Primary Ciliary Dyskinesia (PCD) via the DNAAF5 (HEATR2) 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). For more information, see GeneReviews (Zariwala et al. 2013).

Primary Ciliary Dyskinesia is inherited most commonly in an autosomal recessive manner due to defects in motile cilia. To date, defects in at least 30 genes, including HEATR2 (DNAAF5), have been reported to cause PCD (Horani et al. 2012; Watson et al. 2014). 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). 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. DNAAF5 encodes a protein involved in either transport or assembly of dynein arms (Horani et al. 2012). Pathogenic variants in DNAAF5 have been found in individuals with autosomal recessive PCD with and without laterality defects (Horani et al. 2012; Watson et al. 2014). Affected individuals had outer dynein arm defects and most outer doublets lacked inner dynein arms (Horani et al. 2012). Heterozygous carriers were not affected (Horani et al. 2012).

Clinical sensitivity cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all pathogenic variants reported are detectable by sequencing.

This test provides full coverage of all coding exons of the DNAAF5 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).