Primary ciliary dyskinesia (PCD) is a recessive, genetically heterogeneous disorder with defective mucociliary clearance. This ongoing project is designed to identify additional disease-causing mutations in PCD using whole exome sequencing, and then to correlate the molecular etiologies with the ciliary phenotype (ultrastructure, beat frequency and wave form), production of nasal nitric oxide in vivo, and clinical phenotype. We have published extensive data that discrete sets of genes contribute to the structure and function of the ciliary outer dynein arm (ODA), inner dynein arm (IDA), and ?9+2? axonemal structure. For patients with these ciliary ultrastructural defects, nasal nitric oxide (nNO) production is low (~ 20 ml/min), including patients with mutations we recently discovered by exome sequencing in a novel gene that causes ODA defects (C11orf70). We are also identifying an increasing number of PCD patients with normal or non-diagnostic ciliary ultrastructure (up to 32% of PCD patients at UNC), including two novel genes we recently discovered (CFAP221/PCDP1 & CFAP57/WDR65)). Over the past 4 years, we have made great progress by identifying mutations in 14 of the 39 genes that cause 65-70% of PCD, but we need to identify additional PCD-causing genes. We are now whole exome sequencing 100 additional patients at an NIH-supported sequencing center (Yale; Dr. Shrikant Mane; 2UM1HG006504-05). This exome sequencing project will extend our search for disease-causing mutations by including patients who have a PCD-compatible clinical phenotype, but with nNO values that are higher than typical for PCD patients. Followup studies will be performed at UNC to validate novel gene discoveries, and characterize gene/protein expression and function in human ciliated airway cells. Taken together, these studies will provide new insights regarding the relationship of mutations in novel genes to ciliary ultrastructural and functional defects. These studies will not only greatly enhance our ability to diagnose PCD, but may also lead to discovery of milder genetic mutations associated with normal ciliary ultrastructure, and likely some residual ciliary function. Ultimately, results from this proposal will improve clinical genetic testing for PCD, and enable earlier diagnosis, clinical monitoring, and improved outcomes for patients with PCD.

Public Health Relevance

The overall goal of this project is to use whole exome sequencing to identify mutations in cilia genes, which cause primary ciliary dyskinesia (PCD), a life-shortening lung disease. We will also characterize the effects of these genetic mutations on ciliary function and clinical disease. Successful completion of this project will improve clinical genetic testing for PCD, which will enable earlier diagnosis, clinical monitoring, and improved outcomes for patients with PCD. Long-term, we hope to better understand the underlying genetic variability that adversely modifies ciliary function and predisposes to common airway diseases, such as chronic obstructive pulmonary disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Lachowicz-Scroggins, Marrah Elizabeth
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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Fedick, Anastasia M; Jalas, Chaim; Treff, Nathan R et al. (2015) Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population. Mol Genet Genomic Med 3:137-42

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