Whole genome sequencing in the diagnosis of primary ciliary dyskinesia
Whole genome sequencing in the diagnosis of primary ciliary dyskinesia
Background: It is estimated that 1–13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a “gold standard” diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability. Methods: UK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC. Results: 16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort. Conclusions: Genetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.
Diagnosis, Gene discovery, Non-CF bronchiectasis, Primary ciliary dyskinesia, Whole genome sequencing
Wheway, Gabrielle
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Thomas, N. Simon
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Carroll, Mary
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Coles, Janice
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Doherty, Regan
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Goggin, Patricia
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Green, Ben
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Harris, Amanda
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Hunt, David
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Jackson, Claire
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Lord, Jenny
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Mennella, Vito
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Thompson, James
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Walker, Woolf
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Lucas, Jane
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Genomics England Research Consortium
23 September 2021
Wheway, Gabrielle
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Thomas, N. Simon
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Carroll, Mary
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Coles, Janice
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Doherty, Regan
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Goggin, Patricia
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Green, Ben
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Harris, Amanda
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Hunt, David
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Jackson, Claire
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Lord, Jenny
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Mennella, Vito
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Thompson, James
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Walker, Woolf
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Lucas, Jane
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Wheway, Gabrielle, Thomas, N. Simon, Carroll, Mary, Coles, Janice, Doherty, Regan, Goggin, Patricia, Green, Ben, Harris, Amanda, Hunt, David, Jackson, Claire, Lord, Jenny, Mennella, Vito, Thompson, James, Walker, Woolf and Lucas, Jane
,
Genomics England Research Consortium
(2021)
Whole genome sequencing in the diagnosis of primary ciliary dyskinesia.
Springer Nature, 14 (1), [234].
(doi:10.1186/s12920-021-01084-w).
Abstract
Background: It is estimated that 1–13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a “gold standard” diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability. Methods: UK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC. Results: 16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort. Conclusions: Genetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.
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Accepted/In Press date: 14 September 2021
Published date: 23 September 2021
Additional Information:
Funding Information:
GW acknowledges funding from Wellcome Trust (award number 204378/Z/16/Z). The National PCD Centre in Southampton is commissioned and funded by NHS England; PCD research is supported by NIHR Southampton Biomedical Research Centre, NIHR Clinical Research Facility, National Institute for Health Research (RfPB PB-PG-1215-20014; and 200470) and The AAIR Charity (Reg. No. 1129698). JL is supported by an NIHR Research Professorship awarded to Prof Diana Baralle (DB NIHR RP-2016-07-011). The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Funding Information:
We thank the patients and their families for taking part in this research for diagnostics. The National PCD Centre in Southampton is commissioned and funded by NHS England; PCD research is supported by NIHR Southampton Biomedical Research Centre, NIHR Clinical Research Facility, National Institute for Health Research (RfPB PB-PG-1215-20014; and 200470) and The AAIR Charity (Reg. No. 1129698). SNV and SV confirmation was carried out by Dave Bunyan (Wessex Regional Genetics Laboratory). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.
Funding Information:
We thank the patients and their families for taking part in this research for diagnostics. The National PCD Centre in Southampton is commissioned and funded by NHS England; PCD research is supported by NIHR Southampton Biomedical Research Centre, NIHR Clinical Research Facility, National Institute for Health Research (RfPB PB-PG-1215-20014; and 200470) and The AAIR Charity (Reg. No. 1129698). SNV and SV confirmation was carried out by Dave Bunyan (Wessex Regional Genetics Laboratory). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.
Publisher Copyright:
© 2021, The Author(s).
Keywords:
Diagnosis, Gene discovery, Non-CF bronchiectasis, Primary ciliary dyskinesia, Whole genome sequencing
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Local EPrints ID: 451543
URI: http://eprints.soton.ac.uk/id/eprint/451543
PURE UUID: 25a551bf-bc0a-439d-9655-02aa1b927081
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Date deposited: 06 Oct 2021 19:12
Last modified: 17 Mar 2024 03:54
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Contributors
Author:
N. Simon Thomas
Author:
Mary Carroll
Author:
Janice Coles
Author:
Regan Doherty
Author:
Patricia Goggin
Author:
Ben Green
Author:
Amanda Harris
Author:
David Hunt
Author:
Claire Jackson
Author:
Jenny Lord
Author:
James Thompson
Author:
Woolf Walker
Corporate Author: Genomics England Research Consortium
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