Review
Primary ciliary dyskinesia in the genomics age

https://doi.org/10.1016/S2213-2600(19)30374-1Get rights and content

Summary

Primary ciliary dyskinesia is a genetically and clinically heterogeneous syndrome. Impaired function of motile cilia causes failure of mucociliary clearance. Patients typically present with neonatal respiratory distress of unknown cause and then continue to have a daily wet cough, recurrent chest infections, perennial rhinosinusitis, otitis media with effusion, and bronchiectasis. Approximately 50% of patients have situs inversus, and infertility is common. While understanding of the underlying genetics and disease mechanisms have substantially advanced in recent years, there remains a paucity of evidence for treatment. Next-generation sequencing has increased gene discovery, and mutations in more than 40 genes have been reported to cause primary ciliary dyskinesia, with many other genes likely to be discovered. Increased knowledge of cilia genes is challenging perceptions of the clinical phenotype, as some genes reported in the last 5 years are associated with mild respiratory disease. Developments in genomics and molecular medicine are rapidly improving diagnosis, and a genetic cause can be identified in approximately 70% of patients known to have primary ciliary dyskinesia. Groups are now investigating novel and personalised treatments, although gene therapies are unlikely to be available in the near future.

Introduction

Primary ciliary dyskinesia is a rare syndrome, characterised by extensive genetic heterogeneity and clinical variability. Mutations in over 40 genes have been reported to cause this syndrome, and genes continue to be discovered. Abnormal ciliary function leads to unexpected neonatal respiratory distress in term infants, persistent wet cough from early infancy, bronchiectasis, chronic rhinosinusitis, and conductive hearing impairment; 50% of patients have situs inversus, and infertility is common.1 Disease progression is highly variable, with some patients maintaining reasonably good lung function and quality of life into later adulthood, whereas other patients have worse outcomes.2, 3, 4, 5 Evidence shows that mutations in different genes lead to variable phenotypes; for example, some genes are never associated with situs anomalies, and variants in other genes are more likely to cause infertility.6, 7 A few studies have suggested an association between some genes and the severity of pulmonary disease, but the evidence remains scarce.8, 9, 10, 11

Primary ciliary dyskinesia is estimated to affect 1 in 10 000 to 1 in 15 000 Europeans and is more common in populations with closed genetic pools;12, 13, 14 interestingly, genetic heterogeneity is seen in socially isolated consanguineous populations.15, 16 Estimates of prevalence are scarce outside of Europe, but primary ciliary dyskinesia is expected to be more common in certain populations (eg, in Arab countries).17, 18 A survey of specialists in Europe reported that only a small proportion of patients estimated to have primary ciliary dyskinesia have been diagnosed, and that 37% of patients reported in an international survey that they had visited a doctor for primary ciliary dyskinesia-related symptoms more than 40 times before being referred for testing.12, 19 The reasons for underdiagnosis are multifactorial, including difficulty accessing diagnostic services and the lack of awareness of the syndrome among general physicians.19 Symptoms are non-specific, and patients with situs inversus, which is rare in the general population, are diagnosed earlier than those with normal organ positioning.12 Clinical tools have been developed to help physicians identify patients for testing,20, 21 but these tools are based on typical symptoms; however, awareness of genotypes associated with atypical presentations is increasing.

As with other rare diseases, the evidence for treating patients with primary ciliary dyskinesia is scarce. In addition to the few small studies for this syndrome, consensus guidelines are based on evidence from more common disorders, such as cystic fibrosis and chronic rhinosinusitis.22, 23

Key messages

  • Primary ciliary dyskinesia is a syndrome caused by mutations in genes responsible for structure and function of motile cilia; although mutations have been identified in more than 40 responsible genes, the genetic cause of this syndrome is not known in approximately 25% of patients

  • A diagnosis of primary ciliary dyskinesia can be confirmed by identification of a hallmark ultrastructural defect by transmission electron microscopy or bi-allelic pathogenic mutations in a known primary ciliary dyskinesia gene

  • Genetic advances are identifying patients with atypical presentations of primary ciliary dyskinesia and have confirmed some overlaps with non-motile ciliopathies

  • No diagnostic test is perfect for primary ciliary dyskinesia; therefore, diagnosis relies on a combination of tests and no test can be used in isolation

  • Some genotype–phenotype associations have been described in small studies. International collaborations and prospective registries are needed to properly understand these associations

  • In the absence of disease-specific evidence, respiratory management of primary ciliary dyskinesia is based on evidence from cystic fibrosis. Guidelines for primary ciliary dyskinesia recommend regular airway clearance and treatment of pulmonary exacerbations with antibiotics for all patients. Early steps towards personalised medicine are being taken in light of genetic understanding

In this Review, we discuss the information available regarding the underlying mechanisms of primary ciliary dyskinesia and how this knowledge might inform our understanding of clinical presentation and natural disease progression. We review current diagnostic and management strategies for patients with primary ciliary dyskinesia. We will discuss how the improving knowledge of primary ciliary dyskinesia genetics is affecting the understanding of the phenotype, the conduct of diagnostic testing, and management of patients. We reflect on the expanding phenotype, and how this challenges the definition of primary ciliary dyskinesia.

Section snippets

Clinical features

Patients with primary ciliary dyskinesia usually present with a classic clinical phenotype.1, 20, 21, 24 Defining and understanding these manifestations allows for earlier recognition and identification of these patients. In primary ciliary dyskinesia, more than 80% of the population will present with respiratory distress at birth despite being born at term. This distress typically occurs 12–24 h after birth and many infants require prolonged oxygen because of hypoxaemia.25 Furthermore, chest

Diagnosis

Multiple investigations are usually required to make a diagnosis of primary ciliary dyskinesia. Two evidence-based diagnostic guidelines have been published by the European Respiratory Society34 (ERS) and by the American Thoracic Society (ATS).38 Both guidelines recognise that there is no perfect diagnostic test for primary ciliary dyskinesia. Most tests used have low sensitivity and specificity, specialist equipment and expertise are required, and consequently access to testing can be

Genetics and disease mechanisms

Mutations of more than 40 different genes have been reported that cause primary ciliary dyskinesia (figure 1). Most primary ciliary dyskinesia variants are transmitted in an autosomal recessive fashion. However, X chromosomal recessive inheritance has also been reported for a few genes.59, 60 Motility of respiratory cilia is generated and regulated by complex mechanisms involving several large multimeric protein complexes. Mutations affecting many of these proteins can result in primary ciliary

Genotype–phenotype relationships

Delineation of genotype–phenotype relationships have recently been described in the primary ciliary dyskinesia population. Patients with absent inner dynein arm with microtubular disorganisation who have a CCDC39 or CCDC40 mutation, have lower body-mass indices and worse lung function that declines more rapidly compared with the primary ciliary dyskinesia population with outer dynein arm defects and those whom have a DNAH5 mutation, respectively.9 Interestingly, patients with microtubular

Syndromes associated with primary ciliary dyskinesia

Advances in imaging and genotyping have revealed primary ciliary dyskinesia-like features in some patients with non-motile ciliopathies. Non-motile primary cilia have a role in cell signalling and sensing of the extracellular environment. Symptoms among ciliopathies include polycystic kidneys, skeletal abnormalities, developmental delay, and retinal degeneration. Increasingly, abnormalities in motile cilia are described in several non-motile ciliopathies, including Jeune syndrome,106

Management

Since there is no cure for primary ciliary dyskinesia, the aim of treatment is to delay the decline in pulmonary airways disease, while maintaining patients’ health, social, and psychological wellbeing. The variability in clinical manifestations and the scarcity of data from clinical trials makes the creation of a standardised management plan that is suitable for all patients difficult. Management is often extrapolated from other diseases, such as cystic fibrosis and chronic rhinosinusitis.

Conclusion

Primary ciliary dyskinesia is a syndrome caused by genetic mutations effecting motile cilia, causing disease of the upper and lower airways. Next-generation sequencing has led to advances in the discovery of new primary ciliary dyskinesia genes over the past decade, and over 40 genes are now reported to cause this rare disease. This remarkable progress is affecting diagnostic capabilities, genetic counselling, and has the potential to lead to new therapeutic options and personalised care.

The

Search strategy and selection criteria

This manuscript is not a systematic review but consists of the authors’ expert knowledge of the disease area informed by the literature. We searched PubMed, for evidence relating to primary ciliary dyskinesia in the English language from Jan 1, 2000 to Nov 25, 2018: using the search term “primary ciliary dyskinesia” in combination with (diagnosis; clinical symptoms/clinical presentation/phenotype; treatment/clinical trial). After identifying eligible studies, we checked for additional citations

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