Genetics of Primary Ciliary Dyskinesia

Research Genetic Testing for Primary Ciliary Dyskinesia Using a Panel of Genes

This study is designed to study DNA sequencings for mutations in a research genetic test panel of genes (which contains all 32 known and/or published genes associated with PCD). The study aims to show that about 70% of PCD patients have biallelic mutations in one of these genes. This project will enroll patients who have already had a clinical evaluation, and have clinical features consistent with PCD.

Study Overview

• Status: Completed
• Conditions: Primary Ciliary Dyskinesia; Kartagener Syndrome

Detailed Description

The investigators have established a Consortium of 9 geographically-dispersed clinical research sites to study rare disease of the airways, including Primary Ciliary Dyskinesia (PCD). PCD is a genetic disorder with defective mucociliary clearance (MCC), sinus and pulmonary disease with chronic infection, and organs located on the wrong side of the body in about 50% of patients (Kartagener Syndrome). Lung disease occurs early in children with PCD, but establishing a diagnosis remains a major challenge, based on the traditional approaches of using electron microscopy and/or ciliary waveform analysis to define abnormalities of ciliary ultrastructure and/or function.

For this study, blood or buccal samples for DNA will be collected and genetic testing in patients with known or suspected PCD will be performed. This study can include term neonates with respiratory distress of unknown etiology and features of PCD, particular laterality defects (situs inversus or heterotaxy). The key hypothesis for this study is that a genetic test panel of 32 genes will confirm a diagnosis in most patients with PCD.

• Study Type: Observational
• Enrollment (Actual): 320

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • The Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada
      • McGill University
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital, Denver
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University, St. Louis
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • The University of North Carolina at Chapel Hill
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center, Seattle

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

Study participants should have 2 or more clinical features of PCD.

Description

Inclusion Criteria:

• Any patient who has ≥ 2 clinical features (+/- lab) characteristic of PCD, including:

  • Neonatal respiratory distress after term (or near-term) birth
  • and/or laterality defect ( situs inversus or heterotaxy)
  • and/or daily wet cough before 6 months of age
  • and/or middle ear disease
  • and/or chronic nasal congestion before 6 months of age
  • and/or bronchiectasis
  • and/or male infertility due to sperm tail dysfunction
  • and/or low nasal nitric oxide levels (<77 nanoliters/minute)
  • and/or defective ciliary ultrastructure

Exclusion Criteria:

• Known diagnosis of cystic fibrosis with classic clinical presentation and elevated sweat chloride levels and/or two known disease-causing Cystic Fibrosis transmembrane conductance regulator (CFTR) mutations, or documented primary or acquired immunodeficiency.
• Known explanation for bronchiectasis (and other clinical features), such as α1-antitrypsin deficiency (ZZ or ZS), inflammatory bowel disease or rheumatoid arthritis.
• Any patient who is unwilling or unable to provide consent or to comply with the testing required in this protocol

A participant should not be in the study if they have not had a standard clinical evaluation to address other potential causes of chronic oto-sino- pulmonary disease.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirm PCD diagnosis in patients using a panel of 32 genes	The primary objective is to perform research genetic (Ampliseq panel) testing in patients who are known or suspected to have PCD, based on previous research or future clinical and lab characterization by certified clinical research sites. We will define the prevalence of biallelic PCD-causing mutations in patients who fulfill criteria of very high likelihood of PCD, as well as prevalence in other patients with some features of PCD. We anticipate successful completion of this objective will provide the foundation for development of clinically available genetic test panels, particularly as additional PCD genes are identified.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify patients with PCD who do not have a biallelic PCD-causing mutation	The secondary objective is to perform research genetic testing to identify patients with PCD who do not have biallelic PCD-causing mutations in known PCD genes, so they can be exome sequenced to discover novel genes associated with PCD. We anticipate that successful completion of this objective will enable the development of more extensive genetic test panels that are more robust to diagnose PCD.	Up to 5 years

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); Rare Diseases Clinical Research Network
• Investigators: Principal Investigator: Michael Knowles, MD, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: March 9, 2015
• First Submitted That Met QC Criteria: March 13, 2015
• First Posted (Estimate): March 17, 2015

Study Record Updates

• Last Update Posted (Actual): August 10, 2022
• Last Update Submitted That Met QC Criteria: August 9, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Primary Ciliary Dyskinesia; Kartagener Syndrome
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Neurologic Manifestations; Congenital Abnormalities; Bronchial Diseases; Genetic Diseases, Inborn; Otorhinolaryngologic Diseases; Movement Disorders; Heart Defects, Congenital; Cardiovascular Abnormalities; Abnormalities, Multiple; Ciliopathies; Bronchiectasis; Respiratory System Abnormalities; Dextrocardia; Situs Inversus; Dyskinesias; Ciliary Motility Disorders; Kartagener Syndrome
• Other Study ID Numbers: 14-1225; U54HL096458-11 (U.S. NIH Grant/Contract)