Research Article: Genomic profiling supports the diagnosis of primary ciliary dyskinesia and reveals novel candidate genes and genetic variants

Date Published: October 9, 2018

Publisher: Public Library of Science

Author(s): Marina Andjelkovic, Predrag Minic, Misa Vreca, Maja Stojiljkovic, Anita Skakic, Aleksandar Sovtic, Milan Rodic, Vesna Skodric-Trifunovic, Nina Maric, Jelena Visekruna, Vesna Spasovski, Sonja Pavlovic, Mohammad R. Akbari.


Primary ciliary dyskinesia (PCD) is a rare inherited autosomal recessive or X-linked disorder that mainly affects lungs. Dysfunction of respiratory cilia causes symptoms such as chronic rhinosinusitis, coughing, rhinitis, conductive hearing loss and recurrent lung infections with bronchiectasis. It is now well known that pathogenic genetic changes lead to ciliary dysfunction. Here we report usage of clinical-exome based NGS approach in order to reveal underlying genetic causes in cohort of 21 patient with diagnosis of PCD. By detecting 18 (12 novel) potentially pathogenic genetic variants, we established the genetic cause of 11 (9 unrelated) patients. Genetic variants were detected in six PCD disease-causing genes, as well as in SPAG16 and SPAG17 genes, that were not detected in PCD patients so far, but were related to some symptoms of PCD. The most frequently mutated gene in our cohort was DNAH5 (27.77%). Identified variants were in homozygous, compound heterozygous and trans-heterozygous state. For detailed characterization of one novel homozygous genetic variant in DNAI1 gene (c. 947_948insG, p. Thr318TyrfsTer11), RT-qPCR and Western Blot analysis were performed. Molecular diagnostic approach applied in this study enables analysis of 29 PCD disease-causing and related genes. It resulted in mutation detection rate of 50% and enabled discovery of twelve novel mutations and pointed two possible novel PCD candidate genes.

Partial Text

Primary ciliary dyskinesia (PCD (OMIM #244400)) is a rare inherited autosomal recessive or X-linked disorder, which affects lungs, reproductive organs, and organ laterality. Major characteristics of PCD are ultrastructural defects of cilia leading to ciliary immotility or abnormal ciliary motility [1, 2]. PCD presents with neonatal respiratory distress in 80% of cases, recurring acute rhinosinusitis [3], rhinitis [4], sinusitis, conductive hearing loss due to otitis media, recurrent or chronic lung infections with bronchiectasis and progressively declining lung function[5]. Since motile cilia are present throughout the respiratory tract, every loss of structural/functional integrity of cilia leads to disorder in the primary innate defense mechanism of mucociliary clearance [6]. Around 50% of PCD patients have situs inversus (SI) [3], and reduced fertility in males and females is observed [7, 8]. The estimated prevalence of PCD is 1 in 15.000–30.000 live births, but recent studies propose that prevalence is higher in consanguineous populations[9]. Early recognition of PCD and the correct diagnosis are often delayed due to the clinical symptoms overlapping with other chronic airway disorders.

In the present study, we analysed the largest PCD cohort from Southeastern Europe ever reported. This is the first study which includes the genetic and molecular profiling, as well as phenotypic characterisation of PCD patients of Serbian ethnicity. Although large cohorts of PCD patients have been reported in Europe, only a small number of studies included molecular analysis of PCD patients [17, 20, 21, 27]. More often they included individual families or analysis of specific genes [22, 25, 28, 29]. Usage of custom-made population-specific platforms is convenient for detailed analysis of known PCD causative genes, but omits to detect novel candidate genes. Such limitations are circumvent by usage of whole-exome or whole-genome approaches. The approach presented in this study enables analysis of all exons of genes reported to be related to some human disorder, and thus enables discovery of potential candidate genes for PCD. The main limitation of this panel is the lack of all known PCD related genes, which can result in unresolved cases and lack of final genetic diagnosis.




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