Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia.

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.