Primary Ciliary Dyskinesia (PCD) via the RSPH1 Gene

Primary Ciliary Dyskinesia (PCD) is a genetic disorder affecting the function of motile cilia (Leigh et al. 2009. PubMed ID: 19606528). 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. PubMed ID: 19876930). 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. PubMed ID: 17515466). For more information, see GeneReviews (Zariwala et al. 2015. PubMed ID: 20301301).

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 RSPH1, have been reported to cause PCD (Kott et al. 2013. PubMed ID: 23993197; Onoufriadis et al. 2014. PubMed ID: 24518672; Knowles et al. 2014. PubMed ID: 24568568). 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.

RSPH1 encodes a radial-spoke (RS)-head protein, and individuals with biallelic pathogenic variants in RSPH1 are found to have central-complex (CC) defects and abnormal ciliary motion. A mix of single nucleotide substitutions and small insertions/deletions have been described; most pathogenic variants result in premature protein termination (nonsense, frameshift, splicing), but missense variants located in conserved domains have also been reported to be pathogenic (Kott et al. 2013. PubMed ID: 23993197; Onoufriadis et al. 2014. PubMed ID: 24518672; Knowles et al. 2014. PubMed ID: 24568568; Raidt et al. 2014. PubMed ID: 25186273).

This test is predicted to detect RSPH1 pathogenic variants in ~2% of all patients diagnosed with Primary Ciliary Dyskinesia (PCD), and ~21% of PCD patients with central-complex defects (Kott et al. 2013. PubMed ID: 23993197; Zariwala et al. 2017. PubMed ID: 20301301).

This test provides full coverage of all coding exons of the RSPH1 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).