Advances in the Genetics of Primary Ciliary Dyskinesia: Clinical Implications

Abstract

Primary ciliary dyskinesia is a rare genetic disease of the motile cilia and is one of a rapidly expanding collection of disorders known as ciliopathies. Patients with primary ciliary dyskinesia have diverse clinical manifestations, including chronic upper and lower respiratory tract disease, left-right laterality defects, and infertility. In recent years, our understanding of the genetics of primary ciliary dyskinesia has rapidly advanced. A growing number of disease-associated genes and pathogenic mutations have been identified, which encode axonemal, cytoplasmic, and regulatory proteins involved in the assembly, structure, and function of motile cilia. Our knowledge of cilia genetics and the function of the proteins encoded has led to a greater understanding of the clinical manifestations of motile ciliopathies. These advances have changed our approach toward diagnostic testing for primary ciliary dyskinesia. In this review, we will describe how new insights into genetics have allowed us to define the clinical features of primary ciliary dyskinesia, revolutionize diagnostics, and reveal previously unrecognized genotype-phenotype relationships in primary ciliary dyskinesia.

Keywords: axoneme; bronchiectasis; cilia; ciliopathy; mucociliary clearance.

Figure 1

Schematic diagrams that show the microtubular structure and ultrastructural elements of normal motile 9 + 2, nonmotile primary 9 + 0, and motile nodal 9 + 0 ciliary axonemes.

Figure 2

Classification of ultrastructural phenotypes of the ciliary axoneme and genes associated with primary ciliary dyskinesia.