PCD New Gene Discovery

The objective of this study is to better define how the genes that cause primary ciliary dyskinesia (PCD) are related to the clinical symptoms of individuals with PCD. PCD is a rare disease that affects the function of motor cilia throughout the body. This results in a variety of clinical symptoms, but chief among them are a chronic wet cough, recurrent sinusitis, and frequent pneumonia. These clinical symptoms can result in further structural lung disease, including bronchiectasis, with eventual worsening of lung function. The treatment for this condition largely focuses on augmenting airway clearance and appropriate use of antimicrobial therapies, in conjunction with monitoring for evidence of pulmonary impairment. Thus, it is important to identify and diagnose individuals with PCD early in life.

Making a diagnosis of PCD can be difficult as their is some overlap of the clinical symptoms with other conditions and there are limitation in the current diagnostic testing modalities. Historically, the diagnosis has been made by identification of structural abnormalities in cilia by electron microscopy (ciliary biopsy). However, this testing has limitations secondary to the somewhat invasive nature of the procedures and often inconclusive results secondary to sampling challenges (getting enough cilia). Furthermore, a normal ciliary biopsy result does not rule-out PCD as it is now known that there are individuals with PCD who have ciliary dysfunction secondary to ciliary abnormalities that are not routinely identified on standard electron micrograph. Genetic testing for PCD is available, but current testing only accounts for about 60-65% of the PCD population. Thus normal results in this regard do not rule-out PCD either. Nasal nitric oxide (nNO) testing is an emerging research-based testing that is being used more frequently to identify individuals with PCD. More specifically, it has been frequently observed that individuals with PCD have low levels of nitric oxide in their sinus cavities. Measuring a low level of nitric oxide of multiple different occasions has proven to have diagnostic utility in an individual with a clinical symptom history consistent with PCD. While nNO testing is helpful for identifying individuals likely to have PCD, this testing does not give further information as to reason for ciliary dysfunction. Current testing availability has resulted in a group of individuals who are being managed as "probable PCD" which is defined by having clinical symptoms consistent with PCD (such as year-round wet cough and rhinitis) at least two separate positive (low value) nNO testing results, but negative PCD genetics and a non diagnostic ciliary biopsy. While these individuals are often managed the same as other individuals with more defined PCD, including augmentation of airway clearance therapies, in order for more specific care to be applied in the future it is important to better define the ciliary structural reason for their clinical symptoms. This could also be described as needing to better understand the genotype-phenotype of all individuals with PCD.

This investigation seeks to better define the genotypic-phenotypic relationship of individuals by initially focusing on new gene discovery in individuals with probable PCD. More specifically, through whole-exome evaluation of individuals with probable PCD and unaffected first-degree relatives, we will focus on identifying new mutations in ciliary structural proteins and other related pulmonary genes. New gene targets will then be further studied through analysis of ciliary structure and function.