Primary Ciliary Dyskinesia (PCD) via the DNAI1 Gene

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder affecting the function of motile cilia (reviewed by Leigh et al. 2009). Motile cilia line the upper and lower respiratory airways, the ventricular system of the brain and spinal cord, and the female fallopian tubes. They are also components of the male sperm flagellum and required for sperm motility. Ciliary movement sweeps mucus, dirt, and bacteria out of the lungs, nasal passageways, and ear canals, thus protecting them from recurrent infections. In the developing embryo, nodal cilia generate a rotational motion that determines the position of the internal organs. Without functional nodal cilia, thoracoabdominal orientation is random. The hallmark features of PCD are neonatal respiratory distress, chronic coughing, and recurrent sinus or ear infections or both; 80-100% of all PCD patients have one or more of these symptoms. In about 50% of individuals with PCD, the major visceral organs are reversed from their normal positions (also called situs inversus or Kartagener’s syndrome). Fetal cerebral ventriculomegaly and hydrocephalus can also occur due to impaired circulation of the cerebrospinal fluid. In adults with PCD, male infertility and female sub-fertility are also common features. Prompt diagnosis of PCD is critical for the prevention of secondary respiratory complications, such as bronchiectasis, pneumonia, or progressive loss of lung function.

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 (reviewed in Ferkol & 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, which serve as molecular motors that drive microtubule sliding. Most frequently, patients with PCD have structural defects in the outer dynein arms (ODA), rendering the cilia immotile and non-functional. DNAI1 encodes a dynein intermediate chain of the ODA, and recessive variants in DNAI1 are known to cause PCD (Zariwala et al. 2001). DNAI1 consists of 20 exons (Pennarun et al. 1999) and pathogenic variants can be found throughout the gene (Zariwala et al. 2006). A mix of single nucleotide substitutions and small insertions/deletions have been described; most variants result in premature protein termination (i.e. nonsense, frameshift, splicing), but a handful of missense variants located in conserved domains also cause PCD (Human Gene Mutation Database; www.hgmd.org). To date, no gross deletions within the DNAI1 locus have been described.

This test is predicted to detect at least one causative variant in ~9% of all patients diagnosed with PCD, and ~13% of PCD patients selected for ODA structural defects (Zariwala et al. 2006).

This test provides full coverage of all coding exons of the DNAI1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.