Primary Ciliary Dyskinesia (PCD) via the CFAP298 (C21ORF59) 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 CFAP298 (C21ORF59), have been reported to cause PCD (Austin-Tse et al. 2013). 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 inner and outer dynein arms (ODAs) attached at regular intervals to the nine peripheral microtubule doublets, which serve as molecular motors that drive microtubule sliding. Most frequently, patients with PCD have structural defects in the cilia, rendering them immotile.

Individuals with biallelic variants in CFAP298 were found to have primary ciliary dyskinesia with and without laterality defects (Austin-Tse et al. 2013). Affected individuals had both inner and outer dynein arm defects (Austin-Tse et al. 2013). All documented pathogenic variants were nonsense or frameshift variants (Austin-Tse et al. 2013). One nonsense variant, c.735C>G (p.Tyr245*) was observed in the homozygous state in three individuals, two with known Ashkenazi Jewish ancestry. Haplotype analysis revealed these three individuals shared a common haplotype of ~1Mb, suggesting that this is a founder mutation (Austin-Tse et al. 2013).

This test is predicted to detect two causative variants in 1% of all patients diagnosed with Primary Ciliary Dyskinesia (Austin-Tse et al. 2013).

This test provides full coverage of all coding exons of the CFAP298 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).