Limitations of Nasal Nitric Oxide Measurement for Diagnosis of Primary Ciliary Dyskinesia with Normal Ultrastructure

Raidt, Johanna; Krenz, Henrike; Tebbe, Johannes J.; Große-Onnebrink, Jörg; Olbrich, Heike; Loges, Niki T.; Biebach, Luisa; Schmalstieg, Christian; Keßler, Christina; Wallmeier, Julia; Dworniczak, Bernd; Pennekamp, Petra; Dugas, Martin; Werner, Claudius; Omran, Heymut

doi:10.1513/annalsats.202106-728oc

Cited by 22 publications

(16 citation statements)

References 37 publications

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“…Defects of the CP associated apparatus are difficult to diagnose. They are not associated with situs abnormalities and diagnostic tests in respiratory cilia, such as TEM are inconclusive and HSVM is difficult to interpret (Olbrich et al, 2012;Cindrić et al, 2019;Raidt et al, 2022). The CP complex associated genes HYDIN and SPEF2 are also associated with male infertility due to asthenoteratozoospermia (Olbrich et al, 2012;Cindrić et al, 2019;Sha et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…As recommended by the American Thoracic-and European Respiratory Society (ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005, American Thoracic Society and European Respiratory Society, 2005), nasal nitric oxide (nNO)-production rates are determined as part of the PCD routine diagnostic setup. Assessment of the nNO-production rates were performed as previously described (Werner et al, 2015;Raidt et al, 2022). Specifically, a chemiluminescence analyzer was used according to current PCD diagnostic guidelines (Lucas et al, 2017).…”

Section: Nasal Nitric Oxide (Nno)-production Ratesmentioning

confidence: 99%

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Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility

et al. 2023

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Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder affecting the function of motile cilia in several organ systems. In PCD, male infertility is caused by defective sperm flagella composition or deficient motile cilia function in the efferent ducts of the male reproductive system. Different PCD-associated genes encoding axonemal components involved in the regulation of ciliary and flagellar beating are also reported to cause infertility due to multiple morphological abnormalities of the sperm flagella (MMAF). Here, we performed genetic testing by next generation sequencing techniques, PCD diagnostics including immunofluorescence-, transmission electron-, and high-speed video microscopy on sperm flagella and andrological work up including semen analyses. We identified ten infertile male individuals with pathogenic variants in CCDC39 (one) and CCDC40 (two) encoding ruler proteins, RSPH1 (two) and RSPH9 (one) encoding radial spoke head proteins, and HYDIN (two) and SPEF2 (two) encoding CP-associated proteins, respectively. We demonstrate for the first time that pathogenic variants in RSPH1 and RSPH9 cause male infertility due to sperm cell dysmotility and abnormal flagellar RSPH1 and RSPH9 composition. We also provide novel evidence for MMAF in HYDIN- and RSPH1-mutant individuals. We show absence or severe reduction of CCDC39 and SPEF2 in sperm flagella of CCDC39- and CCDC40-mutant individuals and HYDIN- and SPEF2-mutant individuals, respectively. Thereby, we reveal interactions between CCDC39 and CCDC40 as well as HYDIN and SPEF2 in sperm flagella. Our findings demonstrate that immunofluorescence microscopy in sperm cells is a valuable tool to identify flagellar defects related to the axonemal ruler, radial spoke head and the central pair apparatus, thus aiding the diagnosis of male infertility. This is of particular importance to classify the pathogenicity of genetic defects, especially in cases of missense variants of unknown significance, or to interpret HYDIN variants that are confounded by the presence of the almost identical pseudogene HYDIN2.

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Section: Discussionmentioning

confidence: 99%

Section: Nasal Nitric Oxide (Nno)-production Ratesmentioning

confidence: 99%

Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility

et al. 2023

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“…Mutations in many different genes can cause PCD due to marked genetic heterogeneity. We divided the individuals into two groups depending on the mutated genes, as described previously ( Raidt et al, 2022 ; Kinghorn et al, 2023 ). One gene group predicted abnormal axonemal ultrastructure detectable by TEM.…”

Section: Methodsmentioning

confidence: 99%

“…This group comprised i) outer dynein arm (ODA)-, ii) combined inner dynein arm (IDA)/ODA-, and iii) microtubular disorganization and IDA defects ( Shoemark et al, 2020 ). The other gene group predicted normal or near-normal ultrastructural phenotypes [referred to as (near) normal ultrastructure ] of the respiratory ciliary axonemes ( Raidt et al, 2022 ; Kinghorn et al, 2023 ). Please refer to Table 1 for the different gene groups.…”

Section: Methodsmentioning

confidence: 99%

“…Genetic diagnoses were established using regular gene testing including Sanger sequencing of PCD genes. In most cases, targeted PCD gene panels were used as previously described ( Raidt et al, 2022 ; Aprea et al, 2023 ). In a few cases, whole-exome sequencing was performed, and data were analyzed only for DNA variants in previously published PCD genes.…”

Section: Methodsmentioning

confidence: 99%

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Molecular defects in primary ciliary dyskinesia are associated with agenesis of the frontal and sphenoid paranasal sinuses and chronic rhinosinusitis

Schramm,

Raidt,

Gross

et al. 2023

Front. Mol. Biosci.

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Background: Primary ciliary dyskinesia (PCD; MIM 242650) is a rare genetic disorder characterized by malfunction of the motile cilia resulting in reduced mucociliary clearance of the airways. Together with recurring infections of the lower respiratory tract, chronic rhinosinusitis (CRS) is a hallmark symptom of PCD. Data on genotype–phenotype correlations in the upper airways are scarce.Materials and methods: We investigated the prevalence, radiologic severity, and impact on health-related quality of life (HrQoL) of CRS in 58 individuals with genetically confirmed PCD. Subgroup analysis was performed according to the predicted ultrastructural phenotype based on genetic findings.Results: Among 58 individuals harboring pathogenic variants in 22 distinct genes associated with PCD, all were diagnosed with CRS, and 47% underwent sinus surgery. A total of 36 individuals answered a German-adapted version of the 20-item Sinonasal Outcome Test (SNOT-20-GAV) with a mean score of 35.8 ± 17, indicating a remarkably reduced HrQoL. Paranasal sinus imaging of 36 individuals showed moderate-to-severe opacification with an elevated Lund–Mackay Score (LMS) of 10.2 ± 4.4. Bilateral agenesis of frontal sinus (19%) and sphenoid sinus (9.5%) was a frequent finding in individuals aged 16 years or older. Subgroup analysis for predicted ultrastructural phenotypes did not identify differences in HrQoL, extent of sinus opacification, or frequency of aplastic paranasal sinuses.Conclusion: PCD is strongly associated with CRS. The high burden of disease is indicated by decreased HrQoL. Therefore, the upper airways of PCD individuals should be evaluated and managed by ear–nose–throat (ENT) specialists. Genetically determined PCD groups with predicted abnormal versus (near) normal ultrastructure did not differ in disease severity. Further studies are needed to gain evidence-based knowledge of the phenotype and management of upper airway manifestations in PCD. In addition, individuals with agenesis of the frontal and sphenoid paranasal sinuses and chronic respiratory symptoms should be considered for a diagnostic evaluation of PCD.

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Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia

Black,

de Proce,

Campos

et al. 2024

Pediatric Pulmonology

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BackgroundPrimary ciliary dyskinesia (PCD) is a genetic disorder affecting motile cilia. Most cases are inherited recessively, due to variants in >50 genes that result in abnormal or absent motile cilia. This leads to chronic upper and lower airway disease, subfertility, and laterality defects. Given overlapping clinical features and genetic heterogeneity, diagnosis can be difficult and often occurs late. Of those tested an estimated 30% of genetically screened PCD patients still lack a molecular diagnosis. A molecular diagnosis allows for appropriate clinical management including prediction of phenotypic features correlated to genotype. Here, we aimed to identify how readily a genetic diagnosis could be made using whole genome sequencing (WGS) to facilitate identification of pathogenic variants in known genes as well as novel PCD candidate genes.MethodsWGS was used to screen for pathogenic variants in eight patients with PCD.Results7/8 cases had homozygous or biallelic variants in DNAH5, DNAAF4 or DNAH11 classified as pathogenic or likely pathogenic. Three identified variants were deletions, ranging from 3 to 13 kb, for which WGS identified precise breakpoints, permitting confirmation by Sanger sequencing. WGS yielded identification of a de novo variant in a novel PCD gene TUBB4B.ConclusionHere, WGS uplifted genetic diagnosis of PCD by identifying structural variants and novel modes of inheritance in new candidate genes. WGS could be an important component of the PCD diagnostic toolkit, increasing molecular diagnostic yield from current (70%) levels, and enhancing our understanding of fundamental biology of motile cilia and variants in the noncoding genome.

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Limitations of Nasal Nitric Oxide Measurement for Diagnosis of Primary Ciliary Dyskinesia with Normal Ultrastructure

Cited by 22 publications

References 37 publications

Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility

Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility

Molecular defects in primary ciliary dyskinesia are associated with agenesis of the frontal and sphenoid paranasal sinuses and chronic rhinosinusitis

Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia

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