Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia.

Variation in the non-coding genome represents an understudied mechanism of disease and it remains challenging to predict if single nucleotide variants, small insertions and deletions, or structural variants in non-coding genomic regions will be detrimental. Our approach using complementary RNA-seq and targeted long-read DNA sequencing can prioritize identification of non-coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the SPAG1 gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern.

Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia.

Background: 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]).

Research Question: Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT?

Study Design And Methods: This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD.

Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial.

Background: Mucociliary clearance is dysfunctional in people with primary ciliary dyskinesia, resulting in the accumulation of dehydrated mucus in the airways that is difficult to clear. We undertook a study to assess the benefit on lung function of treatment with a nebulised epithelial sodium channel (ENaC) blocker, idrevloride, with or without hypertonic saline, in people with primary ciliary dyskinesia.

Methods: The CLEAN-PCD trial was a phase 2, randomised, double-blind, placebo-controlled crossover trial conducted at 32 tertiary adult and paediatric care centres and university hospitals in Canada, Denmark, Germany, Italy, the Netherlands, Poland, the UK, and the USA.

Airway Disease in Children with Primary Ciliary Dyskinesia: Impact of Ciliary Ultrastructure Defect and Genotype.

Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance, recurrent respiratory infections, progressive airway damage, and obstructive lung disease. Although the association of ciliary ultrastructure defect/genotype with the severity of airflow obstruction has been well characterized, their association with airway abnormalities on chest computed tomography (CT) has been minimally evaluated. We sought to delineate the association of ciliary defect class/genotype with chest CT scores in children with PCD.

Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.

The association between organ laterality abnormalities and ciliary ultrastructural defect or genotype in primary ciliary dyskinesia is poorly understood. To determine if there is an association between presence and/or type of laterality abnormality and ciliary ultrastructural defect or genotype. Participants with primary ciliary dyskinesia in a multicenter, prospective study were grouped based on ciliary ultrastructural defect or genotype.

A multi-disciplinary, comprehensive approach to management of children with heterotaxy.

Heterotaxy (HTX) is a rare condition of abnormal thoraco-abdominal organ arrangement across the left-right axis of the body. The pathogenesis of HTX includes a derangement of the complex signaling at the left-right organizer early in embryogenesis involving motile and non-motile cilia. It can be inherited as a single-gene disorder, a phenotypic feature of a known genetic syndrome or without any clear genetic etiology.

The Impact on Parents of Diagnosing PCD in Young Children.

Primary ciliary dyskinesia (PCD) is an incurable, rare, inherited, chronic condition. Treatment includes the regular clearing of airway mucus, aggressive treatment of infections and management of hearing loss. Caregiver burden has not been explored, hence we interviewed 18 mothers and 6 fathers of children under 6 years to understand the impact of diagnostic testing and implications of a positive diagnosis.

Airway Inflammation in Children with Primary Ciliary Dyskinesia.

The role of airway inflammation in disease pathogenesis in children with primary ciliary dyskinesia (PCD) is poorly understood. We investigated relationships between sputum inflammation measurements, age, lung function, bronchiectasis, airway infection, and ultrastructural defects in children with PCD. Spontaneously expectorated sputum was collected from clinically stable children and adolescents with PCD ages 6 years and older participating in a multicenter, observational study.

Leveraging Open Electronic Health Record Data and Environmental Exposures Data to Derive Insights Into Rare Pulmonary Disease.

Research on rare diseases has received increasing attention, in part due to the realized profitability of orphan drugs. Biomedical informatics holds promise in accelerating translational research on rare disease, yet challenges remain, including the lack of diagnostic codes for rare diseases and privacy concerns that prevent research access to electronic health records when few patients exist. The Integrated Clinical and Environmental Exposures Service (ICEES) provides regulatory-compliant open access to electronic health record data that have been integrated with environmental exposures data, as well as analytic tools to explore the integrated data.

Association of Neonatal Hospital Length of Stay with Lung Function in Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD), an inherited lung disease, is characterized by abnormal ciliary function leading to progressive bronchiectasis. There is wide variability in respiratory disease severity at birth and later in life. To evaluate the association between neonatal hospital length of stay (neonatal-LOS) and supplemental oxygen duration (SuppO) with lung function in pediatric PCD.

The role of SPAG1 in the assembly of axonemal dyneins in human airway epithelia.

Mutations in SPAG1, a dynein axonemal assembly factor (DNAAF) that facilitates the assembly of dynein arms in the cytoplasm before their transport into the cilium, result in primary ciliary dyskinesia (PCD), a genetically heterogenous disorder characterized by chronic oto-sino-pulmonary disease, infertility and laterality defects. To further elucidate the role of SPAG1 in dynein assembly, we examined its expression, interactions and ciliary defects in control and PCD human airway epithelia. Immunoprecipitations showed that SPAG1 interacts with multiple DNAAFs, dynein chains and canonical components of the R2TP complex.

Expression of a Truncated Form of Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype.

Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in > 50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of (), a component of the outer dynein arm docking complex, results in a failure to assemble outer dynein arms (ODAs), mostly immotile cilia, and a typical PCD phenotype.

Otolaryngology Manifestations of Primary Ciliary Dyskinesia: A Multicenter Study.

Objective: This project aims to prospectively and objectively assess otolaryngological manifestations and quality of life of children with primary ciliary dyskinesia (PCD) and compare these findings with healthy pediatric controls.

Study Design: Cross-sectional.

Setting: Two high-volume pediatric PCD specialty centers.

Access to medicines for rare diseases: beating the drum for primary ciliary dyskinesia.

https://bit.ly/3j5blfM.

Motile ciliopathies.

Motile cilia are highly complex hair-like organelles of epithelial cells lining the surface of various organ systems. Genetic mutations (usually with autosomal recessive inheritance) that impair ciliary beating cause a variety of motile ciliopathies, a heterogeneous group of rare disorders. The pathogenetic mechanisms, clinical symptoms and severity of the disease depend on the specific affected genes and the tissues in which they are expressed.

Comparison of Multiple Breath Washout and Spirometry in Children with Primary Ciliary Dyskinesia and Cystic Fibrosis and Healthy Controls.

In cystic fibrosis (CF), the lung clearance index (LCI), derived from multiple breath washout (MBW), is more sensitive in detecting early lung disease than FEV; MBW has been less thoroughly evaluated in young patients with primary ciliary dyskinesia (PCD). Our objectives were ) to evaluate the sensitivity of MBW and spirometry for the detection of mild lung disease in young children with PCD and CF compared with healthy control (HC) subjects and ) to compare patterns of airway obstruction between disease populations. We used a multicenter, single-visit, observational study in children with PCD and CF with a forced expiratory volume in 1 second (FEV) greater than 60% predicted and HC subjects, ages 3-12 years.

Sinus Development and Pneumatization in a Primary Ciliary Dyskinesia Cohort.

Background: Primary ciliary dyskinesia (PCD) is a genetically diverse disease which causes impaired mucociliary clearance, and results in pulmonary, otologic, and rhinologic disease in affected patients. Genetic mutations in multiple genes impair the ability of patients to clear mucous from the lungs, middle ear, and sinonasal cavity and lead to chronic pulmonary and sinonasal symptoms.

Methods: We identified 17 PCD patients who had available CT scans.