Primary Ciliary Dyskinesia (PCD) via the NME8 (TXNDC3) 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; 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 subfertility 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 inner and outer dynein arms 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 outer dynein arms (ODA), rendering the cilia immotile and nonfunctional. NEM8 (TXNDC3) encodes a component of the ODA, and compound heterozygous variants in TXNDC3 have been found to cause PCD (Duriez et al. 2007). Duriez et al. recently reported that a single patient with PCD was heterozygous for a nonsense variant in exon 15 (c.1277T>A) and heterozygous for a functional polymorphism in intron 6 (c.271-27C>T). Normally, two alternative TXNDC3 mRNA isoforms are expressed: (1) a full-length isoform consisting of all 17 exons (TXNDC3fl) and (2) an isoform excluding exon 7 (TXNDC3d7). Interestingly, the c.271-27C>T variant (present in ~1% of the control subjects) was found to alter the ratio of TXNDC3fl to TXNDC3d7 isoforms. On its own, the c.271-27C>T polymorphism does not alter the TXNDC3fl/TXNDCd7 ratio enough to cause a problem. However, in combination with a clearly non-functional variant, such as the c.1277T>A nonsense variant, the c.271-27C>T variant can apparently lead to primary ciliary dyskinesia.

This test is predicted to detect at least one causative variant in ~1-2% of all patients diagnosed with PCD (Duriez et al. PNAS 104:3336-3341, 2007).

This test provides full coverage of all coding exons of the NME8 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).