Ciliary Dyskinesia, Primary, 11
A number sign (#) is used with this entry because primary ciliary dyskinesia-11 (CILD11) is caused by homozygous or compound heterozygous mutation in the RSPH4A gene (612647) on chromosome 6q22.
For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).
Clinical FeaturesCastleman et al. (2009) reported 5 families, 4 of whom were of Pakistani origin, with primary ciliary dyskinesia. Clinical features included reduced exercise tolerance, chronic wet cough, recurrent respiratory infections, bronchiectasis, and nasal symptoms such as rhinorrhea, rhinitis, nasal blockage, and sinusitis. There was also ear obstruction with consequent hearing problems, low weight, and short stature. Electron microscopic studies of affected individuals in all families showed an unusual complete loss of the central pair of the ciliary axoneme. Cilia-motility studies showed an abnormal circular movement with a close to normal beat velocity. Laterality defects were not observed.
Daniels et al. (2013) reported 10 patients from 8 unrelated families with CILD11 confirmed by genetic analysis. All had classic features of the disorder, including neonatal respiratory distress, otitis media, sinusitis, and bronchiectasis, as well as decreased nasal nitric oxide. None had situs inversus. Ultrastructural analysis of patient cilia showed that about 50% of cilia had normal structure, whereas 50% had central apparatus defects, including absence of the central pair (18%) and translocation of an outer doublet into the central region (12%), among other variable microtubule defects. Videomicroscopy showed decreased ciliary beat frequency, dyskinesia, and circular movement. Daniels et al. (2013) noted that the specialized motile cilia at the embryonic node does not have the central pair of microtubules (9+0 axonemal structure); therefore, altered left-right placement of organs during embryogenesis, or situs inversus, does not occur with mutations in genes involved in the radial spoke, such as RSPH4A. Radial spokes extend from the outer doublets to the central pair and provide support for the axonemal structure.
MappingBy genomewide linkage analysis of 5 families with primary ciliary dyskinesia and loss of the central microtubule pair of cilia, Castleman et al. (2009) found linkage to a 6.7-Mb region on chromosome 6q22.1 between rs2030926 and rs937091 (peak multipoint lod score of 7.0 across rs873460 to rs941815). Four Pakistani families shared a common haplotype, suggesting a founder effect.
Molecular GeneticsIn affected members of 4 Pakistani families with CILD11, Castleman et al. (2009) identified a homozygous mutation in the RSPH4A gene (612647.0001). In affected members of a family of northern European descent with CILD11, they identified compound heterozygosity for 2 mutations in the RSPH4A gene (612647.0002; 612647.0003).
Kott et al. (2013) identified pathogenic mutations in the RSPH4A gene (see, e.g., 612647.0004-612647.0005) in 7 (14%) of families with a specific CILD phenotype characterized by ciliary central microtubule complex and radial spoke defects. None of the patients had situs inversus.
Population GeneticsDaniels et al. (2013) identified a common founder mutation in the RSPH4A gene (612647.0006) in 9 patients with CILD11, all of whom had Puerto Rican ancestry. The mutation was thought to originate from the Taino Indians, which is the predominant maternal ancestry in Puerto Rico, rather than from Spanish colonization.