Genetic Testing for PCD: The Basics PCD is what is known as a heterogeneous disorder, meaning there are multiple

genes from multiple parts of the genome that cause PCD. In contrast, cystic fibrosis is a single gene disorder. However, there are thousands of known mutations on that single gene that cause CF. The same is true in PCD. On each identified gene, there are multiple separate PCD-causing mutations. The challenge of finding all these genes and all their mutations and then developing a genetic test sophisticated enough to test for them all is a massive undertaking. Still, we are making progress. To date, there are 15 known PCD genes and we have an initial PCD genetic test that picks up a number of the more commonly seen PCD mutations. Efforts are underway to improve the current PCD genetic test, but for now here are the limitations you need to know about the commercially available genetic tests for PCD (genetic testing done as part of the GDMCC research study is far more comprehensive, so this does not apply to testing study participants have had done): Outer dynein arm (ODA) defects are the most common cause of PCD and the genes for faulty ODA proteins were the first to be identified in PCD patients. Mutations identified on two of these genes, DNAI1 and DNAH5, account for approximately 38% of all cases of PCD and up to 65% of PCD related to outer dynein arm defects. These 61 known mutations on DNAI1 and DNAH5 make up the Ambry Genetics PCD61 test. Please note that the available genetic tests for PCD, while a huge advancement over what we had even a decade ago, still pose some limitations. First, they both only include mutations from two known genes and both of those genes are for ODAs. This means that PCD caused by inner dynein arm (IDA) defects or defects of the central apparatus or other structure, these mutations will not be picked up on this test. Also, while the tests pick up a majority of ODA defects, they do not pick up all. A genetic test is said to be positive for PCD when two known PCD-causing mutations or markers are identifiedone from each parentAND there is clinical evidence of PCD. In this case, genetic testing confirms the diagnosis. However, it is important to note that due to limitations both in our current knowledge of PCD genes and in the genetic test, a negative genetic test for PCD does not mean you dont have PCD. Genetic Testing Resources for PCD As mentioned above, there are currently two sources for clinical genetic testing for PCD: Ambry Genetics PCD61 For more information:
http://dev4.group22.com/clinical_diagnostic_and_carrier_testing/test_PCD_61.asp McLendonClinicalLaboratoriesattheUniversityofNorthCarolina,ChapelHill.Formoreinformation: http://labs.unchealthcare.org/labstestinfo/p_tests/pcd_seq.htm

Interpreting the Results Because PCD is a recessive disorder, genetic confirmation of the diagnosis requires positive identification of two known PCD mutations. When two mutations are identified, there is high specificity for a diagnosis of PCD. However, a negative result or a result positive for only a single mutation does not rule-out a diagnosis of PCD, nor does it suggest that a clinical diagnosis of PCD is incorrect. Individuals may harbor disease causing mutations not yet identified, therefore not detectable with current genetic panels. In this case, patients and their physicians may want to explore ongoing research studies which are seeking to identify additional disease causing mutations in these and possibly other genes. It is very important that genetic testing be part of a comprehensive clinical evaluation.*

Who Should Consider Genetic Testing? Ambry Genetics PCD Panel 61 suggests that clinical genetic testing for PCD is appropriate for the following indications: Known or suspected PCD Chronic sinusitis or bronchiectasis not due to cystic fibrosis Suspected PCD with heterotaxy, situs ambiguus, or situs inversus (aka Kartagener syndrome) Congenital heart defect associated with recurrent respiratory disease or heterotaxy Chronic otitis media with effusion Male infertility with other signs of PCD Idiopathic respiratory distress in full-term neonates Carrier status determination for relatives of patients with known mutations The decision to pursue genetic testing cannot be taken lightly. Interpretation of inconclusive results and access to genetic counseling regardless of the results, are factors to be considered before making the decision. Both Ambry Genetics and the UNC Molecular Genetics Laboratory are committed to working with patients and clinicians to ensure that appropriate candidates for testing are identified and that necessary follow-up is available to patients and ordering clinicians. As always, please consult with your physician if you have any questions.