consent from the patient and their families.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBarber, A. 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Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial. \u003cem\u003eLancet Respir Med, 12\u003c/em\u003e(1), 21-33. doi:10.1016/s2213-2600(23)00226-6\u003c/li\u003e\n \u003cli\u003eSauna, Z. E., \u0026amp; Kimchi-Sarfaty, C. (2011). Understanding the contribution of synonymous mutations to human disease. \u003cem\u003eNat Rev Genet, 12\u003c/em\u003e(10), 683-691. doi:10.1038/nrg3051\u003c/li\u003e\n \u003cli\u003eSchofield, L. M., Duff, A., \u0026amp; Brennan, C. (2018). Airway Clearance Techniques for Primary Ciliary Dyskinesia; is the Cystic Fibrosis literature portable? \u003cem\u003ePaediatr Respir Rev, 25\u003c/em\u003e, 73-77. doi:10.1016/j.prrv.2017.03.011\u003c/li\u003e\n \u003cli\u003eShen, C., Shen, Y., Huang, W., Zhang, A., Zou, T., Guo, D., . . . Ye, B. (2024). A novel homozygous RSPH4A variant in a family with primary ciliary dyskinesia and literature review. \u003cem\u003eFrontiers in Genetics, 15\u003c/em\u003e. doi:10.3389/fgene.2024.1364476\u003c/li\u003e\n \u003cli\u003eShen, C., Shen, Y., Huang, W., Zhang, A., Zou, T., Guo, D., . . . Ye, B. (2024). A novel homozygous RSPH4A variant in a family with primary ciliary dyskinesia and literature review. \u003cem\u003eFront Genet, 15\u003c/em\u003e, 1364476. doi:10.3389/fgene.2024.1364476\u003c/li\u003e\n \u003cli\u003eWang, L., Wang, R., Yang, D., Lu, C., Xu, Y., Liu, Y., . . . Luo, H. (2022). Novel RSPH4A Variants Associated With Primary Ciliary Dyskinesia-Related Infertility in Three Chinese Families. \u003cem\u003eFront Genet, 13\u003c/em\u003e, 922287. doi:10.3389/fgene.2022.922287\u003c/li\u003e\n \u003cli\u003eZhao, Y., Pinskey, J., Lin, J., Yin, W., Sears, P. R., Daniels, L. A., . . . Nicastro, D. (2021). Structural insights into the cause of human RSPH4A primary ciliary dyskinesia. \u003cem\u003eMol Biol Cell, 32\u003c/em\u003e(12), 1202-1209. doi:10.1091/mbc.E20-12-0806\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"adolescent patients, primary ciliary dyskinesia, compound heterozygous mutation, RSPH4A, case report","lastPublishedDoi":"10.21203/rs.3.rs-8990118/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8990118/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe Radius Spoke Head Protein 4 Homolog A (RSPH4A) gene is one of over 50 genes responsible for causing primary ciliary dyskinesia (PCD)(De Jes\u0026uacute;s-Rojas et al., 2023).Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder characterized by dysfunction of motile cilia, with or without detectable ultrastructural abnormalities(Chenling Shen et al., 2024).This study analyzed the clinical and genetic data of an index case suspected of having PCD based on her relevant test results.\u003c/p\u003e","manuscriptTitle":"Novel Compound Heterozygous RSPH4A Variants in a Chinese Family with Primary Ciliary Dyskinesia: A Case Report and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-12 07:21:59","doi":"10.21203/rs.3.rs-8990118/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d0a0de7c-f313-4776-896c-e88e705db474","owner":[],"postedDate":"March 12th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-14T07:40:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-12T20:27:38+00:00","index":110,"fulltext":""},{"type":"reviewerAgreed","content":"26188410469434951420579351616340808754","date":"2026-05-04T10:50:07+00:00","index":107,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-14T07:55:30+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-12 07:21:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8990118","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8990118","identity":"rs-8990118","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}