Ciliary Dyskinesia, Primary, 12

A number sign (#) is used with this entry because primary ciliary dyskinesia-12 (CILD12) is caused by homozygous mutation in the RSPH9 gene (612648) on chromosome 6p21.

For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).

Clinical Features

Castleman et al. (2009) reported 2 unrelated but consanguineous Bedouin families with primary ciliary dyskinesia. One family was from the United Arab Emirates (Emirati), and the other was from Israel. 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. One patient had a collapsed lower pulmonary lobe. Electron microscopic studies of affected individuals in 1 family showed an unusual intermittent loss of the central pair of the cilia, such that cilia cross-sections showed a small proportion with 9 + 0 structure in addition to the normal 9 + 2 structure. In the other family, electron microscopy showed a normal axoneme ultrastructure. However, this family was included in the study because of respiratory symptoms, dysmotility of the respiratory cilia, and sperm dysmotility, all consistent with a diagnosis of CILD. Cilia-motility studies showed an abnormal circular movement with a close to normal beat velocity in both families. No patients had laterality defects.


Bianchi et al. (1992) found linkage to the HLA locus on chromosome 6p21 in 2 Italian families, each with 2 sibs affected with CILD. All 4 affected sibs, a male and a female in one family and 2 females in the other, shared the HLA-DR7;DQw2 haplotype. Furthermore, linkage of an ICS susceptibility locus with 6p21 was suggested by the fact that the affected sibs were HLA-identical, whereas the healthy brother in the second family was HLA-different.

By genomewide linkage analysis of an Israeli Bedouin family and an Emirati Bedouin family, both with primary ciliary dyskinesia, Castleman et al. (2009) defined a common 1.9-Mb region on chromosome 6p21.1 between markers D6S400 and rs3734693 (multipoint lod score of 6.7 across D6S1604 to D6S451).

Molecular Genetics

In all 7 affected members of the Israeli Bedouin and Emirati Bedouin families with CILD12, Castleman et al. (2009) identified a homozygous deletion in the RSPH9 gene (612648.0001).

Kott et al. (2013) identified pathogenic homozygous mutations in the RSPH9 gene (see, e.g., 612647.0002 and 612647.0003) in 7 families with CILD12. None of the patients had situs inversus. RSPH9 mutations accounted for 8.3% (4 of 48 families) of cases with the specific CILD phenotype characterized by ciliary central microtubule complex and radial spoke defects.

Population Genetics

Reish et al. (2010) found only a small 1.9-Mb region of homozygosity that showed identity by descent at the chromosome 6p21.1 locus that was shared between the Israeli Bedouin and Emirati Bedouin families with CILD12 reported by Castleman et al. (2009). Haplotype analysis suggested that the most recent common ancestor carrying the mutation was less than 17 generations ago in the Emirati family and less than 95 generations ago in the Israeli family. If the mutations in the 2 families are identical by descent, the mutation probably arose about 150 generations ago. However, the population genetic analysis could not determine whether the mutation was descended from a common ancestor or occurred as 2 independent events.