Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11).
To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology.
82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease.
Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations.
Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.
"One of the patients had Kartagener syndrome. Knowles et al.  sequenced DNAH11 in patients with a PCD clinical phenotype without a known genetic etiology and found that 69% had nonsense, insertion/deletion or loss of function splice site mutation and 22% had biallelic mutations in DNAH11. "
[Show abstract][Hide abstract] ABSTRACT: A 20 year old male was initially diagnosed suffering from Primary ciliary dyskinesia with symptoms of bronchiectasis, severe frontal, maxillary and ethmoid sinus disease. At the age of 20, the patient was also diagnosed with Myelodysplastic syndrome requiring Bone marrow transplant due to the advanced stage at time of presentation. Primary ciliary dyskinesia and Myelodsyplastic syndrome are both rare clinical conditions found in the general population, especially in young adults. This rare combination of disorders has never been reported in literature to the best of the author's knowledge. The presence of an advanced cancer and a genetic abnormality due to two deletions occurring in two arms of the same chromosome can be explained on the base of chromothripsis. A number of evidences have been published in the literature, about multiple deletions in chromosome 5 and advanced stages of MDS being associated with chromothripsis however this is the first case report on two deletions in chromosome 7 giving rise to two different clinical entities requiring multiple modes of management.
[Show abstract][Hide abstract] ABSTRACT: Primary ciliary dyskinesia (PCD) is a rare disorder with variable disease progression. To date, mutations in more than 20 different genes have been found. At present, PCD subtypes are described according to the ultrastructural defect on transmission electron microscopy (TEM) of the motile cilia. PCD with normal ultrastructure (NU) is rarely reported because it requires additional testing. Biallelic mutations in DNAH11 have been described as one cause of PCD with NU.The aim of our study was to describe the clinical characteristics of a large population of patients with PCD, in relation to the ultrastructural defect. Additionally, we aimed to demonstrate the need for biopsy and cell culture to reliably diagnose PCD, especially the NU subtype.
We retrospectively analyzed data from 206 patients with PCD. We compared the clinical characteristics, lung function, microbiology and imaging results of 68 patients with PCD and NU to those of 90 patients with dynein deficiencies and 41 patients with central pair abnormalities. In addition, we aimed to demonstrate the robustness of the diagnosis of the NU subtype in cell culture by data from genetic analysis.
PCD with NU comprised 33% (68/206) of all patients with PCD. Compared to other subtypes, patients with PCD and NU had a similar frequency of upper and lower respiratory tract problems, as well as similar lung function and imaging. With the currently widely applied approach, without cell culture, the diagnosis would have been missed in 16% (11/68) of patients with NU. Genetic analysis was performed in 29/68 patients with PCD and NU, and biallelic mutations were found in 79% (23/29) of tested patients.
We reported on the clinical characteristics of a large population of patients with PCD and NU. We have shown that systematic performance of biopsy and cell culture increases sensitivity to detect PCD, especially the subtype with NU.PCD with NU has similar clinical characteristics as other PCD types and requires biopsy plus ciliogenesis in culture for optimal diagnostic yield.
"More recently, mutations in several genes coding for several cytoplasmic proteins not found in the axoneme have been linked to PCD. These proteins are presumed to have roles in cilia assembly or protein transport, and mutations lead to ultrastructural abnormalities: HEATR2, DNAAF1, DNAAF2, DNAAF3, CCDC103, LRRC6, and CCDC114 (30, 42-44, 50-68). Little is known about most of these proteins, but their association with PCD has contributed to advances in our knowledge of cilia biogenesis. "
[Show abstract][Hide abstract] ABSTRACT: Abnormal ciliary axonemal structure and function are linked to the growing class of genetic disorders collectively known as ciliopathies, and our understanding of the complex genetics and functional phenotypes of these conditions has rapidly expanded. While progress in genetics and biology has uncovered numerous cilia-related syndromes, primary ciliary dyskinesia (PCD) remains the sole genetic disorder of motile cilia dysfunction. The first disease-causing mutation was described just thirteen years ago, and since that time the pace of gene discovery has quickened. These mutations separate into genes that encode axonemal motor proteins, structural and regulatory elements, and cytoplasmic proteins that are involved in assembly and preassembly of ciliary elements. These findings have yielded novel insights into the processes involved in ciliary assembly, structure, and function, which will allow us to better understand the clinical manifestations of primary ciliary dyskinesia. Moreover, advances in techniques for genetic screening and sequencing are improving diagnostic approaches. In this manuscript, we will describe the structure, function, and emerging genetics of respiratory cilia, review the genotype-phenotype relationships of motor ciliopathies, and explore the implications of recent discoveries for diagnostic testing for primary ciliary dyskinesia.Pediatric Research (2013); doi:10.1038/pr.2013.200.
Pediatric Research 11/2013; 75. DOI:10.1038/pr.2013.200 · 2.31 Impact Factor
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