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Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype

Whole-exome sequencing has expedited the diagnostic work-up of primary ciliary dyskinesia (PCD), when used in addition to clinical phenotype and nasal nitric oxide. However, it reveals variants of uncertain significance (VUS) in established PCD genes or (likely) pathogenic variants in genes of uncer...

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Autores principales: Staar, Ben O., Hegermann, Jan, Auber, Bernd, Ewen, Raphael, von Hardenberg, Sandra, Olmer, Ruth, Pink, Isabell, Rademacher, Jessica, Wetzke, Martin, Ringshausen, Felix C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670349/
https://www.ncbi.nlm.nih.gov/pubmed/37998386
http://dx.doi.org/10.3390/cells12222651
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author Staar, Ben O.
Hegermann, Jan
Auber, Bernd
Ewen, Raphael
von Hardenberg, Sandra
Olmer, Ruth
Pink, Isabell
Rademacher, Jessica
Wetzke, Martin
Ringshausen, Felix C.
author_facet Staar, Ben O.
Hegermann, Jan
Auber, Bernd
Ewen, Raphael
von Hardenberg, Sandra
Olmer, Ruth
Pink, Isabell
Rademacher, Jessica
Wetzke, Martin
Ringshausen, Felix C.
author_sort Staar, Ben O.
collection PubMed
description Whole-exome sequencing has expedited the diagnostic work-up of primary ciliary dyskinesia (PCD), when used in addition to clinical phenotype and nasal nitric oxide. However, it reveals variants of uncertain significance (VUS) in established PCD genes or (likely) pathogenic variants in genes of uncertain significance in approximately 30% of tested individuals. We aimed to assess genotype–phenotype correlations in adults with bronchiectasis, clinical suspicion of PCD, and inconclusive whole-exome sequencing results using transmission electron microscopy (TEM) and ciliary image averaging by the PCD Detect software. We recruited 16 patients with VUS in CCDC39, CCDC40, CCDC103, DNAH5, DNAH5/CCDC40, DNAH8/HYDIN, DNAH11, and DNAI1 as well as variants in the PCD candidate genes DNAH1, DNAH7, NEK10, and NME5. We found normal ciliary ultrastructure in eight patients with VUS in CCDC39, DNAH1, DNAH7, DNAH8/HYDIN, DNAH11, and DNAI1. In six patients with VUS in CCDC40, CCDC103, DNAH5, and DNAI1, we identified a corresponding ultrastructural hallmark defect. In one patient with homozygous variant in NME5, we detected a central complex defect supporting clinical relevance. Using TEM as a targeted approach, we established important genotype–phenotype correlations and definite PCD in a considerable proportion of patients. Overall, the PCD Detect software proved feasible in support of TEM.
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spelling pubmed-106703492023-11-18 Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype Staar, Ben O. Hegermann, Jan Auber, Bernd Ewen, Raphael von Hardenberg, Sandra Olmer, Ruth Pink, Isabell Rademacher, Jessica Wetzke, Martin Ringshausen, Felix C. Cells Article Whole-exome sequencing has expedited the diagnostic work-up of primary ciliary dyskinesia (PCD), when used in addition to clinical phenotype and nasal nitric oxide. However, it reveals variants of uncertain significance (VUS) in established PCD genes or (likely) pathogenic variants in genes of uncertain significance in approximately 30% of tested individuals. We aimed to assess genotype–phenotype correlations in adults with bronchiectasis, clinical suspicion of PCD, and inconclusive whole-exome sequencing results using transmission electron microscopy (TEM) and ciliary image averaging by the PCD Detect software. We recruited 16 patients with VUS in CCDC39, CCDC40, CCDC103, DNAH5, DNAH5/CCDC40, DNAH8/HYDIN, DNAH11, and DNAI1 as well as variants in the PCD candidate genes DNAH1, DNAH7, NEK10, and NME5. We found normal ciliary ultrastructure in eight patients with VUS in CCDC39, DNAH1, DNAH7, DNAH8/HYDIN, DNAH11, and DNAI1. In six patients with VUS in CCDC40, CCDC103, DNAH5, and DNAI1, we identified a corresponding ultrastructural hallmark defect. In one patient with homozygous variant in NME5, we detected a central complex defect supporting clinical relevance. Using TEM as a targeted approach, we established important genotype–phenotype correlations and definite PCD in a considerable proportion of patients. Overall, the PCD Detect software proved feasible in support of TEM. MDPI 2023-11-18 /pmc/articles/PMC10670349/ /pubmed/37998386 http://dx.doi.org/10.3390/cells12222651 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Staar, Ben O.
Hegermann, Jan
Auber, Bernd
Ewen, Raphael
von Hardenberg, Sandra
Olmer, Ruth
Pink, Isabell
Rademacher, Jessica
Wetzke, Martin
Ringshausen, Felix C.
Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype
title Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype
title_full Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype
title_fullStr Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype
title_full_unstemmed Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype
title_short Ciliary Ultrastructure Assessed by Transmission Electron Microscopy in Adults with Bronchiectasis and Suspected Primary Ciliary Dyskinesia but Inconclusive Genotype
title_sort ciliary ultrastructure assessed by transmission electron microscopy in adults with bronchiectasis and suspected primary ciliary dyskinesia but inconclusive genotype
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10670349/
https://www.ncbi.nlm.nih.gov/pubmed/37998386
http://dx.doi.org/10.3390/cells12222651
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