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
VO 6
IS 4
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/6/4/00213-2020.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 11 known PCD-causing genes in 34 subjects. A nNO<77 nL·min was nonspecific when including patients younger than 5 years (area under the receiver operating characteristic 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.Untargeted whole-exome sequencing in subjects with clinical symptoms highly suggestive of PCD has an excellent diagnostic accuracy and, as prices drop, may be the genetic test of choice for confirming PCD or establishing an alternative diagnosis https://bit.ly/3j2jMbu