Ciliary Dyskinesia, Primary, 20
A number sign (#) is used with this entry because primary ciliary dyskinesia-20 (CILD20) is caused by homozygous or compound heterozygous mutation in the CCDC114 gene (615038) on chromosome 19q13.
DescriptionCILD20 is an autosomal recessive ciliopathy characterized by infantile onset of chronic sinopulmonary infections resulting from immotile cilia and defective clearance. Patients may also have situs inversus or cardiac anomalies. Electron microscopy of respiratory epithelial cells shows absence of the outer dynein arms. Unlike other forms of CILD, patients with CILD20 do not appear to be infertile.
For a phenotypic description and a discussion of genetic heterogeneity of primary ciliary dyskinesia, see 244400.
Clinical FeaturesOnoufriadis et al. (2013) reported a large multigenerational consanguineous family from Volendam, North Holland, in which 8 individuals had primary ciliary dyskinesia. Eight additional patients with this disorder from 7 other families were also ascertained. Affected individuals presented with early neonatal respiratory symptoms, including cough, shortness of breath, pneumonia, increased mucus production, chronic respiratory infections, recurrent otitis media, atelectasis, and bronchiectasis. Six (38%) of patients had situs-related abnormalities, either complete left-right organ reversal or isolated thoracic/abdominal complications. Two had complex heart malformations. Patient respiratory epithelial cells showed abnormal ciliary motility with static cilia or few cilia with stiff, slow, twitching or flickering movement, and transmission electron microscopy showed loss of the outer dynein arms. There was also a decrease in expression of DNAH5 (603335) in patient cilia. Although infertility is usually associated with CILD, 5 affected individuals had offspring, and fertility problems were not noted. Sperm analysis of 1 patient showed normal count and motility.
Knowles et al. (2013) reported 6 patients from 4 families with CILD20. All patients had respiratory symptoms, but none had situs inversus, and infertility was not reported. Electron microscopic analysis of patient cells showed absence of the outer dynein arms. Patient nasal epithelial cells showed complete ciliary immotility in most cells, with some cells showing stiff and dyskinetic cilia.
InheritanceThe transmission pattern of CILD20 in the families reported by Onoufriadis et al. (2013) and Knowles et al. (2013) was consistent with autosomal recessive inheritance.
Molecular GeneticsIn affected members of a large multigenerational family from an isolated region of North Holland with primary ciliary dyskinesia-20, Onoufriadis et al. (2013) identified a homozygous mutation in the CCDC114 gene (742G-A; 615038.0001), demonstrated to result in a frameshift and premature termination. The mutation was identified by exome sequencing of 2 individuals, segregated with the disorder, and was also found in 8 patients from 7 additional families from this region. A second homozygous truncating mutation (615038.0002) was identified in a woman from the U.K. with a similar phenotype.
Simultaneously and independently, Knowles et al. (2013) identified homozygous and compound heterozygous mutations in the CCDC114 gene (615038.0001 and 615038.0002-615038.0005) in 6 patients from 4 families with CILD20. All carried the 742G-A transition on at least 1 allele, and all shared a common haplotype surrounding that mutation.
Population GeneticsOnoufriadis et al. (2013) reported 9 families with CILD20 from Volendam, a small fishing village in North Holland that has been genetically isolated for geographic and religious reasons since the 15th century. All affected individuals were homozygous for the same mutation (742G-A; 615038.0001), and haplotype analysis indicated a founder effect. However, the mutation was estimated to have occurred prior to the founding of the Volendam village in 1462. Knowles et al. (2013) also observed a founder effect among 6 CILD patients with the 742G-A allele.