Primary Ciliary Dyskinesia (PCD)/Immotile Cilia Syndrome and Cystic Fibrosis Panel

Primary ciliary dyskinesia (PCD) is a genetic disorder affecting the function of motile cilia with an incidence of 1 in 16,000 individuals (Leigh et al. 2009. PubMed ID: 19606528). The hallmark features of PCD are neonatal respiratory distress, chronic coughing, and recurrent sinus or ear infections; 80-100% of all PCD patients have one or more of these symptoms. In 20-50% of individuals with PCD, the major visceral organs are reversed from their normal positions (also called situs inversus; Sutherland and Ware. 2009. PubMed ID: 19876930). Kartagener’s syndrome is a similar condition defined by the symptomatic triad of situs inversus, sinusitis, and bronchiectasis. Patients with PCD can also have abnormal orientation of some organs, but not others (a condition called situs ambiguous or heterotaxy; Kennedy et al. 2007. PubMed ID: 17515466). For more information, see GeneReviews (Zariwala et al. 2019. PubMed ID: 20301301).

The majority of PCD patients have neonatal symptoms and around half have situs inversus but, despite these signs, diagnosis is often delayed (Collins et al. 2014. PubMed ID: 26237387). This prevents early use of regular airway clearance therapy, aggressive management of infections, monitoring, and treatment of hearing impairment and genetic counselling for the family. Genetic testing is helpful in identifying patients that need functional assessment and improving the diagnostic process.

To date, defects in over 50 genes have been reported to cause PCD, which is mostly inherited in an autosomal recessive manner (Zariwala et al. 2019. PubMed ID: 20301301). In rare cases, PCD has been found to be inherited in X-linked or autosomal dominant manners due to loss-of-function variants in OFD1, RPGR, DNAAF6/PIH1D3, and FOXJ1 (Budny et al. 2006. PubMed ID: 16783569; Moore et al 2006. PubMed ID: 16055928; Olcese et al. 2017. PubMed ID: 28176794; Wallmeier. 2019. PubMed ID: 31630787). De novo variants have been reported in the FOXJ1 gene (Wallmeier. 2019. PubMed ID: 31630787). Copy number variants have been documented in the ODAD2/ARMC4, CCDC40, CFTR, DNAAF1, DNAAF2, DNAH11, DNAH5, DNAAF4, SPAG1, OFD1, DNAAF6, RPGR, and ZMYND10 genes (Human Gene Mutation Database). In addition, the INVS/NPHP2 gene has been associated with situs inversus either with or without biliary complications (Schön et al. 2002. PubMed ID: 11935322; Otto et al. 2003. PubMed ID: 12872123). Symptoms of cystic fibrosis can sometimes mimic those of PCD. 

PCD is caused by defects in motile cilia. Cilia in the respiratory tract, brain, and sperm flagella consist of nine peripheral microtubule doublets surrounding two central microtubules; nodal cilia in the embryo lack the central microtubules (Ferkol and Leigh. 2006. PubMed ID: 17142159). All motile cilia have both inner and outer dynein arms attached at regular intervals to the peripheral microtubule doublets. The dynein arms consist of heavy, intermediate, and light dynein chains and serve as molecular motors that drive microtubule sliding. Most frequently, patients with PCD have structural defects in the outer dynein arms, rendering the cilia immotile and non-functional.

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Clinical sensitivity is ~80% (Zariwala et al. 2019. PubMed ID: 20301301).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 91.3% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Due to technical difficulties, only exons 1-5 and 85-86 of the HYDIN gene are included in this panel.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).