Cargando…

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 identifie...

Descripción completa

Detalles Bibliográficos
Autores principales: Gileles-Hillel, Alex, Mor-Shaked, Hagar, Shoseyov, David, Reiter, Joel, Tsabari, Reuven, Hevroni, Avigdor, Cohen-Cymberknoh, Malena, Amirav, Israel, Brammli-Greenberg, Shuli, Horani, Amjad, Kerem, Eitan, Breuer, Oded
Formato: Online Artículo Texto
Lenguaje:English
Publicado: European Respiratory Society 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792814/
https://www.ncbi.nlm.nih.gov/pubmed/33447612
http://dx.doi.org/10.1183/23120541.00213-2020
_version_ 1783633870032207872
author Gileles-Hillel, Alex
Mor-Shaked, Hagar
Shoseyov, David
Reiter, Joel
Tsabari, Reuven
Hevroni, Avigdor
Cohen-Cymberknoh, Malena
Amirav, Israel
Brammli-Greenberg, Shuli
Horani, Amjad
Kerem, Eitan
Breuer, Oded
author_facet Gileles-Hillel, Alex
Mor-Shaked, Hagar
Shoseyov, David
Reiter, Joel
Tsabari, Reuven
Hevroni, Avigdor
Cohen-Cymberknoh, Malena
Amirav, Israel
Brammli-Greenberg, Shuli
Horani, Amjad
Kerem, Eitan
Breuer, Oded
author_sort Gileles-Hillel, Alex
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7792814
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher European Respiratory Society
record_format MEDLINE/PubMed
spelling pubmed-77928142021-01-13 Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia Gileles-Hillel, Alex Mor-Shaked, Hagar Shoseyov, David Reiter, Joel Tsabari, Reuven Hevroni, Avigdor Cohen-Cymberknoh, Malena Amirav, Israel Brammli-Greenberg, Shuli Horani, Amjad Kerem, Eitan Breuer, Oded ERJ Open Res Original Articles 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. European Respiratory Society 2020-12-21 /pmc/articles/PMC7792814/ /pubmed/33447612 http://dx.doi.org/10.1183/23120541.00213-2020 Text en Copyright ©ERS 2020 http://creativecommons.org/licenses/by-nc/4.0/This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.
spellingShingle Original Articles
Gileles-Hillel, Alex
Mor-Shaked, Hagar
Shoseyov, David
Reiter, Joel
Tsabari, Reuven
Hevroni, Avigdor
Cohen-Cymberknoh, Malena
Amirav, Israel
Brammli-Greenberg, Shuli
Horani, Amjad
Kerem, Eitan
Breuer, Oded
Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
title Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
title_full Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
title_fullStr Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
title_full_unstemmed Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
title_short Whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
title_sort whole-exome sequencing accuracy in the diagnosis of primary ciliary dyskinesia
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792814/
https://www.ncbi.nlm.nih.gov/pubmed/33447612
http://dx.doi.org/10.1183/23120541.00213-2020
work_keys_str_mv AT gileleshillelalex wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT morshakedhagar wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT shoseyovdavid wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT reiterjoel wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT tsabarireuven wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT hevroniavigdor wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT cohencymberknohmalena wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT amiravisrael wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT brammligreenbergshuli wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT horaniamjad wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT keremeitan wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia
AT breueroded wholeexomesequencingaccuracyinthediagnosisofprimaryciliarydyskinesia