Added complexity to genotype–phenotype relationships in primary ciliary dyskinesia: TAS2R38 as a gene modifier

Primary ciliary dyskinesia (PCD), an inherited motile ciliopathy, is characterised by recurrent upper and lower respiratory tract infections, organ laterality defects, subfertility and neonatal respiratory distress due to impaired ciliary function.1 Over 50 PCD disease-causing genes have been identified that impact the structure and function of the cilia (figure 1, originally in Despotes et al 1). Significant clinical heterogeneity is associated with PCD, in part driven by genotype; genotype–phenotype relationships are an emerging area of great importance within this rare disease.2–4 However, clinical heterogeneity has also been reported among patients with the same genetic variants,3 suggesting that genetic modifiers may play an important role in disease manifestations. In their Thorax paper, Pifferi and colleagues have helped uncover our incomplete understanding of this heterogeneity by evaluating the impact of TAS2R38 polymorphisms within specific PCD genotypes. The authors specifically explored the impact of these polymorphisms on Pseudomonas aeruginosa (PA) infections, lung function and nasal nitric oxide (nNO) levels.5 Figure 1 : The location and function of the 54 currently known disease-causing genes implicated in PCD, originally published in Despotes et al (1). Panel A: Respiratory Epithelial Cell. * DNAH9 and DNAH11 are represented twice (panel A and panel C) as these genes are important in ODA structure at different locations along the axoneme length, as demonstrated in panel A. Panel B: Cilium and Intraflageller Transport. Panel C: Axoneme (in cross-section). The outer doublet A and B microtubules are labeled. The cross-section of the axoneme shows the “9 + …