Ciliary Dyskinesia, Primary, 40

A number sign (#) is used with this entry because of evidence that primary ciliary dyskinesia-40 (CILD40) with situs inversus is caused by homozygous or compound heterozygous mutation in the DNAH9 gene (603330) on chromosome 17p12.

Description

CILD40 is an autosomal recessive primary ciliary dyskinesia with a relatively mild respiratory phenotype compared to other CILDs. Patients present in childhood with mild upper respiratory symptoms and infections, but typically do not develop serious lung disease. Nitric oxide levels are low-normal or normal. All reported patients have had situs inversus, including several with severe congenital cardiac malformations, but left-right body asymmetry is still theoretically random and would occur in 50% of patients (summary by Loges et al., 2018).

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

Clinical Features

Fassad et al. (2018) reported 4 patients from 3 unrelated families, 2 of which were consanguineous, with primary ciliary dyskinesia. None of the patients had neonatal respiratory distress, but all presented in childhood with rhinosinusitis, chronic cough, and situs inversus. One patient had complex congenital heart disease. Nasal nitric oxide levels were within or close to the normal range, and lung function was essentially normal; none had bronchiectasis. Ciliary beat frequencies were at the low end of the normal range, there was a subtle defect in the bend of the cilia in the distal portion, and the cilia showed decreased ciliary clearance in in vitro studies. One male who was tested had marked azoospermia, with only 3% of sperm having preserved motility.

Loges et al. (2018) reported 5 unrelated patients with CILD40 with situs inversus. They had only mild respiratory symptoms, such as recurrent cold-like infections. Nasal nitric oxide was mildly decreased compared to controls. One patient with severe congenital cardiac malformations died at age 8 days.

Inheritance

The transmission pattern of CILD40 in the families reported by Fassad et al. (2018) and Loges et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 3 unrelated families with CILD40, Fassad et al. (2018) identified homozygous or compound heterozygous mutations in the DNAH9 gene (603330.0001-603330.0004). The mutations, which were found by targeted next-generation sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the families from whom familial DNA was available. Western blot and immunofluorescence studies of patient-derived nasal brushings showed reduced or absent DNAH9 expression in the cilia of respiratory epithelial cells, particularly at the distal end of type 2 outer dynein arms where DNAH9 is usually located. DNAH5 (603335) levels were also decreased in the distal portion of type 2 outer dynein arms. Transmission electron microscopy of patient cilia showed ultrastructural defects and decreased volume of the distal portion of outer dynein arms, and motility studies showed a reduced ciliary beating frequency and a subtle beating pattern defect compared to controls. RNAi silencing of Dnah9 in Paramecium caused a reduction of swimming velocity and ciliary beat frequency, as well a loss of the outer dynein arms compared to controls.

In 5 patients from unrelated families with CILD40, Loges et al. (2018) identified 8 different homozygous or compound heterozygous mutations in the DNAH9 gene (see, e.g., 603330.0005-603330.0008). The mutations, which were found by a combination of sequencing approaches and confirmed by Sanger sequencing, segregated in the families from whom DNA was available. Seven of the mutations represented putative null alleles, including splice site, nonsense, and frameshift mutations, consistent with a loss of function. The patients were ascertained from several cohorts of patients and through the GeneMatcher database. Analysis of respiratory epithelial cells from 3 patients showed normal ciliary beat frequency, but an abnormal beat pattern with reduced bending of the distal ciliary axoneme compared to controls. Immunofluorescence studies showed complete absence of DNAH9 and decreased levels of DNAH5 from the distal ciliary axoneme. Levels of DNAI1 (604366) and DNAI2 (605483) were also decreased, indicating a central role of DNAH9 in the assembly of type 2 distal axonemal arms. Ultrastructural analysis of 1 patient's cilia showed absence of outer dynein arms specifically from the distal axoneme.