The overall goals for Project 1 are to define the clinical and laboratory features of pediatric and adult patients with rare suppurative respiratory diseases, and identify the genetic cause of the disorders. This study will be performed through the 8-site rare disease Genetic Disorders of Mucociliary Clearance (GDMCC) Consortium in North America. Pulmonary physicians and immunologists have referrals of some patients with recurrent infections and suppurative respiratory disease due to rare genetic defects in cilia function (primary ciliary dyskinesia, PCD) and/or genetic defects in host immune function (primary immunodeficiencies, PID). If not appropriately diagnosed and treated, these patients have progressive airway damage and decline in lung function over time. Genetic discoveries over the past two decades have identified many genetic causes of PCD (mutations in 40 genes) and PID (mutations in > 350 genes). However, there is an overlap of clinical features of patients with rare disorders with more common diseases, such as asthma and recurrent viral illnesses; thus, recognition of these rare disorders is challenging for pulmonary and immunology physicians. The GDMCC Consortium will perform a systematic diagnostic evaluation of patients who are referred with suppurative lung disease of unknown etiology, utilizing a multidisciplinary collaborative effort by pulmonary and immunology experts. After standardized clinical and lab workup, genetic testing will be performed to identify which patients have PCD or PID, and which defective gene is causative. Collaborative support from NIAID (Drs. Steve Holland and Luigi Notarangelo) and NHLBI (Dr. Ken Olivier) will offer specialized laboratory capabilities for functional studies of immunologic genetic variants. Successful completion of this project will establish guiding principles for the recognition of PID or PCD in patients presenting with suppurative respiratory disease. Establishing a diagnosis will enable clinical monitoring and tailored care to slow or prevent the progression of lung disease and decline in lung function, including the use of novel genetic defect-specific therapeutics.
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