An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia
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ORIGINAL INVESTIGATION
An exome‑first approach to aid in the diagnosis of primary ciliary dyskinesia Hanan E. Shamseldin1 · Ibrahim Al Mogarri2 · Mansour M. Alqwaiee3 · Adel S. Alharbi3 · Khaled Baqais3 · Muslim AlSaadi4 · Talal AlAnzi3 · Amal Alhashem3,7 · Afaf Saghier2 · Waleed Ameen5 · Niema Ibrahim1 · Jason Yang6 · Firdous Abdulwahab1 · Mais Hashem1 · Raghu R. Chivukula6 · Fowzan S. Alkuraya1,7 Received: 19 December 2019 / Accepted: 25 April 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Unlike disorders of primary cilium, primary ciliary dyskinesia (PCD) has a much narrower clinical spectrum consistent with the limited tissue distribution of motile cilia. Nonetheless, PCD diagnosis can be challenging due to the overlapping features with other disorders and the requirement for sophisticated tests that are only available in specialized centers. We performed exome sequencing on all patients with a clinical suspicion of PCD but for whom no nasal nitric oxide test or ciliary functional assessment could be ordered. Among 81 patients (56 families), in whom PCD was suspected, 68% had pathogenic or likely pathogenic variants in established PCD-related genes that fully explain the phenotype (20 variants in 11 genes). The major clinical presentations were sinopulmonary infections (SPI) (n = 58), neonatal respiratory distress (NRD) (n = 2), laterality defect (LD) (n = 6), and combined LD/SPI (n = 15). Biallelic likely deleterious variants were also encountered in AKNA and GOLGA3, which we propose as novel candidates in a lung phenotype that overlaps clinically with PCD. We also encountered a PCD phenocopy caused by a pathogenic variant in ITCH, and a pathogenic variant in CEP164 causing Bardet–Biedl syndrome and PCD presentation as a very rare example of the dual presentation of these two disorders of the primary and motile cilia. Exome sequencing is a powerful tool that can help “democratize” the diagnosis of PCD, which is currently limited to highly specialized centers.
Introduction Unlike ubiquitously distributed primary cilia, motile cilia are only observed in a few cell types: respiratory epithelium, ependymal lining of brain ventricles, oviducts, and embryonic node, while the sperm flagellum displays a highly similar structure (Horani et al. 2016). Dysfunction of motile cilia results in a predictable set of clinical features that are consistent with the established role and distribution of these dynamic structures (Leigh et al. 2016). Impaired mucociliary clearance by the respiratory epithelium results in chronic Hanan E. Shamseldin and Ibrahim Al Mogarri have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02170-2) contains supplementary material, which is available to authorized users. * Fowzan S. Alkuraya [email protected] Extended author information available on the last page of the article
respiratory infections that manifest as chronic non-seasonal rhinorrhea, sinusitis, and che
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