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Background Methods Results Conclusions Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disease. Due to difficulty accessing diagnostic services and a lack of awareness of the syndrome, clinicians often fail to recognize the classic phenotype, leading to missed diagnoses.Relevant medical records were accessed through The BIG DATA QUERY AND ANALYSIS SYSTEM of Peking Union Medical College Hospital from September 1, 2012 to March 31, 2024. The search strategy included the following key terms: (bronchiectasis OR atelectasis OR recurrent cough OR recurrent expectoration OR hemoptysis) AND (sinusitis OR nasal polyps OR otitis media OR neonatal pneumonia OR neonatal respiratory distress OR ectopic pregnancy OR infertility OR artificial insemination OR assisted reproduction OR hydrocephalus OR congenital heart disease OR organ laterality defect OR right‐sided heart OR semen OR consanguineous marriage). Patients were filtered according to inclusion and exclusion criteria, and those with clinical suspicion of PCD were invited for screening, which included nasal nitric oxide and whole exome sequencing.A total of 874 medical records were retrieved. After filtering based on inclusion and exclusion criteria, 65 patients with clinical suspicion of PCD were identified, 21 of whom accepted our invitation to complete PCD‐related screening. Among them, four were diagnosed with PCD, one was diagnosed with cystic fibrosis, and one was diagnosed with immunodeficiency‐21.This is the first study to use an electronic medical record retrieval system to identify missed diagnoses PCD. We believe that the methods used in this study can be extended to other rare diseases in the future. [ABSTRACT FROM AUTHOR]

Digital high-speed videomicroscopy (DHSV) is a crucial tool for evaluating ciliary function in children suspected of primary ciliary dyskinesia (PCD). However, until now, samples are taken without anesthesia due to uncertainty about its effect on ciliary function and DHSV interpretation. This study aimed to investigate the impact of general anesthesia on ciliary functional analysis by DHSV in a series of three patients listed for ENT surgeries, which could improve diagnostic procedures for pediatric patients. Patient 1 (7-year-old girl) underwent adenotonsillectomy and tympanostomy placement tube, while patients 2 (17-month-old boy) and 3 (15-month-old girl) underwent adenoidectomy and tympanostomy placement tube. All patients underwent nasal brushing before general anesthesia (control sample). Experimental samples were taken in the contralateral nostril at the time of equilibration of the anesthetic agents (sevoflurane, propofol, sufentanil). Ciliary beat frequency and pattern were measured using digital high-speed videomicroscopy. Our findings highlighted the variability of respiratory ciliary function under general anesthesia among individuals. Our results emphasize the need for caution when interpreting ciliary function data obtained during general anesthesia. Further research with larger cohorts is warranted for validation. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by the malfunction of motile cilia and a specific etiology of adult bronchiectasis of unknown prevalence. A better understanding of the clinical phenotype of adults with PCD is needed to identify individuals for referral to diagnostic testing. What is the frequency of PCD among adults with bronchiectasis; how do people with PCD differ from those with other etiologies; and which clinical characteristics are independently associated with PCD? We investigated the proportion of PCD among the participants of the Prospective German Non-CF-Bronchiectasis Registry (PROGNOSIS) study; applied multiple imputation to account for missing data in 64 (FEV 1), 58 (breathlessness), 26 (pulmonary exacerbations), and two patients (BMI), respectively; and identified predictive variables from baseline data using multivariate logistic regression analysis. We consecutively recruited 1,000 patients from 38 centers across all levels of the German health care system. Overall, PCD was the fifth most common etiology of bronchiectasis in 87 patients (9%) after idiopathic, postinfective, COPD, and asthma. People with PCD showed a distinct clinical phenotype. In multivariate regression analysis, the chance of PCD being the etiology of bronchiectasis increased with the presence of upper airway disease (chronic rhinosinusitis and/or nasal polyps; adjusted OR [aOR], 6.3; 95% CI, 3.3-11.9; P <.001), age < 53 years (aOR, 5.3; 95% CI, 2.7-10.4; P <.001), radiologic involvement of any middle and lower lobe (aOR, 3.7; 95% CI, 1.3-10.8; P =.016), duration of bronchiectasis > 15 years (aOR, 3.6; 95% CI, 1.9-6.9; P <.001), and a history of Pseudomonas aeruginosa isolation from respiratory specimen (aOR, 2.4; 95% CI, 1.3-4.5; P =.007). Within our nationally representative cohort, PCD was a common etiology of bronchiectasis. We identified few easy-to-assess phenotypic features, which may promote awareness for PCD among adults with bronchiectasis. ClinicalTrials.gov; No.: NCT02574143 ; URL: www.clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Data are limited on the genetic profile of primary ciliary dyskinesia (PCD) from developing countries. Here, we report one of the first study on genetic profile of patients with suspected PCD from India. In this prospective cross‐sectional study, we enrolled 162 children with suspected PCD. We recorded clinical features, relevant laboratory tests for PCD and performed whole exome sequencing (WES). We are reporting 67 patients here who had positive variant/s on WES. We had 117 variants in 40 genes among 67 patients. Among the 108 unique variants, 33 were categorized as pathogenic or likely pathogenic (P/LP). We had nine novel variants in out cohort. The 29 definite PCD cases, diagnosed by composite reference standards, had variants in 16 genes namely LRRC6/DNAAF11 (5), DNAH5 (3), CCDC39 (3), HYDIN (3), DNAH11 (2), CCDC40 (2), CCDC65 (2) and one each DNAAF3, DNAAF2, CFAP300, RPGR, CCDC103, CCDC114, SPAG1, DNAI1, and DNAH14. To conclude, we identified 108 unique variants in 40 genes among 67 patients. The common genes involved in definite cases of PCD in Indian patients were LRRC6, DNAH5, CCDC39, and HYDIN. Our findings suggest a need to develop a separate genetic panel for PCD in the Indian population. [ABSTRACT FROM AUTHOR]

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ABSTRACT Primary ciliary dyskinesia (PCD; OMIM 244400) is a rare genetic disorder affecting motile cilia and is characterized by impaired mucociliary clearance in the airway epithelium that leads to chronic oto‐sinopulmonary manifestations. To date, over 50 PCD‐causing genes have been identified, with these genes and their variants varying globally across populations. We performed targeted resequencing of 42 PCD‐causative genes in 150 Japanese patients suspected of having PCD and identified pathogenic or likely pathogenic variants in 51 patients. Among these, 24 patients exhibited a homozygous deletion of DRC1 exons 1–4, the most common cause of PCD in Japan. The allele frequency of this deletion was estimated at 0.0034 (95% CI: 0.0025–0.0044), based on bioinformatic analysis of 7906 whole‐genome sequences from the general Japanese population. Additionally, RNA sequencing of nasal samples supplemented in silico variant predictions, aiding in the identification of causative variants. Considering potential ethnic differences, it is essential to accumulate global data on these variants and their functional impacts. [ABSTRACT FROM AUTHOR]

The prevalence of asthma exceeds 3% of the population. Asthma is observed to be more common in children following severe viral lower respiratory illnesses that affect ciliary function, but mechanisms linking ciliary function to asthma pathogenesis have been obscure. Recent data regarding primary ciliary dyskinesia (PCD) may help us to understand the association. Here, I will review what is known about the relationship between ciliary function and asthma. PCD is caused by pathologic variants in over 50 different genes that affect the structure and function of motile cilia. At the cellular level, a characteristic feature shared by most PCD patients is that antigens and other particles are not cleared from the epithelial surface. Poor antigen clearance results in pro-oxidant pathway activation and airway epithelial damage and may predispose PCD patients to DUOX1- and IL33-mediated asthma. Secondary ciliary dysfunction, such as that caused by viruses or by smoking, can also contribute to asthma development. Moreover, variants in genes that affect the function of cilia can be associated with poor lung function, even in the absence of PCD, and with increased asthma severity. The role of antigen stasis on the surface of dysfunctional airway cilia in the pathophysiology of asthma is a novel area for research, because specific airway clearance techniques and other therapeutic interventions, such as antioxidants, could be of value in preventing the development of asthma. [ABSTRACT FROM AUTHOR]

Abstract Background Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left–right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited. Results The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients` respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population. Conclusions The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants.

Primary ciliary dyskinesia (PCD) is a rare monogenic disorder primarily associated with structural and functional abnormalities of motile cilia. It is typically inherited in an autosomal recessive pattern. The disease affects multiple organs, and the variability in clinical phenotypes, along with genetic heterogeneity significantly complicates its diagnosis. Although the application of clinical exome sequencing has significantly improved the diagnostic rate of PCD, more than 30% of patients are still unable to obtain a definitive diagnosis. This article reviews and discusses the pathogenesis, diagnostic methods, and expanding genetic diagnostic approaches for patients with PCD that are negative for exome sequencing. The aim of this article is to assist clinicians in selecting more advanced emerging genetic testing technologies, with the hope of increasing the positive diagnostic rate of PCD, deepening the understanding of its genetic pathogenesis, and laying a foundation for the practice of gene therapy in the future.

Abstract Background Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease characterized by recurrent respiratory infections. In clinical manifestations, DNAH5 (NM_001361.3) is one of the recessive pathogenic genes. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcification in the basal ganglia and other brain regions. PFBC can be inherited in an autosomal dominant or recessive manner. A family with PCD caused by a DNAH5 compound heterozygous variant and PFBC caused by a MYORG homozygous variant was analyzed. Methods In this study, we recruited three generations of Han families with primary ciliary dyskinesia combined with primary familial brain calcification. Their clinical phenotype data were collected, next-generation sequencing was performed to screen suspected pathogenic mutations in the proband and segregation analysis of families was carried out by Sanger sequencing. The mutant and wild-type plasmids were constructed and transfected into HEK293T cells instantaneously, and splicing patterns were detected by Minigene splicing assay. The structure and function of mutations were analyzed by bioinformatics analysis. Results The clinical phenotypes of the proband (II10) and his sister (II8) were bronchiectasis, recurrent pulmonary infection, multiple symmetric calcifications of bilateral globus pallidus and cerebellar dentate nucleus, paranasal sinusitis in the whole group, and electron microscopy of bronchial mucosa showed that the ciliary axoneme was defective. There was also total visceral inversion in II10 but not in II8. A novel splice variant C.13,338 + 5G > C and a frameshift variant C.4314delT (p. Asn1438lysfs *10) were found in the DNAH5 gene in proband (II10) and II8. c.347_348dupCTGGCCTTCCGC homozygous insertion variation was found in the MYORG of the proband. The two pathogenic genes were co-segregated in the family. Minigene showed that DNAH5 c.13,338 + 5G > C has two abnormal splicing modes: One is that part of the intron bases where the mutation site located is translated, resulting in early translation termination of DNAH5; The other is the mutation resulting in the deletion of exon76. Conclusions The newly identified DNAH5 splicing mutation c.13,338 + 5G > C is involved in the pathogenesis of PCD in the family, and forms a compound heterozygote with the pathogenic variant DNAH5 c.4314delT lead to the pathogenesis of PCD.

Abstract To evaluate the genetic etiology of fetal dextrocardia, associated ultrasound anomalies, and perinatal outcomes, we investigated the utility of whole exome sequencing (WES) for prenatal diagnosis of dextrocardia. Fetuses with dextrocardia were prospectively collected between January 2016 and December 2022. Trio-WES was performed on fetuses with dextrocardia, following normal karyotyping and/or chromosomal microarray analysis (CMA) results. A total of 29 fetuses with dextrocardia were collected, including 27 (93.1%) diagnosed with situs inversus totalis and 2 (6.9%) with situs inversus partialis. Cardiac malformations were present in nine cases, extra-cardiac anomalies were found in seven cases, and both cardiac and extra-cardiac malformations were identified in one case. The fetal karyotypes and CMA results of 29 cases were normal. Of the 29 cases with dextrocardia, 15 underwent WES, and the other 14 cases refused. Of the 15 cases that underwent WES, clinically relevant variants were identified in 5/15 (33.3%) cases, including the diagnostic variants DNAH5, DNAH11, LRRC56, PEX10, and ZIC3, which were verified by Sanger sequencing. Of the 10 cases with non-diagnostic results via WES, eight (80%) chose to continue the pregnancies. Of the 29 fetuses with dextrocardia, 10 were terminated during pregnancy, and 19 were live born. Fetal dextrocardia is often accompanied by cardiac and extra-cardiac anomalies, and fetal dextrocardia accompanied by situs inversus is associated with a high risk of primary ciliary dyskinesia. Trio-WES is recommended following normal karyotyping and CMA results because it can improve the diagnostic utility of genetic variants of fetal dextrocardia, accurately predict fetal prognosis, and guide perinatal management and the reproductive decisions of affected families.

Kartagener’s Syndrome, alternatively known as Primary Ciliary Dyskinesia (PCD) is a rare and intricate inherited disorder that impacts the structure and function of cilia, leading to compromised mucociliary clearance. The defining features of this condition consist of chronic sinusitis, situs inversus totalis, and bronchiectasis, forming a characteristic triad. Kartagener’s Syndrome presents numerous challenges in its diagnosis and management, and its clinical implications have significant ramifications for affected individuals. This review aims to comprehensively review and analyse the clinical impact of this syndrome, focusing on the diagnosis, treatment, and management modalities. The ciliary dysfunction in Kartagener’s Syndrome disrupts the mucus clearance and pathogens from the respiratory tract, resulting in chronic infections, progressive lung damage, and respiratory failure in severe cases. Through a narrative review of literature, reviews, and case studies, the authors have explored clinicians’ diagnostic challenges and the advances in genetic testing methods that aid in early and accurate diagnosis. The authors have discussed the multidisciplinary approach to manage Kartagener’s Syndrome, which involves respiratory therapies, antibiotics, and surgical interventions to improve the patient’s quality of life and prevent complications. The review paper also includes in-depth case studies of individuals with Kartagener’s Syndrome, highlighting the variability in clinical presentations and treatment outcomes. These case studies provide valuable insights into the diverse manifestations of this syndrome, further enhancing the existing understanding of the disease and its management. Ultimately, this review is directed to raise awareness among healthcare professionals about Kartagener’s Syndrome, its clinical implications, and its diagnostic and treatment challenges. By shedding light on this rare and intricate genetic disorder, the authors here promote early recognition and proactive management, leading to improved outcomes and better quality of life for individuals with Kartagener’s Syndrome.

Kartagener's Syndrome is a rare autosomal recessive genetic condition, that affects the structure and function of cilia and includes a condition of situs inversus, chronic sinusitis, and bronchiectasis associated sometimes with infertility.A young patient who had a long-time fever, cough, and infertility after a clinical evaluation performed a chest X-ray and a CT scan that revealed the unexpected condition of Situs Inversus Totalis (SIT). Imaging also showed bronchiectasis and sinusitis: all findings consistent with Kartagener's syndrome, confirmed a second time by the genetic test.This case highlights the importance of knowing and considering situs inversus in clinical practice, particularly when interpreting imaging studies and planning medical interventions. Furthermore, as situs inversus may be associated with cardiovascular and pulmonary pathologies in several syndromic conditions, such as Kartagener's syndrome in this case, these conditions should always be carefully examined.

In recent years, questionnaires were published in English to assess the quality of life of patients with PCD (Primary Ciliary Diskinesia) for adults, adolescents aged 13–17 years, and children aged 6–12 years and their caregivers. This study aimed to prepare Polish versions of the questionnaires and validate them in specific age groups with the participation of Polish patients with PCD. The individual questionnaires were translated and discussed with the involvement of the creator of the original questionnaire in English. Patients completed the questionnaires according to their affiliation with one of the groups. Validation was based on internal consistency analysis (Cronbach’s alpha coefficient and split-half reliability) and test–retest reliability (intraclass correlation coefficient—ICC). The internal consistency of all questionnaires was from moderate to very good (Cronbach’s alpha 0.67–0.91, split-half reliability 0.53–0.95). The consistency of the measurements showed excellent repeatability (ICC 0.67–0.91). The surveyed Polish PCD patients rated their quality of life quite well (63–77%). QOL questionnaires for patients with PCD can be used routinely during each medical check-up as a simple tool to provide the doctor with an indication of the effectiveness of treatment and the impact of the disease on the patient’s quality of life.

Background: Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left–right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited. Results: The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients' respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population. Conclusions: The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants. [ABSTRACT FROM AUTHOR]

Several chronic respiratory diseases could be risk factors for acquiring SARS-CoV-2 infection: among them, Primary Ciliary Dyskinesia (PCD) is a rare (about 1:10.000) inherited ciliopathy (MIM 242650) characterized by recurrent upper and lower respiratory tract infections due to a dysfunction of the respiratory cilia. In this study, we aimed to investigate whether PCD subjects are more susceptible to infection by SARS-CoV-2 and whether some polymorphisms of the TAS2R38 bitter taste receptor correlate with an increased prevalence of SARS-CoV-2 infection and severity of symptoms. Patients answered several questions about possible SARS-CoV-2 infection, experienced symptoms, and vaccinations; in the case of infection, they also filled out a SNOT-22 questionnaire and ARTIQ. Forty PCD adult patients (mean age, 36.6 ± 16.7 years; 23 females, 17 males) participated in this study, out of which 30% had tested positive for COVID-19 during the last four years; most of them reported a mildly symptomatic disease. We found no differences in age or sex, but a statistically significant difference (p = 0.03) was observed in body mass index (BMI), which was higher in the COVID-acquired group (23.2 ± 3.3 vs. 20.1 ± 4.1 kg/m2). Genotyping for TAS2R38 polymorphisms showed a prevalence of 28.6% PAV/PAV, 48.6% PAV/AVI, and 22.8% AVI/AVI individuals in our cohort. In contrast to our hypothesis, we did not observe a protective role of the PAV allele towards SARS-CoV-2 infection. Conclusions: Our findings suggest that subjects with PCD may not be at increased risk of severe outcomes from COVID-19 and the TAS2R38 bitter taste receptor genotype does not affect SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by alterations in motile cilia function. The diagnosis of PCD is challenging due to the lack of standardized methods in clinical practice. High-speed video microscopy analysis (HSVA) directly evaluates ciliary beat frequency (CBF) in PCD. Recently, open-source ciliary analysis software applications have shown promise in measuring CBF accurately. However, there is limited knowledge about the performance of different software applications, creating a gap in understanding their comparative effectiveness in measuring CBF in PCD. We compared two open-source software applications, CiliarMove (v219) and Cilialyzer (v1.2.1-b3098cb), against the manual count method. We used high-speed videos of nasal ciliary brush samples from PCD RSPH4A-positive (PCD (RSPH4A)) patients and healthy controls. All three methods showed lower median CBF values for patients with PCD (RSPH4A) than in healthy controls. CiliarMove and Cilialyzer identified lower CBF in patients with PCD (RSPH4A), similarly to the manual count. Cilialyzer, CiliarMove, and manual count methods demonstrated statistical significance (p-value < 0.0001) in the difference of median CBF values between patients with PCD (RSPH4A) and healthy controls. Correlation coefficients between the manual count values against both software methods demonstrated positive linear relationships. These findings support the utility of open-source software-based analysis tools. Further studies are needed to validate these findings with other genetic variants and identify the optimal software for accurate CBF measurement in patients with PCD. [ABSTRACT FROM AUTHOR]

Though PCD usually presents after birth in term neonates, diagnosing PCD during the neonatal and infancy stages is uncommon, particularly in children who do not exhibit laterality defects. We report our recent experience with the diagnosis of PCD in the neonatal and early infantile period in a highly consanguine population. This was achieved by implementing a novel genetic-based diagnostic approach based on direct testing for recognized regional genetic variants. We conducted a retrospective analysis of children diagnosed with PCD at Soroka University Medical Center during the neonatal or early infantile period between 2020 and 2023. We included children under 3 months of age who had a genetic confirmation of PCD, as evidenced by the presence of two pathogenic variants in recognized genes. Genetic testing targeted regional genetic variants in previously identified PCD genes. Eight patients were included. The median age at diagnosis was 12.5 days. Three (38%) were born prematurely < 34 weeks gestational age. All patients were presented with respiratory distress and hypoxemia after birth. The median duration of oxygen support was 23 days, and upper lobe atelectasis was present in five patients (63%). Congenital cardiac malformation was present in four patients. Organ laterality defects were present in four patients. Genetic mutations identified were in the DNAAF5, DNAL1, DNAAF3, and DNAH1 genes. Conclusion: Neonatal diagnosis of PCD is uncommon, especially in atypical presentations such as children without laterality defects or preterms. Focusing on a genetic diagnosis of the local tribal pathogenic variants promotes a potential cost-efficient test leading to earlier diagnosis. There is a need for a standardized protocol for earlier diagnosis of PCD in high-consanguinity areas. What is Known: • Primary ciliary dyskinesia (PCD) typically presents after birth in term neonates. • Diagnosing PCD during neonatal and infancy stages is challenging, particularly in children without laterality defects. What is New: • A novel genetic-based diagnostic approach was implemented on the neonatal population in a highly consanguine community, focusing on direct testing for regional genetic variants, leading to early and rapid diagnosis of PCD. [ABSTRACT FROM AUTHOR]

Introduction: Primary ciliary dyskinesia (PCD) is caused by the dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. This study aimed to map novel PCD variants and determine their pathogenicity in PCD patients in Kuwait. Methods: Herein, we present five PCD individuals belonging to a cohort of 105 PCD individuals recruited from different hospitals in Kuwait. Genomic DNAs from the family members were analysed to screen for pathogenic PCD variants. Transmission electron microscopy (TEM) and immunofluorescence (IF) analyses were performed on the nasal biopsies to detect specific structural abnormalities within the ciliated cells. Results: Genetic screening and functional analyses confirmed that the five PCD individuals carried novel pathogenic variants of DNAH5 causing PCD in three Arabic families. Of these, one multiplex family with two affected individuals showed two novel homozygous missense variants in DNAH5 causing PCD with situs inversus; another multiplex family with two affected individuals showed two newly identified compound heterozygous variants in DNAH5 causing PCD with situs solitus. In addition, novel heterozygous variants were identified in a child with PCD and situs solitus from a singleton family with unrelated parents. TEM analysis demonstrated the lack of outer dynein arms (ODAs) in all analysed samples, and IF analysis confirmed the absence of the dynein arm component of DNAH5 from the ciliary axoneme. Conclusion: The newly identified pathogenic variants of DNAH5 are associated with PCD as well as variable pulmonary clinical manifestations in Arabic families. [ABSTRACT FROM AUTHOR]

To evaluate the genetic etiology of fetal dextrocardia, associated ultrasound anomalies, and perinatal outcomes, we investigated the utility of whole exome sequencing (WES) for prenatal diagnosis of dextrocardia. Fetuses with dextrocardia were prospectively collected between January 2016 and December 2022. Trio-WES was performed on fetuses with dextrocardia, following normal karyotyping and/or chromosomal microarray analysis (CMA) results. A total of 29 fetuses with dextrocardia were collected, including 27 (93.1%) diagnosed with situs inversus totalis and 2 (6.9%) with situs inversus partialis. Cardiac malformations were present in nine cases, extra-cardiac anomalies were found in seven cases, and both cardiac and extra-cardiac malformations were identified in one case. The fetal karyotypes and CMA results of 29 cases were normal. Of the 29 cases with dextrocardia, 15 underwent WES, and the other 14 cases refused. Of the 15 cases that underwent WES, clinically relevant variants were identified in 5/15 (33.3%) cases, including the diagnostic variants DNAH5, DNAH11, LRRC56, PEX10, and ZIC3, which were verified by Sanger sequencing. Of the 10 cases with non-diagnostic results via WES, eight (80%) chose to continue the pregnancies. Of the 29 fetuses with dextrocardia, 10 were terminated during pregnancy, and 19 were live born. Fetal dextrocardia is often accompanied by cardiac and extra-cardiac anomalies, and fetal dextrocardia accompanied by situs inversus is associated with a high risk of primary ciliary dyskinesia. Trio-WES is recommended following normal karyotyping and CMA results because it can improve the diagnostic utility of genetic variants of fetal dextrocardia, accurately predict fetal prognosis, and guide perinatal management and the reproductive decisions of affected families. [ABSTRACT FROM AUTHOR]

Background: Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease characterized by recurrent respiratory infections. In clinical manifestations, DNAH5 (NM_001361.3) is one of the recessive pathogenic genes. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcification in the basal ganglia and other brain regions. PFBC can be inherited in an autosomal dominant or recessive manner. A family with PCD caused by a DNAH5 compound heterozygous variant and PFBC caused by a MYORG homozygous variant was analyzed. Methods: In this study, we recruited three generations of Han families with primary ciliary dyskinesia combined with primary familial brain calcification. Their clinical phenotype data were collected, next-generation sequencing was performed to screen suspected pathogenic mutations in the proband and segregation analysis of families was carried out by Sanger sequencing. The mutant and wild-type plasmids were constructed and transfected into HEK293T cells instantaneously, and splicing patterns were detected by Minigene splicing assay. The structure and function of mutations were analyzed by bioinformatics analysis. Results: The clinical phenotypes of the proband (II10) and his sister (II8) were bronchiectasis, recurrent pulmonary infection, multiple symmetric calcifications of bilateral globus pallidus and cerebellar dentate nucleus, paranasal sinusitis in the whole group, and electron microscopy of bronchial mucosa showed that the ciliary axoneme was defective. There was also total visceral inversion in II10 but not in II8. A novel splice variant C.13,338 + 5G > C and a frameshift variant C.4314delT (p. Asn1438lysfs *10) were found in the DNAH5 gene in proband (II10) and II8. c.347_348dupCTGGCCTTCCGC homozygous insertion variation was found in the MYORG of the proband. The two pathogenic genes were co-segregated in the family. Minigene showed that DNAH5 c.13,338 + 5G > C has two abnormal splicing modes: One is that part of the intron bases where the mutation site located is translated, resulting in early translation termination of DNAH5; The other is the mutation resulting in the deletion of exon76. Conclusions: The newly identified DNAH5 splicing mutation c.13,338 + 5G > C is involved in the pathogenesis of PCD in the family, and forms a compound heterozygote with the pathogenic variant DNAH5 c.4314delT lead to the pathogenesis of PCD. [ABSTRACT FROM AUTHOR]

Objectives: Coronavirus disease 2019 pandemic caused many changes in the social behaviors of individuals and the provision of health systems. Many studies revealed reductions in the number of diagnoses and delays in diagnosis time during the pandemic. This study aimed to evaluate the effect of the pandemic on the time to diagnosis of major diseases of pediatric pulmonology. Materials and Methods: Newly diagnosed patients with cystic fibrosis (CF), childhood interstitial lung disease (chILD), tuberculosis (TB), and primary ciliary dyskinesia (PCD) were grouped into pandemic (group 1) and 2 consecutive pre-pandemic periods divided into equal intervals (groups 2 and 3). For each disease group, the time to diagnosis was compared between the specified periods. Results: A total number of patients were 171 in this study. In the CF group, there was no statistically difference in time to diagnosis between periods. In the chILD group, there was a statistically significant difference in time to diagnosis (P = .036) between groups (group 1: 2 months, group 2: 4 months and group 3: 10.5 months) that was not originated from pandemic period. In TB group there was no statistically significant difference between groups. In the PCD group, the impact of the pandemic on the time to diagnosis could not be clarified because the time interval to diagnosis (minimum: 2 years, maximum: 16 years) exceeded the studied periods (21 months). Conclusion: In our study, no effect found between the pandemic and age at diagnosis or time to diagnosis in patients with PCD, chILD, CF, and TB at our center. [ABSTRACT FROM AUTHOR]

Kartagener’s Syndrome, alternatively known as Primary Ciliary Dyskinesia (PCD) is a rare and intricate inherited disorder that impacts the structure and function of cilia, leading to compromised mucociliary clearance. The defining features of this condition consist of chronic sinusitis, situs inversus totalis, and bronchiectasis, forming a characteristic triad. Kartagener’s Syndrome presents numerous challenges in its diagnosis and management, and its clinical implications have significant ramifications for affected individuals. This review aims to comprehensively review and analyse the clinical impact of this syndrome, focusing on the diagnosis, treatment, and management modalities. The ciliary dysfunction in Kartagener’s Syndrome disrupts the mucus clearance and pathogens from the respiratory tract, resulting in chronic infections, progressive lung damage, and respiratory failure in severe cases. Through a narrative review of literature, reviews, and case studies, the authors have explored clinicians’ diagnostic challenges and the advances in genetic testing methods that aid in early and accurate diagnosis. The authors have discussed the multidisciplinary approach to manage Kartagener’s Syndrome, which involves respiratory therapies, antibiotics, and surgical interventions to improve the patient’s quality of life and prevent complications. The review paper also includes in-depth case studies of individuals with Kartagener’s Syndrome, highlighting the variability in clinical presentations and treatment outcomes. These case studies provide valuable insights into the diverse manifestations of this syndrome, further enhancing the existing understanding of the disease and its management. Ultimately, this review is directed to raise awareness among healthcare professionals about Kartagener’s Syndrome, its clinical implications, and its diagnostic and treatment challenges. By shedding light on this rare and intricate genetic disorder, the authors here promote early recognition and proactive management, leading to improved outcomes and better quality of life for individuals with Kartagener’s Syndrome. [ABSTRACT FROM AUTHOR]

Objective: To describe lung volumetry and spirometric changes in patients with primary ciliary dyskinesia. Identify morphological changes associated with primary ciliary dyskinesia and demonstrate lung volumetry usefulness for air trapping early identification in small airway. Method: Descriptive, observational and cross-sectional study of patients with primary ciliary dyskinesia; a lung volumetry tomography scan was performed to evaluate morphological, parenchymal and airway characteristics with Somatom X, Sango CT VA40, Siemens Healthcare Diagnostics equipment; as well as baseline and bronchodilator spirometry to evaluate lung function by obtaining forced expiratory volume in one second, force vital capacity, and the ratio between them and their Z-score with a portable incentive EasyOne Air equipment. Results: A total of 12 patients in whom it was demonstrated that 75% showed morphological alterations, being mosaic attenuation pattern the most frequent (41.6%). Quantitatively, some degree of air trapping and a greater subsegmental than segmental wall area percentage was identified without spirometric changes. Conclusions: Primary ciliary dyskinesia is associated with a persistent inflammatory process of the small airway with visible morphological changes involving clinical-radiological dissociation, without spirometric changes. [ABSTRACT FROM AUTHOR]

In this study, we report two cases of siblings diagnosed with primary ciliary dyskinesia (PCD) sharing an identical genotype yet exhibiting distinct phenotypes. A 13-year-old girl with acute pneumonia was admitted to our hospital. Chest and sinus radiography revealed situs inversus and bilateral maxillary sinusitis. Chest computed tomography revealed bronchiectasis. Her 6-year-old brother with acute bronchitis was admitted and was diagnosed with bronchial asthma due to recurrent wheezing. Unlike his sister, he did not have situs inversus. Both patients had a chronic wet cough and were diagnosed with bronchial asthma by their family doctor. The mean PCD rule (PICADAR) scores were 9 and 7, respectively. Genetic analysis confirmed the presence of the same homozygous mutation (c.546C > A,pTyr182Ter) in DNAI2. To date, there have been four reports of the same pathogenic variants but different PCD phenotypes. Pathological variants of DNAI2 cause the loss of the outer dynein arm, the absence of which results in a lack of primary ciliary movement involved in the left-right axis formation during the embryonic period. A lack of functional cilia results in randomized visceral asymmetry; hence, the same pathogenic variant may exhibit different phenotypes. PCD is often overlooked and is sometimes managed as bronchial asthma, as in these siblings. In our case, the PICADAR score was useful in predicting the clinical diagnosis of PCD. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the prevalence of infertility and ectopic pregnancies among individuals with primary ciliary dyskinesia (PCD)? SUMMARY ANSWER We found that 39 of 50 men (78%) and 72 of 118 women (61%) with PCD were infertile and that women with PCD had an increased risk of ectopic pregnancies (7.6 per 100 pregnancies, 95% CI 4.7–12.2). WHAT IS KNOWN ALREADY PCD is a heterogeneous multiorgan disease caused by mutations in genes required for the function and structure of motile cilia. Previous studies identified a link between PCD and infertility, but original data on prevalence of infertility and risk of ectopic pregnancies, the use and efficacy of medically assisted reproduction (MAR), and the association of fertility with PCD genotype are extremely limited. STUDY DESIGN, SIZE, DURATION We performed a cross-sectional survey about fertility within the Living with PCD study (formerly COVID-PCD). Living with PCD is an international, online, participatory study that collects information directly from people with PCD. People with PCD of any age from anywhere in the world can participate in the study. At the time of the survey, 482 adults with PCD were registered within the Living with PCD study. PARTICIPANTS/MATERIALS, SETTING, METHODS We sent a questionnaire on fertility on 12 July 2022, to all participants older than 18 years enrolled in the Living with PCD study. Responses were collected until 8 March 2023. The fertility questionnaire covered topics related to pregnancy attempts, use of MAR, and pregnancy outcomes. Data were collected via the Research Electronic Data Capture (REDCap) platform. We defined infertility as failure to achieve a clinical pregnancy after 12 months or use of MAR for at least one pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE In total, 265 of 482 adult participants (55%) completed the fertility questionnaire. Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile. Of the infertile men, 28 had tried MAR, and 17 of them (61%) fathered a child with the help of MAR. Among infertile women, 59 had used MAR, and 41 of them (69%) became pregnant with the help of MAR. In our population, women with PCD showed a relatively high risk of ectopic pregnancies: 1 in 10 women who became pregnant had at least one ectopic pregnancy and 7.6% of pregnancies were ectopic (95% CI 4.7–12.2). We evaluated the association between fertility and affected PCD genes in 46 individuals (11 men, 35 women) with available genetic and fertility information, and found differences between genotypes, e.g. all five women with a mutation in CCDC40 were infertile and all five with DNAH11 were fertile. LIMITATIONS, REASONS FOR CAUTION The study has limitations, including potential selection bias as people experiencing problems with fertility might be more likely to fill in the questionnaire, which may have influenced our prevalence estimates. We were unable to validate clinical data obtained from participant self-reports owing to the anonymous study design, which is likely to lead to recall bias. WIDER IMPLICATIONS OF THE FINDINGS The study underlines the need for addressing infertility in routine PCD care, with a focus on informing individuals with PCD about their increased risk. It emphasizes the utility and efficacy of MAR in PCD-related infertility. Additionally, women attempting conception should be made aware of the increased risk of ectopic pregnancies and seek systematic early consultation to confirm an intrauterine pregnancy. Fertility, efficacy of MAR, and risk for adverse pregnancy outcomes differ between people with PCD—depending on genotypes—and close monitoring and support might be needed from fertility specialists to increase chances of successful conception. STUDY FUNDING/COMPETING INTEREST(S) Our research was funded by the Swiss National Science Foundation, Switzerland (SNSF 320030B_192804), the Swiss Lung Association, Switzerland (2021-08_Pedersen), and we also received support from the PCD Foundation, USA; the Verein Kartagener Syndrom und Primäre Ciliäre Dyskinesie, Germany; the PCD Support UK, UK; and PCD Australia, Australia. M. Goutaki received funding from the Swiss National Science Foundation, Switzerland (PZ00P3_185923). B. Maitre participates in the RaDiCo-DCP funded by INSERM France. The study authors participate in the BEAT-PCD Clinical Research Collaboration supported by the European Respiratory Society. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER ClinicalTrials.gov ID NCT04602481. [ABSTRACT FROM AUTHOR]

Background Objectives Materials and methods Results Discussion and conclusion Dysfunction of motile cilia, including respiratory cilia and sperm flagella, typically leads to primary ciliary dyskinesia and male infertility or low fertility in humans. Genetic defects of LRRC6 have been associated with primary ciliary dyskinesia and asthenozoospermia due to abnormal ultrastructure of ciliated axonemes.To identify novel mutations of the LRRC6 gene related to multiple morphological abnormalities of the sperm flagella and male infertility and investigate the underlying molecular mechanisms involved.The LRRC6 mutations were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning, and transmission electron microscopy were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Further tandem mass tagging proteomics analyses were performed to explore the effect of mutations and confirmed by immunostaining and western blotting. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic LRRC6 mutations.In this study, we identified a novel homozygous LRRC6 mutation in a consanguineous family, characterized by asthenozoospermia and primary ciliary dyskinesia. Further Semen parameter and morphology analysis demonstrate that the novel LRRC6 mutation leads to a significant reduction in sperm flagella length, a decrease in sperm progressive motility parameters, and abnormalities of sperm ultrastructure. Specifically, the absence of outer dynein arms and inner dynein arms, and incomplete mitochondrial sheath in the flagellar mid‐piece were observed by transmission electron microscopy. In addition, tandem mass tagging proteomics analysis revealed that spermatozoa obtained from patients harboring the LRRC6 mutation exhibited a significant decrease in the expression levels of proteins related to the assembly and function of dynein axonemal arms. Functional analysis revealed that this novel LRRC6 mutation disrupted the function of the leucine‐rich repeat containing 6 protein, which in turn affects the expression of the dynein arm proteins and leucine‐rich repeat containing 6‐interacting proteins CCDC40, SPAG1, and ZMYND10. Finally, we reported a successful pregnancy through assisted reproductive technology with intracytoplasmic sperm injection in the female partner of the proband.This study highlights the identification of a novel homozygous LRRC6 mutation in a consanguineous family and its impact on sperm progressive motility, morphology, and sperm kinetics parameters, which could facilitate the genetic diagnosis of asthenozoospermia and offer valuable perspectives for future genetic counseling endeavors. [ABSTRACT FROM AUTHOR]

Background: Disorders of mucociliary clearance, such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and bronchiectasis of unknown origin, are characterised by periods with increased respiratory symptoms, referred to as pulmonary exacerbations. These exacerbations are hard to predict and associated with lung function decline and the loss of quality of life. To optimise treatment and preserve lung function, there is a need for non-invasive and reliable methods of detection. Breath analysis might be such a method. Methods: We systematically reviewed the existing literature on breath analysis to detect pulmonary exacerbations in mucociliary clearance disorders. Extracted data included the study design, technique of measurement, definition of an exacerbation, identified compounds and diagnostic accuracy. Results: Out of 244 identified articles, 18 were included in the review. All studies included patients with CF and two also with PCD. Age and the definition of exacerbation differed between the studies. There were five that measured volatile organic compounds (VOCs) in exhaled breath using gas chromatography with mass spectrometry, two using an electronic nose and eleven measured organic compounds in exhaled breath condensate. Most studies showed a significant correlation between pulmonary exacerbations and one or multiple compounds, mainly hydrocarbons and cytokines, but the validation of these results in other studies was lacking. Conclusions: The detection of pulmonary exacerbations by the analysis of compounds in exhaled breath seems possible but is not near clinical application due to major differences in results, study design and the definition of an exacerbation. There is a need for larger studies, with a longitudinal design, international accepted definition of an exacerbation and validation of the results in independent cohorts. [ABSTRACT FROM AUTHOR]

Odad3 gene loss-of-function mutation leads to Primary Ciliary Dyskinesia (PCD), a disease caused by motile cilia dysfunction. Previously, we demonstrated that knockout of the Odad3 gene in mice replicates several features of PCD, such as hydrocephalus, defects in left–right body symmetry, and male infertility, with a complete absence of sperm in the reproductive tract. The majority of Odad3 knockout animals die before sexual maturation due to severe hydrocephalus and failure to thrive, which precludes fertility studies. Here, we performed the expression analysis of the Odad3 gene during gonad development and in adult testes. We showed that Odad3 starts its expression during the first wave of spermatogenesis, specifically at the meiotic stage, and that its expression is restricted to the germ cells in the adult testes, suggesting that Odad3 plays a role in spermatozoa formation. Subsequently, we conditionally deleted the Odad3 gene in adult males and demonstrated that even partial ablation of the Odad3 gene leads to asthenoteratozoospermia with multiple morphological abnormalities of sperm flagella (MMAF) in mice. The analysis of the seminiferous tubules in Odad3-deficient mice revealed defects in spermatogenesis with accumulation of seminiferous tubules at the spermiogenesis and spermiation phases. Furthermore, analysis of fertility in heterozygous Odad3+/− knockout mice revealed a reduction in sperm count and motility as well as abnormal sperm morphology. Additionally, Odad3+/− males exhibited a shorter fertile lifespan. Overall, these results suggest the important role of Odad3 and Odad3 gene dosage in male fertility. These findings may have an impact on the genetic and fertility counseling practice of PCD patients carrying Odad3 loss-of-function mutations. [ABSTRACT FROM AUTHOR]

Defects in motile cilia, termed motile ciliopathies, result in clinical manifestations affecting the respiratory and reproductive system, as well as laterality defects and hydrocephalus. We previously defined biallelic MNS1 variants causing situs inversus and male infertility, mirroring the findings in Mns1−/− mice. Here, we present clinical and genomic findings in five newly identified individuals from four unrelated families affected by MNS1-related disorder. Ciliopathy panel testing and whole exome sequencing identified one previously reported and two novel MNS1 variants extending the genotypic spectrum of disease. A broad spectrum of laterality defects including situs inversus totalis and heterotaxia was confirmed. Interestingly, a single affected six-year-old girl homozygous for an MNS1 nonsense variant presented with a history of neonatal respiratory distress syndrome, recurrent respiratory tract infections, chronic rhinitis, and wet cough. Accordingly, immunofluorescence analysis showed the absence of MNS1 from the respiratory epithelial cells of this individual. Two other individuals with hypomorphic variants showed laterality defects and mild respiratory phenotype. This study represents the first observation of heterotaxia and respiratory disease in individuals with biallelic MNS1 variants, an important extension of the phenotype associated with MNS1-related motile ciliopathy disorder. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous, motile ciliopathy, characterized by neonatal respiratory distress, recurrent upper and lower respiratory tract infections, subfertility, and laterality defects. Diagnosis relies on a combination of tests for confirmation, including nasal nitric oxide (nNO) measurements, high-speed videomicroscopy analysis (HSVMA), immunofluorescent staining, axonemal ultrastructure analysis via transmission electron microscopy (TEM), and genetic testing. Notably, there is no single gold standard confirmatory or exclusionary test. Currently, 54 causative genes involved in cilia assembly, structure, and function have been linked to PCD; this rare disease has a spectrum of clinical manifestations and emerging genotype–phenotype relationships. In this review, we provide an overview of the structure and function of motile cilia, the emerging genetics and pathophysiology of this rare disease, as well as clinical features associated with motile ciliopathies, novel diagnostic tools, and updates on genotype–phenotype relationships in PCD. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to examine the correlation between clinical characteristics and the pathogenic gene variants in patients with Primary Ciliary Dyskinesia (PCD). Methods: We conducted a retrospective single-center study in patients with PCD followed at the University Hospitals Leuven. We included patients with genetically confirmed PCD and described their genotype, data from ultrastructural ciliary evaluation and clinical characteristics. Genotype/phenotype correlations were studied in patients with the most frequently involved genes. Results: We enrolled 74 patients with a median age of 25.58 years. The most frequently involved genes were DNAH11 (n = 23) and DNAH5 (n = 19). The most frequent types of pathogenic variants were missense (n = 42) and frameshift variants (n = 36) and most patients had compound heterozygous variants (n = 44). Ciliary ultrastructure (p < 0.001), situs (p = 0.015) and age at diagnosis (median 9.50 vs 4.71 years, p = 0.037) differed between DNAH11 and DNAH5. When correcting for situs this difference in age at diagnosis was no longer significant (p = 0.973). Patients with situs inversus were diagnosed earlier (p = 0.031). Respiratory tract microbiology (p = 0.161), lung function (cross-sectional, p = 0.829 and longitudinal, p = 0.329) and chest CT abnormalities (p = 0.202) were not significantly different between DNAH11 and DNAH5 variants. Conclusion: This study suggests a genotype–phenotype correlation for some of the evaluated clinical characteristics of the two most frequently involved genes in this study, namely DNAH11 and DNAH5. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a hereditary disorder characterized by defects in cilia that impair mucociliary clearance. This study focuses on PCD caused by mutations in the Cyclin O (CCNO) gene and reports on three cases involving Chinese children. Case 1 was an 8-year-and-3-month-old boy who presented with respiratory distress after birth and later developed a recurrent productive cough and purulent nasal discharge. He was initially diagnosed with diffuse panbronchiolitis (DPB) due to the presence of diffuse micronodules in lung CT scans. Case 2 was the younger sister of case 1. She also presented with respiratory distress after birth, with a chest radiograph revealing atelectasis. She required oxygen supplementation until the age of 2 months. Case 3 was a 4-year-and-4-month-old girl with a history of neonatal pneumonia, persistent pulmonary atelectasis, and recurrent lower respiratory tract infections. Her chest radiograph also showed diffuse micronodules. In all three cases, the final diagnosis of PCD was confirmed by genetic testing. Cases 1 and 2 exhibited homozygous c.248_252dup TGCCC (p.G85Cfs*11) mutations in the CCNO gene, while case 3 harbored a homozygous c.258_262dup GGCCC (p.Q88Rfs*8) mutation. A literature review indicated that the common clinical features of CCNO-PCD include neonatal respiratory distress (40/49, 81.6%), chronic cough (31/33, 93.9%), rhinosinusitis (30/35, 85.7%), bronchiectasis (26/35, 74.3%), and low nasal nitric oxide (nNO, 40/43, 93.0%). Notably, situs inversus has not been reported. In CCNO-PCD patients, cilia may appear structurally normal but were severely reduced in number or entirely absent. Lung CT scans in these patients may exhibit diffuse micronodules and “tree-in-bud” signs, which can lead to a clinical misdiagnosis of DPB. nNO screening combined with genetic testing is an optimized diagnostic strategy. Treatment options include the use of anti-infective and anti-inflammatory agent, along with daily airway clearance. This study underscores the importance of genetic testing in neonates and children with suspected PCD or those clinically diagnosed with DPB to enable an early diagnosis and prompt intervention, thereby enhancing the prognosis for these patients.

Objective To characterize the clinical features and to identify the pathogenic variants in two Chinese patients with primary ciliary dyskinesia (PCD). Methods The clinical data and peripheral blood sample from the patients were collected, and genomic DNA was subsequently extracted from the peripheral blood. Candidate pathogenic variants were identified using whole exome sequencing (WES) and further confirmed by Sanger sequencing technology. Finally, the pathogenicity of the variants was predicted through bioinformatic analysis. Results Two Chinese patients with PCD had diffuse bronchiectasis cpmlicated with recurrent infection and the decreased level of nasal nitric oxide (nNO). WES results showed that both patients carried frameshift mutations in known pathogenic genes of PCD. Patient 1 carried a homozygous variant in outer dynein arm docking complex subunit 1 (ODAD1) (NM_144577): c.702_705dupGCAG (p.P236Afs*11) and patient 2 carried a hemizygous variant in dynein axonemal assembly factor 6 (DNAAF6) (NM_173494): c.532_533delCT (p.L178Sfs*2). Neither variant had been recorded in The Human Gene Mutation Database (HGMD). Both frameshift variants caused changes in the open reading frame, which resulted in premature termination codon. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, c.702_705dupGCAG in ODAD1 was categorized as a pathogenic variant (PVS1+PM2+PM3+PP4) and c.532_533delCT in DNAAF6 was categorized as a pathogenic variant (PVS1+PM2+PM3+PP4). Conclusions The novel variants c.702_705dupGCAG found in ODAD1 and c.532_533delCT found in DNAAF6 are pathogenic and support their PCD diagnosis for the two patients, respectively. These results may enrich the mutation spectrum of the ODAD1 and DNAAF6.

Introduction: Primary ciliary dyskinesia (PCD) is a rare heterogeneous disease caused by abnormalities in motile cilia. In this case report, we first analyzed the clinical and genetic data of a proband who was suspected of having PCD on the basis of her clinical and radiological findings. Methods: Whole-exome sequencing was performed, and a variant in the RSPH4A gene was identified in the proband. Sanger sequencing was used for validation of RSPH4A variants in the proband, her sister, her daughter and her parents. Finally, the phenotypic features of the patient were analyzed, and the current literature was reviewed to better understand the gene variants in PCD related to hearing loss and the clinical manifestations of the RSPH4A variant in PCD. Results: The chief clinical symptoms of this proband included gradual mixed hearing loss, otitis media, anosmia, sinusitis, recurrent cough and infertility. Her DNA sequencing revealed a novel homozygous T to C transition at position 1321 within exon 3 of RSPH4A according to genetic testing results. This variant had never been reported before. The homozygous variant resulted in an amino acid substitution of tryptophan by arginine at position 441 (p. Trp441Arg). The same variant was also found in the proband's sister, and a heterozygous pathogenic variant was identified among immediate family members, including the proband's daughter and parents. Discussion: A literature review showed that 16 pathogenic variants in RSPH4A have been reported. Hearing loss had only been observed in patients with the RSPH4A (c.921+3_6delAAGT) splice site mutation, and the specific type of hearing loss was not described. [ABSTRACT FROM AUTHOR]

Objective To characterize the clinical features and to identify the pathogenic variants in two Chinese patients with primary ciliary dyskinesia (PCD). Methods The clinical data and peripheral blood sample from the patients were collected, and genomic DNA was subsequently extracted from the peripheral blood. Candidate pathogenic variants were identified using whole exome sequencing (WES) and further confirmed by Sanger sequencing technology. Finally, the pathogenicity of the variants was predicted through bioinformatic analysis. Results Two Chinese patients with PCD had diffuse bronchiectasis cpmlicated with recurrent infection and the decreased level of nasal nitric oxide (nNO). WES results showed that both patients carried frameshift mutations in known pathogenic genes of PCD. Patient 1 carried a homozygous variant in outer dynein arm docking complex subunit 1 (ODAD1) (NM_144577): c.702_705dupGCAG (p.P236Afs*11) and patient 2 carried a hemizygous variant in dynein axonemal assembly factor 6 (DNAAF6) (NM_173494): c.532_533delCT (p.L178Sfs*2). Neither variant had been recorded in The Human Gene Mutation Database (HGMD). Both frameshift variants caused changes in the open reading frame, which resulted in premature termination codon. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, c.702_705dupGCAG in ODAD1 was categorized as a pathogenic variant (PVS1+PM2+PM3+PP4) and c.532_533delCT in DNAAF6 was categorized as a pathogenic variant (PVS1+PM2+PM3+PP4). Conclusions The novel variants c.702_705dupGCAG found in ODAD1 and c.532_533delCT found in DNAAF6 are pathogenic and support their PCD diagnosis for the two patients, respectively. These results may enrich the mutation spectrum of the ODAD1 and DNAAF6. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement (situs solitus [SS]) or mirror image inversion (situs inversus totalis [SIT]). Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD. Participants were classified as having SA, including heterotaxy, or not having SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39 or CCDC40 genotype, using generalized linear models and logistic and Poisson regression. In 397 participants with PCD (mean age, 8.4 years; range, 0.1-21), 42 patients were classified as having SA, including 16 patients (38%) with complex cardiovascular malformations or atrial isomerism, 13 patients (31%) with simple CVM, and 13 patients (31%) without cardiovascular malformations. Of these, 15 patients (36%) underwent cardiac surgery, 24 patients (57%) showed an anatomic spleen abnormality, and seven patients (17%) showed both. The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. Overall, 70 participants (17%) harbored the severe CCDC39 or CCDC40 genotype. Compared with participants without SA, those with SA showed lower median BMI z scores (P =.03), lower FVC z scores (P =.01), and more hospitalizations and IV antibiotic courses for acute respiratory infections during the 5 years before enrollment (P <.01). Participants with cardiovascular malformations requiring surgery or with anatomic spleen abnormalities showed lower median BMI z scores and more hospitalizations and IV therapies for respiratory illnesses compared with participants without SA. Children with PCD and SA achieve worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in participants with SA and PCD are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both. ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background. There is a need to identify the complex interplay between various physiological mechanisms in primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). The study investigated the interaction between respiratory function, exercise capacity, muscle strength, and inflammatory and oxidant/antioxidant responses in patients with PCD and CF. Methods. The study included 30 PCD patients, 30 CF patients, and 29 age and sex-matched healthy subjects. Exercise capacity was assessed using the modified shuttle walk test (MSWT). Handgrip strength (HGS) was used to evaluate general muscle strength. Oxidative stress-inflammatory parameters were also assessed. Pulmonary function test was performed by spirometry. Regarding the forced expiratory volume in 1 second (FEV1) z-score, patients with PCD and CF were subdivided into normal, mild, and severe/moderate groups. Results. Forced vital capacity (FVC) z-scores were lower in PCD and CF patients than controls. FEV1, FEV1/FVC, peak expiratory flow (PEF), and forced mid expiratory flow (FEF25-75%) z-scores were lower in PCD than in the other groups. HGS was lower in both mild PCD and normal CF patients relative to the controls. MSWT distance was lower in severe/moderate PCD patients than controls. Catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels did not differ significantly among the study groups, but superoxide dismutase (SOD) level in severe/moderate PCD, and glutathione (GSH) level in normal CF were higher than in controls. Interleukin-6 (IL-6) level was higher in patients with normal PCD and CF compared to the controls. IL-1ß level was higher in PCD compared to controls. Additionally, correlations among these parameters were also determined in some patient groups. Conclusion. Homeostasis related to respiratory function, aerobic performance, muscle strength, inflammatory response, and oxidant/antioxidant balance were affected in PCD and CF. Evaluating these mechanisms together may contribute to elucidating the pathophysiology of these rare diseases. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is an inherited disorder that impairs motile cilia, essential for respiratory health, with a reported prevalence of 1 in 16,309 within Hispanic populations. Despite 70% of Puerto Rican patients having the RSPH4A [c.921+3_921+6del (intronic)] founder mutation, the characterization of the ciliary dysfunction remains unidentified due to the unavailability of advanced diagnostic modalities like High-Speed Video Microscopy Analysis (HSVA). Our study implemented HSVA for the first time on the island as a tool to better diagnose and characterize the RSPH4A [c.921+3_921+6del (intronic)] founder mutation in Puerto Rican patients. By applying HSVA, we analyzed the ciliary beat frequency (CBF) and pattern (CBP) in native Puerto Rican patients with PCD. Our results showed decreased CBF and a rotational CBP linked to the RSPH4A founder mutation in Puerto Ricans, presenting a novel diagnostic marker that could be implemented as an axillary test into the PCD diagnosis algorithm in Puerto Rico. The integration of HSVA technology in Puerto Rico substantially enhances the PCD evaluation and diagnosis framework, facilitating prompt detection and early intervention for improved disease management. This initiative, demonstrating the potential of HSVA as an adjunctive test within the PCD diagnostic algorithm, could serve as a blueprint for analogous developments throughout Latin America. [ABSTRACT FROM AUTHOR]

Nasal nitric oxide (nNO) is low in most patients with primary ciliary dyskinesia (PCD). Decreased ciliary motion could lead to antigen stasis, increasing oxidant production and NO oxidation in the airways. This could both decrease gas phase NO and increase nitrosative stress. We studied primary airway epithelial cells from healthy controls (HCs) and patients with PCD with several different genotypes. We measured antigen clearance in fenestrated membranes exposed apically to the fluorescently labeled antigen Dermatophagoides pteronyssinus (Derp1-f). We immunoblotted for 3-nitrotyrosine (3-NT) and for oxidative response enzymes. We measured headspace NO above primary airway cells without and with a PCD-causing genotype. We measured nNO and exhaled breath condensate (EBC) H2O2 in vivo. Apical Derp1-f was cleared from HC better than from PCD cells. DUOX1 expression was lower in HC than in PCD cells at baseline and after 24-h Derp1-f exposure. HC cells had less 3-NT and NO3− than PCD cells. However, NO consumption by HC cells was less than that by PCD cells; NO loss was prevented by superoxide dismutase (SOD) and by apocynin. nNO was higher in HCs than in patients with PCD. EBC H2O2 was lower in HC than in patients with PCD. The PCD airway epithelium does not optimally clear antigens and is subject to oxidative and nitrosative stress. Oxidation associated with antigen stasis could represent a therapeutic target in PCD, one with convenient monitoring biomarkers. NEW & NOTEWORTHY: The PCD airway epithelium does not optimally clear antigens, and antigen exposure can lead to NO oxidation and nitrosative stress. Oxidation caused by antigen stasis could represent a therapeutic target in PCD, and there are convenient monitoring biomarkers. [ABSTRACT FROM AUTHOR]

Nontuberculous mycobacteria (NTM) are environmental and ubiquitous, but only a few species are associated with disease, often presented as nodular/bronchiectatic or cavitary pulmonary forms. Bronchiectasis, airways dilatations characterized by chronic productive cough, is the main presentation of NTM pulmonary disease. The current Cole's vicious circle model for bronchiectasis proposes that it progresses from a damaging insult, such as pneumonia, that affects the respiratory epithelium and compromises mucociliary clearance mechanisms, allowing microorganisms to colonize the airways. An important bronchiectasis risk factor is primary ciliary dyskinesia, but other ciliopathies, such as those associated with connective tissue diseases, also seem to facilitate bronchiectasis, as may occur in Lady Windermere syndrome, caused by M. avium infection. Inhaled NTM may become part of the lung microbiome. If the dose is too large, they may grow excessively as a biofilm and lead to disease. The incidence of NTM pulmonary disease has increased in the last two decades, which may have influenced the parallel increase in bronchiectasis incidence. We propose that ciliary dyskinesia is the main promoter of bronchiectasis, and that the bacteria most frequently involved are NTM. Restoration of ciliary function and impairment of mycobacterial biofilm formation may provide effective therapeutic alternatives to antibiotics. [ABSTRACT FROM AUTHOR]