Primary Ciliary Dyskinesia (PCD) via the MCIDAS 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).

Individuals with biallelic MCIDAS variants displayed typical signs of a mucociliary clearance disorder with chronic recurrent infections of the upper (rhinitis, otitis media, nasal polyps and sinusitis) and lower (recurrent pneumonia, bronchiectasis, chronic obstructive airway disease) airways, and postnatal respiratory distress. All affected individuals had normal situs composition (Boon et al. 2014. PubMed ID: 25048963; Maddirevula et al. 2018. PubMed ID: 30237576).

The majority of PCD patients have neonatal symptoms and around half have situs inversus but, despite these signs, diagnosis is often delayed (Collins et al. 2014. PubMed ID: 26237387). 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 MCIDAS, have been reported to cause PCD (Boon et al. 2014. PubMed ID: 25048963; Maddirevula et al. 2018. PubMed ID: 30237576). Biallelic variants in MCIDAS are associated with autosomal recessive primary ciliary dyskinesia. To our knowledge, no de novo variants have been reported in MCIDAS. Variants reported include missense, nonsense, and splicing variants. To date, no copy number changes have been documented in literature. MCIDAS is relatively intolerant to missense variants (Genome Aggregation Database).

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.

MCIDAS encodes the nuclear protein Multicilin that promotes multiciliated cell formation. MCIDAS pathogenic variants cause complete absence or reduced numbers of cilia and a severe decrease of basal bodies, resulting in defective generation of multiple motile cilia. Ectopic expression of MCIDAS pathogenic variants in Xenopus showed that they did not induce the formation of ectopic multiciliated cells as with wildtype MCIDAS, but rather led to reduction in cell number and an abnormal increase in cell size (Boon et al. 2014. PubMed ID: 25048963).

To date, only a few families with MCIDAS pathogenic variants have been reported. Abnormalities in MCIDAS therefore appear to be a relatively rare cause of PCD (Boon et al. 2014. PubMed ID: 25048963; Maddirevula et al. 2018. PubMed ID: 30237576).

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 MCIDAS 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).