RT Journal Article
SR Electronic
T1 Whole Exome Sequencing Accuracy in the Diagnosis of Primary Ciliary Dyskinesia
JF ERJ Open Research
JO erjor
FD European Respiratory Society
SP 00213-2020
DO 10.1183/23120541.00213-2020
A1 Alex Gileles-Hillel
A1 Hagar Mor-Shaked
A1 David Shoseyov
A1 Joel Reiter
A1 Reuven Tsabari
A1 Avigdor Hevroni
A1 Malena Cohen-Cymberknoh
A1 Israel Amirav
A1 Shuli Brammli-Greenberg
A1 Amjad Horani
A1 Eitan Kerem
A1 Oded Breuer
YR 2020
UL http://openres.ersjournals.com/content/early/2020/09/17/23120541.00213-2020.abstract
AB The diagnosis of Primary Ciliary Dyskinesia (PCD) relies on clinical features and sophisticated studies. The detection of bi-allelic disease-causing variants confirms the diagnosis. However, a standardised genetic panel is not widely available and new disease-causing genes are continuously identified.To assess the accuracy of untargeted whole-exome sequencing (WES) as a diagnostic tool for PCD, patients with symptoms highly suggestive of PCD were consecutively included. Patients underwent measurement of nasal nitric oxide (nNO) levels, ciliary transmission electron microscopy analysis (TEM) and WES. A confirmed PCD diagnosis in symptomatic patients was defined as a recognised ciliary ultrastructural defect on TEM and/or two pathogenic variants in a known PCD-causing gene.Forty-eight patients (46% male) were enrolled, with a median age of 10.0 years (range 1.0–37 years). In 36 patients (75%) a diagnosis of PCD was confirmed, of which 14 (39%) patients had normal TEM. A standalone untargeted WES had a diagnostic yield of 94%, identifying bi-allelic variants in eleven known PCD causing genes in 34 subjects. A nNO<77 nL·min was nonspecific when including patients younger than 5 years (area under the ROC curve (AUC) 0.75 (95%CI, 0.60–0.90)). Consecutive WES considerably improved the diagnostic accuracy of nNO in young children (AUC 0.97 (95%CI, 0.93–1). Finally, WES established an alternative diagnosis in four patients.In patients with clinically suspected PCD and low nNO levels, WES is a simple, beneficial and accurate next step to confirm the diagnosis of PCD or suggest an alternative diagnosis, especially in preschool-aged children in whom nNO is less specific.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of interest: Dr. Gileles-Hillel has nothing to disclose.Conflict of interest: Dr. Mor-Shaked has nothing to disclose.Conflict of interest: Dr. Shoseyov has nothing to disclose.Conflict of interest: Dr. Reiter has nothing to disclose.Conflict of interest: Dr. Tsabari has nothing to disclose.Conflict of interest: Dr. Hevroni has nothing to disclose.Conflict of interest: Dr. Cohen-Cymberknoh has nothing to disclose.Conflict of interest: Dr. Amirav has nothing to disclose.Conflict of interest: Dr. Brammli-Greenberg has nothing to disclose.Conflict of interest: Dr. Horani has nothing to disclose.Conflict of interest: Dr. Kerem has nothing to disclose.Conflict of interest: Dr. Breuer has nothing to disclose.