Ciliary Dyskinesia, Primary, 38

A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-38 (CILD38) is caused by homozygous or compound heterozygous mutation in the CFAP300 gene (618058) on chromosome 11q22.

Description

Primary ciliary dyskinesia-38 is an autosomal recessive disorder characterized by chronic airway disease and recurrent sinopulmonary infections beginning in infancy and caused by defective ciliary function. Affected individuals often have neonatal respiratory distress and may later have infertility. About half of patients have laterality defects due to ciliary dysfunction in early embryonic development (summary by Fassad et al., 2018 and Hoben et al., 2018).

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

Clinical Features

Fassad et al. (2018) reported 3 boys from 2 unrelated families with CILD. One of the families was consanguineous and of Pakistani origin (family 1), whereas the other was nonconsanguineous and of Indian origin (family 2). The patients presented early in life with typical symptoms, including neonatal respiratory distress, chronic wet cough, and rhinitis. Studies of 1 patient showed decreased nasal nitric oxide. Dextrocardia or situs abnormalities were observed in all 3 patients. Dynamic examination of nasal respiratory epithelial cells showed completely immotile cilia, and ultrastructural analysis showed significant loss of both the inner and outer dynein arms of the cilia.

Hoben et al. (2018) reported 5 unrelated patients with CILD38. They had classic features of the disorder, including chronic sinusitis, chronic otitis media, and chronic lower respiratory tract infections, as well as bronchiectasis and mucus plugging. Three patients had neonatal respiratory distress syndrome, 1 patient had situs inversus totalis, and all patients had low nasal nitric oxide production. Two of the patients, a woman and a man, had infertility problems; the man had reduced numbers of sperm and immotility of sperm flagella. High-speed video-microscopy of nasal respiratory epithelial cells showed completely immotile cilia, and transmission electron microscopy analysis of respiratory cilia and sperm flagella showed defects in the outer and inner dynein arms.

Inheritance

The transmission pattern of CILD38 in the families reported by Fassad et al. (2018) and Hoben et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with CILD38, Fassad et al. (2018) identified homozygous or compound heterozygous mutations in the CFAP300 gene (618058.0001-618058.0003). The mutations, which were found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants were not performed, but patient nasal respiratory epithelial cells showed completely immotile cilia with significant loss of both the inner and outer dynein arms of the cilia, and immunostaining showed decreased levels of the outer dynein arm marker DNAH5 (603335) and the inner dynein arm marker DNALI1 (602135). The cilia had a normal 9+2 ultrastructure. The patients were part of a cohort of 161 unrelated individuals with primary ciliary dyskinesia who were screened.

In 5 unrelated patients with CILD38, Hoben et al. (2018) identified homozygous loss-of-function mutations in the CFAP300 gene (618058.0002, 618058.0004, and 618058.0005). Functional studies of the variants were not performed, but patient respiratory epithelial cells and sperm flagella showed immotile cilia with loss of the axonemal inner and outer dynein arms, and immunofluorescence studies showed absence of DNAH5 and DNAH9 (603330) in the outer dynein arms and absence of DNALI1 and DNAH6 (603336) in the inner dynein arms. The mutations were found by targeted exome sequencing of 15 probands with primary ciliary dyskinesia.