Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis.

RATIONALE: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia and primary immunodeficiency disorders), but most cases remain idiopathic. OBJECTIVES: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. METHODS: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived, cells, cell cultures and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. MEASUREMENTS AND MAIN RESULTS: We identified bi-allelic pathogenic variants in WFDC2 in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and thus secretion of mature WFDC2. CONCLUSIONS: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

[Case Report of a 14-Year-Old Girl with Addison's Disease Under Initial Presumptive Diagnosis of Anorexia Nervosa: Confusingly Similar and Yet so Different?] / Kasuistik einer früh im Lebensverlauf an Morbus Addison erkrankten 14 Jahre alten Patientin bei Verdachtsdiagnose einer Anorexia nervosa.

Case Report of a 14-Year-Old Girl with Addison's Disease Under Initial Presumptive Diagnosis of Anorexia Nervosa: Confusingly Similar and Yet so Different? Abstract: Objective: Primary adrenal insufficiency (Addison's disease) is a rare differential diagnosis of anorexia nervosa. This case report presents important differential diagnostic aspects. Methods: We prepared a case report of a 14-year-old female patient according to the CARE guidelines, taking the patient's and the child's parents' view into consideration. Results: The diagnosis of primary adrenocortical insufficiency was reached using specific laboratory diagnostics approximately 9 months after the onset of symptoms, including sudden body weight loss. Significant differential diagnostic aspects were the absence of a body schema disorder and skin hyperpigmentation prominent in the physical examination. The patient experienced a high psychosocial burden because of the unclear diagnosis over 9 months. The diagnosis and substitution therapy with hydrocortisone led to a rapid improvement of the physical and psychological symptoms. Conclusions: This case report emphasizes the importance of a thorough somatic differential diagnosis in the context of a suspected anorexia nervosa.

Mapping the Most Common Founder Variant in RSPH9 That Causes Primary Ciliary Dyskinesia in Multiple Consanguineous Families of Bedouin Arabs.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a congenital thoracic disorder caused by dysfunction of motile cilia, resulting in insufficient mucociliary clearance of the lungs. The overall aim of this study is to identify causative defective genes in PCD-affected individuals in the Kuwaiti population. METHODS: A cohort of multiple consanguineous PCD families was identified from Kuwaiti patients and genomic DNA from the family members was isolated using standard procedures. The DNA samples from all affected individuals were analyzed by whole exome sequencing (WES). Transmission electron microscopy (TEM) and immunofluorescent analysis (IF) were performed on samples obtained by nasal brushings to identify specific structural abnormalities within ciliated cells. RESULTS: Here, we present six multiplex families with 11 patients who all presented with typical PCD symptoms. Ten out of eleven patients inherited a 3 bp homozygous deletion of GAA in RSPH9, whereas the eleventh patients inherited this variant in trans with a frameshift deletion in RSPH9. Genetic results were confirmed by segregation analysis. The in-frame deletion of GAA in RSPH9 has previously been published as pathogenic in both annotated RSPH9 transcript variants (1 and 2). In contrast, the previously unpublished RSPH9 frameshift deletion identified in KU-15.IV2 impacts only RSPH9 transcript variant two. Regarding all 11 PCD individuals analyzed, IF results demonstrated absence of RSPH9 protein and TEM analysis showed the typical findings in RSPH9 mutant individuals. CONCLUSIONS: We present the largest cohort of PCD individuals affected by the founder in-frame deletion GAA in RSPH9. This founder variant is the most common PCD-causing variant in Bedouin Arabs in Kuwait.

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

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.

Male minipuberty in human and non-human primates: planting the seeds of future fertility.

In brief: Minipuberty is a transient activity period of the hypothalamic-pituitary-gonadal axis in the postnatal and infant period including surging serum concentrations of reproductive hormones. Increasing evidence points to an important role of this period for maturation of the testes and thereby for male reproductive function. Abstract: Minipuberty is a transient activity period of the hypothalamic-pituitary-gonadal (HPG) axis in the postnatal and infant period in humans and non-human primates. Hallmarks of this period are surging serum concentrations of reproductive hormones. While in females, the role of minipuberty seems to be dispensable for future fertility, in males, it is significantly associated with reproductive function in later life. In males, this activity period promotes further masculinization, including testicular and penile growth, as well as completion of testicular descent if not already achieved at birth. At the testicular level, both, somatic and germ cells undergo proliferation and partial maturation during this period. Minipuberty is thought to prime male gonadal tissue for subsequent growth and maturation. Notably, perturbed or absent minipuberty is associated with reduced male reproductive function in adulthood. While the sustained HPG axis activity during adulthood is known to control reproductive function, minipuberty appears to be a prerequisite for obtaining full male reproductive function in later life, thereby determining future fertility potential, i.e. the ability to father a child. This review maps the role of male minipuberty for reproductive function and presents suitable animal models to study minipuberty. Also, it describes the development and maturation of testicular cell types, discusses short- and long-term effects of minipuberty and highlights future research perspectives.

Primary ciliary dyskinesia.

BACKGROUND AND OBJECTIVES: Primary ciliary dyskinesia (PCD, ORPHA:244) is a group of rare genetic disorders characterized by dysfunction of motile cilia. It is phenotypically and genetically heterogeneous, with more than 50 genes involved. Thanks to genetic, clinical, and functional characterization, immense progress has been made in the understanding and diagnosis of PCD. Nevertheless, it is underdiagnosed due to the heterogeneous phenotype and complexity of diagnosis. This review aims to help clinicians navigate this heterogeneous group of diseases. Here, we describe the broad spectrum of phenotypes associated with PCD and address pitfalls and difficult-to-interpret findings to avoid misinterpretation. METHOD: Review of literature CONCLUSION: PCD diagnosis is complex and requires integration of history, clinical picture, imaging, functional and structural analysis of motile cilia and, if available, genetic analysis to make a definitive diagnosis. It is critical that we continue to expand our knowledge of this group of rare disorders to improve the identification of PCD patients and to develop evidence-based therapeutic approaches.

Mucociliary Wnt signaling promotes cilia biogenesis and beating.

It is widely thought that Wnt/Lrp6 signaling proceeds through the cytoplasm and that motile cilia are signaling-inert nanomotors. Contrasting both views, we here show in the mucociliary epidermis of X. tropicalis embryos that motile cilia transduce a ciliary Wnt signal that is distinct from canonical ß-catenin signaling. Instead, it engages a Wnt-Gsk3-Ppp1r11-Pp1 signaling axis. Mucociliary Wnt signaling is essential for ciliogenesis and it engages Lrp6 co-receptors that localize to cilia via a VxP ciliary targeting sequence. Live-cell imaging using a ciliary Gsk3 biosensor reveals an immediate response of motile cilia to Wnt ligand. Wnt treatment stimulates ciliary beating in X. tropicalis embryos and primary human airway mucociliary epithelia. Moreover, Wnt treatment improves ciliary function in X. tropicalis ciliopathy models of male infertility and primary ciliary dyskinesia (ccdc108, gas2l2). We conclude that X. tropicalis motile cilia are Wnt signaling organelles that transduce a distinct Wnt-Pp1 response.

Pathogenic variants in CLXN encoding the outer dynein arm docking-associated calcium-binding protein calaxin cause primary ciliary dyskinesia.

PURPOSE: Primary ciliary dyskinesia (PCD) is a heterogeneous disorder that includes respiratory symptoms, laterality defects, and infertility caused by dysfunction of motile cilia. Most PCD-causing variants result in abnormal outer dynein arms (ODAs), which provide the generative force for respiratory ciliary beating and proper mucociliary clearance. METHODS: In addition to studies in mouse and planaria, clinical exome sequencing and functional analyses in human were performed. RESULTS: In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms. Consistently, we found that Clxn is expressed in mice left-right organizer. Transmission electron microscopy depicted ODA defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1, and DNAI2 from the distal axonemes, and mislocalization or absence of DNAH9. In addition, CLXN was undetectable in ciliary axonemes of individuals with defects in the ODA-docking machinery: ODAD1, ODAD2, ODAD3, and ODAD4. Furthermore, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility. CONCLUSION: Our results revealed that pathogenic variants in CLXN cause PCD with defects in the assembly of distal ODAs in the respiratory cilia. CLXN should be referred to as ODA-docking complex-associated protein ODAD5.

Crosstalk between cilia and autophagy: implication for human diseases.

Macroautophagy/autophagy is a self-degradative process necessary for cells to maintain their energy balance during development and in response to nutrient deprivation. Autophagic processes are tightly regulated and have been found to be dysfunctional in several pathologies. Increasing experimental evidence points to the existence of an interplay between autophagy and cilia. Cilia are microtubule-based organelles protruding from the cell surface of mammalian cells that perform a variety of motile and sensory functions and, when dysfunctional, result in disorders known as ciliopathies. Indeed, selective autophagic degradation of ciliary proteins has been shown to control ciliogenesis and, conversely, cilia have been reported to control autophagy. Moreover, a growing number of players such as lysosomal and mitochondrial proteins are emerging as actors of the cilia-autophagy interplay. However, some of the published data on the cilia-autophagy axis are contradictory and indicate that we are just starting to understand the underlying molecular mechanisms. In this review, the current knowledge about this axis and challenges are discussed, as well as the implication for ciliopathies and autophagy-associated disorders.

Identification of a novel founder variant in DNAI2 cause primary ciliary dyskinesia in five consanguineous families derived from a single tribe descendant of Arabian Peninsula.

Introduction: Primary ciliary dyskinesia (PCD) is caused by dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. The overall aim of this study is to identify disease causing genetic variants for PCD patients in the Kuwaiti population. Methods: A cohort of multiple consanguineous PCD families was identified from Kuwaiti patients and genomic DNA from the family members was analysed for variant screening. Transmission electron microscopy (TEM) and immunofluorescent (IF) analyses were performed on nasal brushings to detect specific structural abnormalities within ciliated cells. Results: All the patients inherited the same founder variant in DNAI2 and exhibited PCD symptoms. TEM analysis demonstrated lack of outer dynein arms (ODA) in all analysed samples. IF analysis confirmed absence of DNAI1, DNAI2, and DNAH5 from the ciliary axoneme. Whole exome sequencing, autozygosity mapping and segregation analysis confirmed that seven patients carry the same homozygous missense variant (DNAI2:c.740G>A; p.Arg247Gln; rs755060592). Conclusion: DNAI2:c.740G>A is the founder variant causing PCD in patients belonging to a particular Arabian tribe which practices consanguineous marriages.

Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities.

PURPOSE: The clinical spectrum of motile ciliopathies includes laterality defects, hydrocephalus, and infertility as well as primary ciliary dyskinesia when impaired mucociliary clearance results in otosinopulmonary disease. Importantly, approximately 30% of patients with primary ciliary dyskinesia lack a genetic diagnosis. METHODS: Clinical, genomic, biochemical, and functional studies were performed alongside in vivo modeling of DAW1 variants. RESULTS: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction. In early mouse embryos, we showed that Daw1 expression is limited to distal, motile ciliated cells of the node, consistent with a role in left-right patterning. daw1 mutant zebrafish exhibited reduced cilia motility and left-right patterning defects, including cardiac looping abnormalities. Importantly, these defects were rescued by wild-type, but not mutant daw1, gene expression. In addition, pathogenic DAW1 missense variants displayed reduced protein stability, whereas DAW1 loss-of-function was associated with distal type 2 outer dynein arm assembly defects involving axonemal respiratory cilia proteins, explaining the reduced cilia-induced fluid flow in particle tracking velocimetry experiments. CONCLUSION: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction, explaining the ciliary beating defects observed in affected individuals.

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients.

The ERN-LUNG Population Registry: Aims, Software-Implementation and First Results.

The ERN-LUNG Population Registry is a new European-wide collection of patients with rare lung diseases, allowing patients to register online in the registry. Medical experts can recruit patients in the registry for disease-specific registries and care options. The Population Registry was implemented on the basis of the open source software OSSE and extended by functions for the self-registration of patients. Patients were invited through patient organizations between May and November 2022. 115 patients registered online in the registry, whereas 60 of them provided full data in the registry form. After first months of usage, further dissemination of the registry is necessary to reach more patients, e.g. by recruiting them via medical centres directly. Improvements of the registry should be conducted to achieve a higher number of fully completed forms.

The role of cilia for hydrocephalus formation.

Hydrocephalus is a common finding in newborns. In most cases, it is caused by intraventricular hemorrhage associated with prematurity, whereas in some patients the cause of hydrocephalus can be traced back to genetic changes, associated with disease syndromes such as RASopathies, lysosomal storage diseases, dystroglycanopathies, craniosynostosis but also ciliopathies. Ciliopathies are a group of diseases that can affect multiple organ systems due to dysfunction or the absence of cilia. Cilia are small organelles, extending from the cell surface. Nonmotile monocilia are ubiquitously present during cell development fulfilling chemosensory functions, whereas specialized epithelia such as the ependyma, lining the inner surface of the brain ventricles, exhibit multiciliated cells propelling fluids along the cell surface. This review highlights ciliopathies and their pathophysiology in congenital hydrocephalus. While nonmotile ciliopathies are often associated with severe prenatal hydrocephalus combined with other severe congenital brain malformations, motile ciliopathies, especially those associated with defects in multiciliogenesis can cause hydrocephalus and chronic lung disease.

Comparison of the Lung Clearance Index in Preschool Children With Primary Ciliary Dyskinesia and Cystic Fibrosis.

BACKGROUND: Previous studies showed that the lung clearance index (LCI) determined by multiple-breath washout (MBW) is sensitive to detecting early lung disease in preschool children with cystic fibrosis (CF). In preschool children with primary ciliary dyskinesia (PCD), data on the onset and severity of lung disease and on the sensitivity of the LCI as a noninvasive quantitative outcome measure remain limited. RESEARCH AND STUDY QUESTION: Is MBW feasible and sensitive to detect ventilation inhomogeneity in preschool children with PCD? STUDY DESIGN AND METHODS: This was a prospective, cross-sectional, multicenter study and included preschoolers with PCD, preschoolers with CF, and healthy control (HC) participants. LCI was determined using nitrogen MBW and was compared among the three groups. RESULTS: LCI was determined in 27 children with PCD, 34 children with CF, and 30 HC participants (mean age, 4.8 years; range, 2.2-6.9 years). The LCI in preschool children with PCD was increased (median, 9.1; 95% CI, 8.6-10.3) compared with HC participants (median, 7.0; 95% CI, 6.7-7.1; P < .0001), but did not differ from preschool children with CF (median, 8.6; 95% CI, 8.4-9.7; P = .71). The feasibility in the PCD group was 93.1% and was similar to that in the CF group (91.9%) and in HC participants (85.7%; P = .55). INTERPRETATION: This study demonstrated early onset of lung disease in preschool children with PCD and indicated that lung disease severity in PCD may be similar to that in CF during preschool years. These data support a need for early diagnostic monitoring and therapy and suggest the LCI as a noninvasive diagnostic tool and as a potential end point in clinical trials testing early interventions in children with PCD.

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

Rationale: Primary ciliary dyskinesia (PCD) is a heterogeneous, multisystem disorder characterized by defective ciliary beating. Diagnostic guidelines of the American Thoracic Society and European Respiratory Society recommend measurement of nasal nitric oxide (nNO) for PCD diagnosis. Several studies demonstrated low nNO production rates in PCD individuals, but underlying causes remain elusive. Objectives: To determine nNO production rates in a well-characterized PCD cohort, including subgroup analyses with regard to ultrastructural and ciliary beating phenotypes. Methods: This study included 301 individuals assessed according to European Respiratory Society guidelines. Diagnostic cutoffs for nNO production rates for this study cohort and subgroups with normal and abnormal ultrastructure were determined. Diagnostic accuracy was also tested for the widely used 77 nl/min cutoff in this study cohort. The relationship between nNO production rates and ciliary beat frequencies (CBFs) was evaluated. Results: The study cohort comprised 180 individuals with definite PCD diagnosis, including 160 individuals with genetic diagnosis, 16 individuals with probable PCD diagnosis, and 105 disease controls. The 77 nl/min nNO cutoff showed a test sensitivity of 0.92 and specificity of 0.86. Test sensitivity was lower (0.85) in the subgroup of 47 PCD individuals with normal ultrastructure compared with 133 PCD individuals with abnormal ultrastructure (0.95). The optimal diagnostic cutoff for the nNO production rate for the whole study cohort was 69.8 nl/min (sensitivity, 0.92; specificity, 0.89); however, it was 107.8 nl/min (sensitivity, 0.89; specificity, 0.78) for the subgroup of PCD with normal ultrastructure. PCD individuals with normal ultrastructure compared with abnormal ultrastructure showed higher ciliary motility. Consistently, PCD individuals with higher CBFs showed higher nNO production rates. In addition, laterality defects occurred less frequently in PCD with normal ultrastructure. Conclusions: Measurements of nNO below the widely used 77 nl/min cutoff are less sensitive in detecting PCD individuals with normal ultrastructure. Our findings indicate that higher nNO production in this subgroup with a higher cutoff for the nNO production rate (107.8 nl/min) and higher residual ciliary motility is dependent on the underlying molecular PCD defect. Higher nNO production rates, higher residual CBFs, and the lower prevalence of laterality defects hamper diagnosis of PCD with normal ultrastructure. Adjusting the cutoff of nNO production rate to 107.8 nl/min might promote diagnosing PCD with normal ultrastructure.

Consensus nomenclature for dyneins and associated assembly factors.

Dyneins are highly complex, multicomponent, microtubule-based molecular motors. These enzymes are responsible for numerous motile behaviors in cytoplasm, mediate retrograde intraflagellar transport (IFT), and power ciliary and flagellar motility. Variants in multiple genes encoding dyneins, outer dynein arm (ODA) docking complex subunits, and cytoplasmic factors involved in axonemal dynein preassembly (DNAAFs) are associated with human ciliopathies and are of clinical interest. Therefore, clear communication within this field is particularly important. Standardizing gene nomenclature, and basing it on orthology where possible, facilitates discussion and genetic comparison across species. Here, we discuss how the human gene nomenclature for dyneins, ODA docking complex subunits, and DNAAFs has been updated to be more functionally informative and consistent with that of the unicellular green alga Chlamydomonas reinhardtii, a key model organism for studying dyneins and ciliary function. We also detail additional nomenclature updates for vertebrate-specific genes that encode dynein chains and other proteins involved in dynein complex assembly.

Current and Future Treatments in Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.