Ciliary Dyskinesia, Primary, 24

A number sign (#) is used with this entry because primary ciliary dyskinesia-24 (CILD24) is caused by homozygous or compound heterozygous mutation in the RSPH1 gene (609314) on chromosome 21q22.

Description

Primary ciliary dyskinesia-24 is an autosomal recessive disorder resulting from defects of motile cilia. It is characterized clinically by sinopulmonary infection and subfertility; situs inversus is not observed. Ultrastructural examination of mutant cilia shows defects of the central microtubule complex and radial spokes (summary by Kott et al., 2013).

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

Clinical Features

Kott et al. (2013) reported 12 patients from 10 unrelated families with primary ciliary dyskinesia. Affected individuals had a sinopulmonary syndrome characterized by otitis, rhinosinusitis, bronchiectasis, chronic obstructive pulmonary disease, and, in some cases, neonatal respiratory distress. Four patients studied, including 3 females and 1 male, had subfertility. None of the 12 patients had situs inversus. Cilia on patient respiratory epithelial cells showed variable abnormal beating patterns; motility in 1 patient was absent. Electron microscopy showed central microtubule complex and radial spoke defects in 19 to 70% of cilia. Some patients showed decreased nasal nitric oxide, but this was not a consistent finding.

Onoufriadis et al. (2014) reported 2 unrelated girls with CILD without situs inversus. Both had typical symptoms of primary ciliary dyskinesia, including neonatal respiratory distress and chronic symptoms of productive cough, rhinitis and sinusitis, recurrent respiratory infections, and bronchiectasis. Both also had recurrent ear infections and otitis media, resulting in hearing problems. Nasal nitric oxide was reduced in 1 patient. The other patient had 2 similarly affected sibs. Transmission electron microscopy of patient respiratory cilia showed a loss of the central pair apparatus with a 9+0 pattern in 11 to 30% of cilia. There was also occasional transposition of peripheral outer microtubules into the empty central pair (CP) space (8+1) toward the distal end of the cilia. The ciliary beat frequency was normal, but there was a mixed beat waveform, with mostly stiff, unbending, and uncoordinated cilia of reduced amplitude. Immunofluorescent studies showed loss of the spoke head structure, leaving the spoke stalk structure intact.

Inheritance

The transmission pattern of CILD24 in the families reported by Kott et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 12 patients from 10 families with CILD without situs inversus, Kott et al. (2013) identified 7 biallelic mutations in the RSPH1 gene (see, e.g., 609314.0001-609314.0005). The mutation in the first patient was found by a combination of homozygosity mapping and whole-exome sequencing. The subsequent mutations were found in patients from a larger cohort of 36 families with CILD and central complex and radial spoke defects. Respiratory cilia from 1 affected individual showed undetectable RSPH1 protein, consistent with a loss of function. RSPH1 mutations accounted for 20.8% of the 48 families studied with this specific phenotype. Kott et al. (2013) noted that patients with RSPH1 mutations do not have situs inversus because central complex defects do not affect the 9+0 structure of embryonic nodal cilia.

In 2 unrelated patients with CILD24, Onoufriadis et al. (2014) identified biallelic mutations in the RSPH1 gene (609314.0001, 609314.0004, 609314.0006). The mutations, which were found by next-generation sequencing, segregated with the disorder in the families.