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Primary ciliary dyskinesia (PCD) is a congenital disorder of heterogeneous genetic origin. It is inherited in an autosomal recessive manner. It is a member of the ciliopathies, and has diverse clinical features ranging from chronic bronchitis through chronic otitis media to situs inversus with male infertility. It is found to occur in about 1 in 16,000 births.
The importance of this syndrome lies in its being the first human disease to be linked to a disorder of motile cilia. It is caused by one of many recessive mutations involving a number of genes. Most of the mutations identified in PCD are localized to the family involved.
The genes whose mutations result in PCD may be classified on the basis of the localization of their translation products or proteins, the protein function, or according to the nature of the functional or anatomical defect found in the affected individual.
The earliest mutations to be found were associated with the dysfunction of proteins localized to the axonemal ultrastructure. Thus, DNA11 and DNAH5 both code for proteins that make up part of the outer dynein arm, and these are responsible for about a third of all PCD cases. Such mutations cause the cilia to be either deprived of motion or significantly hypomotile.
Most of the genes so far identified include those which encode for components in the outer dynein arms, the outer arm docking complex, the nexin link, or the central apparatus. These latter mutations, in genes RSPH4A and RSPH9, cause the cilia to be lacking in the central microtubule doublet, resulting in a rotational motility. It is noteworthy that such defects are less commonly associated with situs inversus because of the absence of the central pair in the nodal cilia as well.
A few mutations have not been found to result in a specifiable anatomical defect in the cilia and are diagnosed by genetic sequence testing, such as DNAH11 mutations which localize to the outer dynein arm. These mutated cells still have a normal or hyperkinetic beat frequency. It is possible that the affected regions are rendered invisible by the presence of normal proteins, and cryoelectron tomography may be utilized to visualize them.
Other mutations may occur in the coiled-coil domain proteins such as CCDC39, which is a null allele mutation, which means no protein is produced in patients who have the disease. This gene is known as a cilia ruler, which spaces the spokes at predefined positions along the axoneme, and thus enables the precise alignment of the axonemal structures.
Genetic testing is still in an early phase as regards PCD, with tests being small scale and limited in their ability to detect mutations in only a few genes. It is estimated that more than a third of syndromes which appear to be PCD are caused by unknown genetic defects.
The earliest gene to be identified was DNA11, by candidate gene testing, followed by DNAH5 using homozygosity gene mapping in a population composed of large families of consanguineous origin, with one or more affected members.
The first method used for genetic testing in PCD was family-based genome wide linkage studies, combining the data obtained from many different families with one or more members suffering from this condition. This was unsuccessful in that it lacked the power to detect causative mutations in PCD due to the genetic diversity of the syndrome.
Genetic testing was then focused on, picking up the DNAI1 and DNAH5 mutations which were most commonly involved (30-35% of cases) in the causation of PCD. Sequence analysis, in the traditional approach, is followed by targeted analysis involving gene duplication and deletion if only one defective variant has been found to be present. Specific mutations in certain genes are selected if the person has ancestry from high-risk groups such as Ashkenazi Jews.
However, this is not sufficiently sensitive in PCD due to its heterogeneous nature. In addition, two different mutations are often present in the same gene and both need to be detected for the diagnosis. It is not, obviously, cost-effective to screen for a large number of genes in each patient.
Whole-exome sequencing offers a more inexpensive and rapid way to identify new genes. This is still in the research area but may become a first-line test soon.
Many genetic technologies are being used in this research area, such as:
The technique of genetic sequencing by whole exome or genome analysis has resulted in the identification of new ciliary proteins, including those which are cytoplasmic, rather than structural ciliary elements. Some of these are also involved in preassembly tasks. These newly identified mutations involve DNAAF1, DNAAF3, and CCDC103.
These methods have been more successful in identifying more than 27 genes with mutations which lead to the development of PCD, such as DNAH5, DNAH11, DNA11, CCDC39, SPAG1, ZMYND10 and LRRC6. The OFD1 and RPRGR gene mutations also result in PCD but as part of a still wider syndrome, associated with orofaciodigital syndrome 1 and retinitis pigmentosa respectively.