Primary Ciliary Dyskinesia (PCD) via the DNAH11 Gene

Primary Ciliary Dyskinesia (PCD) is a genetic disorder affecting the function of motile cilia (Leigh et al. 2009). 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). 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). For more information, see GeneReviews.

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 DNAH11, have been reported to cause PCD (Bartoloni et al. 2002; Schwabe et al. 2008). 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). 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 (ODA), rendering the cilia immotile and non-functional. DNAH11 is a large gene comprising 82 exons and over 4500 amino acids, encoding for the dynein arm heavy chain. A mix of single nucleotide substitutions and small insertions/deletions have been described; most pathogenic variants result in premature protein termination (i.e. nonsense, frameshift, splicing), but a handful of missense variants located in conserved domains also cause PCD and possibly Asthenozoospermia (Zuccarello et al. 2008; Schwabe et al. 2008; Pifferi et al. 2010, Knowles et al. 2012; Lucas et al. 2014; Boon et al. 2014). Undocumented and rare (allele frequency <1%) missense variants in DNAH11 are commonly found in presumably healthy individuals, making interpretation of rare missense variants difficult (1000genomes.org; ncbi.nlm.nih.gov/SNP; evs.gs.washington.edu/EVS). Interestingly, unlike with mutations in other dynein chains (i.e. DNAH5, DNAI1, and DNAI2), mutations in DNAH11 only affect the beating frequency of the cilia, not the visible structure of the inner or outer dynein arms (Knowles et al. 2012; Boon et al. 2014).

This test is predicted to detect biallelic pathogenic variants in DNAH11 in 22% of PCD individuals without ciliary ultrastructural defects (Knowles et al. 2012). Approximately 33% of individuals with PCD did not have ciliary ultrastructural defects by transmission electron microscopy (Boon et al. 2014). Taken together, we estimate that ~7% of all PCD patients will be found to have biallelic pathogenic variants in DNAH11.

To our knowledge, no gross deletions in DNAH11 have been reported in the literature. We have detected one gross duplication and one gross deletion in DNAH11 by our gene-centric aCGH test at Prevention Genetics. Clinical sensitivity cannot be estimated precisely, but is expected to be low because only a small number of patients with copy number variants have been found.

This test provides full coverage of all coding exons of the DNAH11 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).