Genotype/Phenotype Correlation With Focus on Lung Function in Primary Ciliary Dyskinesia (PCD) (LuFu_PCD)

An International Study on Genotype/Phenotype Correlation With Focus on Lung Function in Patients With Primary Ciliary Dyskinesia (PCD)

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by dysfunction of motile cilia associated with recurrent infections of the airways, laterality defects (Situs inversus totalis in about 50% of cases) and fertility problems. At present, mutations in > 45 genes associated with PCD and mucociliary clearance disorders have been identified, representing most likely two thirds of all human cases.

Aim of this study are:

• Correlation between genotype and lung function of patients with genetically confirmed PCD in an international cohort on a longitudinal basis
• Determination of further parameters, such as body mass index (BMI), possibly associated with lung function in genetically confirmed PCD patients

Study Overview

• Status: Recruiting
• Conditions: Primary Ciliary Dyskinesia; Ciliary Motility Disorders
• Intervention / Treatment: Genetic: Genetic diagnosis

Detailed Description

Background Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by dysfunction of motile cilia associated with recurrent infections of the airways, laterality defects (Situs inversus totalis in about 50% of cases) and fertility problems. At present, mutations in > 40 genes associated with PCD and mucociliary clearance disorders have been identified, representing most likely two thirds of all human cases. While being involved in the majority of identified PCD genes, our working group has a great expertise in genetic analysis and diagnostic work-up of patients with PCD.

Hallmark symptom of PCD is the chronic purulent lung disease due to the reduced mucociliary clearance. Chronic inflammation and recurrent infections of the airways promote continuous lung damage, bronchiectasis and could finally lead to total lung failure. For other congenital diseases with chronic lung conditions, e.g. cystic fibrosis (CF), an affected lung function with a steady decline is well described and spirometry is widely used to monitor disease progression. For PCD there are only limited data available and studies often comprise small cohorts. In general, available data assume a decline of lung function in PCD patients compared to healthy individuals, but less pronounced than in CF. Altogether, results of the studies remain heterogeneous, in particular concerning the influence of an early diagnosis and a proper treatment on lung function.

Furthermore, despite a significant progression in genetically solved cases there are almost no data on genotype specific lung function in patients with PCD. Recently, there are few studies indicating an association between specific ultrastructural or genetic defects, e.g. patients carrying mutations in the genes MCIDAS (Multicilin), CCNO (Cyclin O), CCDC39 (Coiled-Coil Domain Containing 39) and CCDC40 (Coiled-Coil Domain Containing 40) and a severe clinical course in particular a worse respiratory phenotype. There might be a less severe phenotype in PCD sub-types due to mutations in genes encoding radial spoke components.

Currently a systematic review shows the high variation of spirometric indices in a great PCD cohort. These findings underline the great necessity of detailed characterization of genotype specific phenotypes with focus on important parameters such as lung function to better understand the natural history of distinct PCD-variants with a view to improve individual patient care by tailored treatment activity according to likely disease severity.

Aim of this study are:

• Correlation between genotype and lung function of patients with genetically confirmed PCD in an international cohort on a longitudinal basis
• Determination of further parameters, such as body mass index (BMI), possibly associated with lung function in genetically confirmed PCD patients

Inclusion criteria:

• Patients with a genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD and at least one other method confirming PCD-diagnosis
• Children and adults diagnosed with PCD of all age groups and able to perform spirometry
• Longitudinal datasets with measurements of lung function (FEV1 (forced expiratory volume in 1 second), FVC (forced vital capacity), FEV1/FVC, FEF (forced expiratory flow) 25-75) (with date and height at the performed measurement, respectively)
• at least 3-4 different measurements in at least 2 years of follow up are expected - in cases where this is not possible, sporadic data could also be provided
• Delivery of datasets to the international PCD registry (NCT02419365) with all necessary values within the anticipated time schedules

• Study Type: Observational
• Enrollment (Anticipated): 1500

Contacts and Locations

• Study Contact: Name: Johanna Raidt, MD; Phone Number: +49 251 83 40003; Email: Johanna.Raidt@ukmuenster.de
• Study Contact Backup: Name: Simone Helms; Phone Number: + 49 251 83 48358; Email: Simone.Helms@ukmuenster.de

Study Locations

• Germany
  • NRW
    • Münster, NRW, Germany, 48149
      • Recruiting
      • University Hospital Münster
      • Contact: Simone Helms; Phone Number: 48358 +4925183; Email: Simone.Helms@ukmuenster.de
      • Contact: Heymut Omran, Prof. Dr. MD; Phone Number: 41097 004925183; Email: PCDregistry.eu@ukmuenster.de
      • Principal Investigator: Heymut Omran, Prof. Dr. MD
      • Sub-Investigator: Johanna Raidt, MD, Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

PCD patients with proven bi-allelic mutations in a gene known to cause PCD

Description

• Patients with a genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD and at least one other method confirming PCD-diagnosis
• Children and adults diagnosed with PCD of all age groups and able to perform spirometry
• Longitudinal datasets with measurements of lung function (FEV1, FVC, FEV1/FVC, FEF25-75) (with date and height at the performed measurement, respectively) at least 3-4 different measurements in at least 2 years of follow up are expected - in cases where this is not possible, sporadic data could also be provided
• Delivery of datasets to the international PCD registry (14) with all necessary values within the anticipated time schedules

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Genetic diagnosis	Genetic: Genetic diagnosis; No Intervention foreseen, but genetically confirmed diagnosis of PCD (bi-allelic mutations in a gene, known to cause PCD) with typical clinical symptoms of PCD and at least one other method confirming PCD-diagnosis is needed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genotype-Lungfunction Correlation	Lung function (FEV1, FVC, FEF) in correlation to the genetic make-up	up to 20 years (retrospective)

Collaborators and Investigators

• Sponsor: University Hospital Muenster
• Collaborators: University of Pisa; Medical University of Vienna; Hacettepe University; Charite University, Berlin, Germany; Oslo University Hospital; Göteborg University; Hannover Medical School; Federico II University; Rigshospitalet, Denmark; KU Leuven; Hadassah Medical Organization; University College, London; The Leeds Teaching Hospitals NHS Trust; University of Sao Paulo; Bambino Gesù Hospital and Research Institute; Marmara University; University of Southampton; Amsterdam UMC, location VUmc; University of Bern; Ruhr University of Bochum; University of Valencia; University Children's Hospital, Zurich; Royal Brompton & Harefield NHS Foundation Trust; University of Leicester; University of Belgrade; University of Dundee; University Hospital of Cologne; University of Geneva, Switzerland; Schneider Children's Medical Center, Israel; Hospital de Niños R. Gutierrez de Buenos Aires; Hospital Vall d'Hebron; NOVA Medical School; University of Nicosia; University Hospital, Motol; University Hospital, Martin; Abderrahmane Mami Hospital
• Investigators: Study Chair: Heymut Omran, Prof., MD, University Hospital Muenster

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2019
• Primary Completion (Anticipated): June 30, 2023
• Study Completion (Anticipated): November 30, 2023

Study Registration Dates

• First Submitted: January 12, 2021
• First Submitted That Met QC Criteria: January 18, 2021
• First Posted (Actual): January 20, 2021

Study Record Updates

• Last Update Posted (Actual): July 5, 2022
• Last Update Submitted That Met QC Criteria: July 1, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Neurologic Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Otorhinolaryngologic Diseases; Movement Disorders; Abnormalities, Multiple; Ciliopathies; Dyskinesias; Ciliary Motility Disorders
• Other Study ID Numbers: JR_Lufu_PCD_01_2020-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No