Genetic variants of primary ciliary dyskinesia

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disease that results in impaired mucociliary clearance, causing progressive involvement of the respiratory tract manifested by recurrent infections of the lungs, middle ear, and paranasal sinuses. "Classic" forms of PCD reflect total loss of functional mucociliary clearance, and clinical presentations of the disease are dependent on the presence of genetic defects. Variant forms of PCD exist and are likely due to milder mutations in genes associated with partial preservation of ciliary function. Thus, genetic defects leading to abnormal ciliary function may be more common than previously appreciated, and may play a role in or act as a modifier of other lung diseases. Several lines of evidence have shown that neonatal respiratory distress is a common clinical presentation of patients with classic PCD, suggesting that cilia function is critical for effective clearance of fetal lung fluid. This concept has not been a focus of neonatal transition, and provides the framework for the hypothesis that genetic ciliary defects are a leading cause of neonatal respiratory distress in term infants. In this proposal, we will examine the scope of pulmonary manifestations and genetic abnormalities of PCD. In collaboration with our colleagues at the Washington University Genome Sequencing Center, we will first analyze DNA samples banked from patients with confirmed ciliary dyskinesia for candidate gene (DNAI1 and DNAH5) mutations using high-throughput polymerase chain reaction (PCR) and DNA screening. Second, we will sequence DNA samples from term neonates who presented with respiratory distress for mutations and polymorphisms of the same genes that encode proteins shown to be important for effective ciliary function, and compare the genetic variants of candidate genes from this cohort with those found in unaffected newborns. Using this approach, we will define the genetic spectrum of PCD, and correlate specific genetic variants with clinical presentations of this disease, especially during the neonatal period.