Primary Ciliary Dyskinesia (PCD) via the DNAAF1 / LRRC50 Gene

Primary Ciliary Dyskinesia (PCD) is a genetic disorder affecting the function of motile cilia (Leigh et al. 2009). The hallmark features of PCD are neonatal respiratory distress, chronic coughing, and recurrent sinus and/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). Kartagener’s syndrome is a 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 ambiguus or heterotaxy) (Kennedy et al. 2007).

Primary Ciliary Dyskinesia is inherited most commonly in an autosomal recessive manner due to defects in motile cilia. To date, defects in at least 20 genes, including DNAAF1, are known to cause autosomal recessive PCD (Loges et al. 2009; Duquesnoy et al. 2009). 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 & Leigh 2006). All motile cilia have inner and outer dynein arms attached at regular intervals to the nine peripheral microtubule doublets. The dynein arms consist of heavy, intermediate, and light dynein chains, and serve as molecular motors that drive microtubule sliding. Often, patients with PCD have structural defects in the inner (IDA) and/or outer dynein arms (ODA), rendering the cilia immotile and non-functional. DNAAF1, also known as LRRC50, encodes a protein believed to be required for the pre-assembly of both IDA and ODA in the cytoplasm prior to their transport to the plasma membrane for incorporation into motile cilia. Missense, nonsense, frameshifts and large deletions in DNAAF1 are known to cause autosomal recessive PCD (Loges et al. 2009; Duquesnoy et al. 2009).

This test is predicted to detect at least one causative mutation in ~4-5% of all patients diagnosed with PCD and ~15% of PCD patients with both IDA and ODA structural defects (Duquesnoy et al. 2009).

Clinical sensitivity for CNV detection cannot be estimated because no large-scale studies have been done to look for gross deletions or duplications in the DNAAF1 gene. Gross deletions in the DNAAF1 gene have been found in patients with PCD (Loges et al. 2009; Duquesnoy et al. 2009).

This test provides full coverage of all coding exons of the DNAAF1 gene 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 full 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).

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).