This Consortium of 10 geographically-dispersed clinical research sites will continue to study rare diseases of the airways that are associated wit defective mucociliary clearance and airway host defense mechanisms, which result in chronic airways infection and/or bronchiectasis. These disorders include Primary Ciliary Dyskinesia (PCD), idiopathic bronchiectasis (IB), cystic fibrosis (CF), airway infection with non-tuberculous mycobacteria (NTM), rare immune disorders (e.g., RAG1 deficiency), and Cri du Chat syndrome (chr 5pminus;deletion) complicated by concomitant PCD, caused by mutations in DNAH5 (chr5p). Over the past 5 years of this Consortium's work, we have made remarkable progress that is already impacting on clinical practice, particularly in PCD and associated disorders. One major advance was the development of a non-invasive test for PCD (measurement of nasal nitric oxide, NO). This test is now validated as a useful clinical test for PCD, and we are participating in the European BESTCILIA grant to help them implement our methodology for nNO testing in Europe. Our Consortium played a critical role in identifying PCD-causing mutations in 28 genes, which we think will be responsible for the genetic cause of PCD in >70%) of PCD patients. We have developed a genetic test panel containing those 28 genes (Ampliseq), which is being technically validated. On the clinical side, we discovered that PCD-causing mutations are associated with heterotaxy and congenital heart disease (CHD). This discovery resulted in follow-up studies, which showed worse post-operative clinical outcomes for CHD-heterotaxy patients, and has led to a call for genetic studies of patients with CHD. Along different lines, we developed a rigorous quality-of-life (QOL) instrument for PCD, which will be a key outcome measure for therapeutic clinical trials in PCD. Finally, we have developed novel preliminary data that patients with idiopathic bronchiectasis share phenotypic features with heritable connective tissue disorders, including dural ectasia, which may reflect underlying genetic variants. Taken together, the proposed work will lead to earlier diagnoses, improved care, and more effective therapeutic interventions for rare airway diseases.

Public Health Relevance

This RDCRN Consortium research has high public health relevance to our understanding of genetic diseases of the lung. This proposal will define the clinical course and develop new genetic test panels for PCD, and define subgroups of patients with idiopathic bronchiectasis that may have underlying genetic variants that cause heritable disorders of connective tissue. The proposed work will lead to earlier diagnoses and more effective therapy for airways disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1-CI-8 (01))
Program Officer
Smith, Robert A
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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Horani, Amjad; Ferkol, Thomas W (2018) Advances in the Genetics of Primary Ciliary Dyskinesia: Clinical Implications. Chest 154:645-652
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Shapiro, Adam J; Leigh, Margaret W (2017) Value of transmission electron microscopy for primary ciliary dyskinesia diagnosis in the era of molecular medicine: Genetic defects with normal and non-diagnostic ciliary ultrastructure. Ultrastruct Pathol 41:373-385
Blackburn, Kevin; Bustamante-Marin, Ximena; Yin, Weining et al. (2017) Quantitative Proteomic Analysis of Human Airway Cilia Identifies Previously Uncharacterized Proteins of High Abundance. J Proteome Res 16:1579-1592
Shapiro, Adam J; Josephson, Maureen; Rosenfeld, Margaret et al. (2017) Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis. Ann Am Thorac Soc 14:1184-1196

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