Primary Ciliary Dyskinesia (PCD) via the GAS8 Gene

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 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). The similar 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 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 (Collins et al. 2014. PubMed ID: 26237387). Despite these signs, diagnosis is often delayed. This prevents early onset of regular airway clearance therapy, aggressive management of infections, monitoring and treatment of hearing impairment and genetic counselling for the family.

Primary Ciliary Dyskinesia is mostly inherited in an autosomal recessive manner due to defects in motile cilia. To date, defects in at least 40 genes, including GAS8, have been reported to cause PCD (Olbrich et al. 2015. PubMed ID: 26387594; Jeanson et al. 2016. PubMed ID: 27120127; Lewis et al. 2016. PubMed ID: 27472056). Pathogenic variants reported in GAS8 include loss of function variants consisting of nonsense, frameshift, and missense pathogenic variants. No copy number or de novo variants have been reported.

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.

GAS8 encodes a subunit of the nexin-dynein regulatory complex (N-DRC) that plays an important structural and functional role in ciliary movement. Pathogenic variants in GAS8 disrupt the N-DRC and cause axonemal disorganization (Olbrich et al. 2015. PubMed ID: 26387594; Jeanson et al. 2016. PubMed ID: 27120127). Individuals with biallelic loss-of-function variants in GAS8 have been reported to have primary ciliary dyskinesia without situ abnormalities. Affected individuals do not have a clear ultrastructural defect on electron microscopy, but are reported to have subtle abnormalities of ciliary beating and ultrastructure (Olbrich et al. 2015. PubMed ID: 26387594; Jeanson et al. 2016. PubMed ID: 27120127; Lewis et al. 2016. PubMed ID: 27472056). GAS8 has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality).

gas8-null zebrafish embryos showed hydrocephalus, left-right axis defects, and abnormal otolith composition of the inner ear, consistent with ciliary beating defects (Colantonio et al. 2009. PubMed ID: 19043402). Mice with Gas8 pathogenic variants presented with severe motility defects and PCD like symptoms including situs inversus and hydrocephalus (Lewis et al. 2016. PubMed ID: 27472056).

To date, pathogenic variants in GAS8 have been reported in only a few patients with PCD (Olbrich et al. 2015. PubMed ID: 26387594; Jeanson et al. 2016. PubMed ID: 27120127; Lewis et al. 2016. PubMed ID: 27472056). Abnormalities in GAS8 therefore appear to be a relatively rare cause of PCD.

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

This test provides full coverage of all coding exons of the GAS8 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).