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.

Inclusion Criteria:

- • Age 0-90 years

- Confirmed diagnosis of PCD by either ciliary ultrastructure abnormality or two
known disease-causing alleles in a known PCD gene OR individuals with clinical
suspicion of PCD without a confirmatory test (genetics or ciliary biopsy) as
defined by: low nasal nitric oxide testing (<77nl/min) on two separate occasions
at least two months apart or compatible clinical phenotype, but unable to do
nasal nitric oxide testing secondary to age or other factors OR relative of one
of the previously defined individuals with PCD

- Ability to provide informed consent or consent of parent/guardian and assent for
minors

Exclusion Criteria:

- • Inability to understand the requirements of the study or be unwilling to provide
written informed consent (as evidenced by signature on an informed consent document
approved by the IRB) OR inability of parent/guardian to understand the requirements of
the study