Primary ciliary dyskinesia (PCD) is a rare genetic disorder that causes abnormalities in mucociliary clearance in the respiratory epithelium (OMIM: 244400), leading to recurrent infections of the upper and lower airways [1]. Pathogenic variants of nearly 50 disease-causing genes, most of which have been determined to follow a pattern of autosomal recessive inheritance, have been identified to date (Table 1) [1, 2]. Depending on the causative genes, nodal ciliary movement is also hampered during the early embryonic stage, and laterality defects such as situs inversus and heterotaxy can occur, which has been known as Kartagener’s syndrome. When sperm flagellar motility is similarly impaired, it often results in male infertility. Female infertility and hydrocephalus caused by dysfunction of motile cilia lining respective tissues have also been reported. Otitis media and ear-related problems appear to improve with age, but upper- and lower-respiratory disease persists and usually gets more severe in adulthood. The incidence of the disease has generally been estimated at 1 in 10,000 to 20,000 live births. However, it is thought to be underestimated because the number of cases with a confirmed diagnosis is still limited, especially in Asia and Africa; moreover, the diagnostic guidelines used in the USA and Europe have not been globally integrated or standardized.

Table 1 A list of genes causing primary ciliary dyskinesia
Full size table

In a recent article, Xu Y., et al. summarized their previous findings and presented the results of PCD-related gene analyses in 66 Japanese families unrelated to each other [3]. Their findings make us focus on the difficulties in diagnosing this disease at an early stage. First, clinicians frequently assume that recurrent sinopulmonary infections are not related to a congenital disorder, particularly when the majority of patients do not display laterality defects; particularly in Asia, a disease characterized by similar symptoms is ambiguously referred to as “sinobronchial syndrome” or often clinically diagnosed as “diffuse panbronchiolitis” [4,5,6]. Usually, in such cases, no further efforts in seeking a definite diagnosis have been made. Second, all non-genetics-based tests used to aid the diagnosis of PCD, such as nasal nitric oxide (NO) measurements, immunofluorescence staining of key proteins, high-speed video microscopy to evaluate ciliary movement, and transmission electron microscopy-based analysis of ciliary ultrastructure, are not standardized for use with medical equipment, not widely accessible to patients, and not covered by health insurance in many countries. Third, although recent advances in next-generation sequencing techniques have enabled the simultaneous analysis of all exons of multiple PCD-associated genes, variants of unknown significance in a variety of such genes, and pathogenic variants identified in only one allele, make their interpretation quite difficult. Therein, we should carefully and clearly describe variants that contribute to a confirmed diagnosis separately from variants that are not genetically diagnostically certain. It is important to mention the limitations in variant characterization and accurate specification of variant zygosity [3]. Until a reasonable interpretation of the initially identified variants is achieved, these considerations should be taken into account. This includes highlighting the need for new molecular findings, such as the identification of splicing variants at loci distant from canonical exon locations and structural variants that disrupt gene function in the other allele [7]. Fourth, it has recently been reported that the distribution of disease-causing genes and pathogenic variants varies significantly based on ethnicity, and the clinical manifestations and severity of the disease are deeply influenced by the genetic heterogeneity [8]. Although DNAH5, DNAH11, DNAI1, CCDC39 and CCDC40 are the most common genes among genetically determined PCD cases in North America and Europe [1, 2], Morimoto et al. recently identified a biallelic 27,748 bp deletion spanning exons 1–4 of DRC1 in two patients of Japanese and Korean descent, but not in non-Asian populations [5]; subsequent studies have revealed that this large deletion appears to be the most common cause of PCD in Japanese and Korean populations, presumably as a founder mutation [3, 6, 9]. In PCD patients homozygous for this DRC1 variant, the production of nasal NO was generally low, no situs inversus was observed, and no striking abnormalities in ciliary ultrastructure could be detected by electron microscopy [7]. Therefore, in such a clinical setting, measurement of nasal NO levels can be strongly recommended as an initial screening method, followed by genetic analysis using a simple PCR-based detection system [5] and more advanced methods [7] to reach an accurate diagnosis in patients who often experience non-specific recurrent airway infections, that are common manifestations of chronic rhinosinusitis and bronchiectasis.

It might be considered that clinical relevance of genetic diagnosis is poor in PCD, because no specific gene therapy for improving impaired cilia motion is yet available; however, if a confirmed diagnosis is made, an intensive patient care protocol can be initiated; chest physiotherapy to promote sputum clearance, vaccination to prevent respiratory infections, appropriate use of antimicrobials to reduce exacerbations, smoking cessation, and exercise-based therapy are all important components of the management. It is recommended that authorities establish a system for providing lifelong medical care subsidies. Genetic counseling can be beneficial for patients and their families, particularly for those considering having children. Global collaborations among patient associations would be needed to avoid isolation, to share updates on the disease, and to ensure timely participation of patients if and when an international clinical trial is conducted. The first steps toward evidence-based treatment of PCD have already been taken; a recent multicenter phase-3 trial demonstrated that azithromycin reduced the incidence rate of exacerbations by half, and analysis of the already available in vitro data on the restoration of ciliary function is a crucial preliminary step to pave the way for developing new treatment strategies for PCD in the future [10].