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Whole genome sequencing in the diagnosis of primary ciliary dyskinesia

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-specifc 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 identifed genetic confrmation 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 fbrosis (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 confrmed (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 identifed which were missed by panel testing. We identifed 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 confrmed (n=2) or possible (n=1) diagnosis of PCD. We identifed 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 efective 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. Keywords: Primary ciliary dyskinesia, Non-CF bronchiectasis, Whole genome sequencing, Diagnosis, 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, Mary
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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
Wheway, Gabrielle
2e547e5d-b921-4243-a071-2208fd4cc090
Thomas, N. Simon
1a601957-288d-4f12-a9f7-4f4279b7f9b3
Carroll, Mary
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Coles, Janice
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Doherty, Regan
da82ae44-70e7-41d4-9150-6ab3ce459738
Goggin, Patricia, Mary
c2d225c4-b84d-4ead-a433-320057cb5fa9
Green, Ben
9ac4853e-7155-4a96-ab23-bc3264bc4e2e
Harris, Amanda
df17c805-009b-4a54-9dff-e5042e9efa99
Hunt, David
a744ddd0-df7d-44f7-bb9c-c91e188c3bb3
Jackson, Claire
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Lord, Jenny
e1909780-36cd-4705-b21e-4580038d4ec6
Mennella, Vito
43c60e29-c0a7-4ab8-8e5c-fcb59f70a28a
Thompson, James
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Walker, Woolf
0758e514-9212-4388-8879-e5a2dca3dbaa
Lucas, Jane
5cb3546c-87b2-4e59-af48-402076e25313

Wheway, Gabrielle, Thomas, N. Simon, Carroll, Mary, Coles, Janice, Doherty, Regan, Goggin, Patricia, Mary, 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).

Record type: Article

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-specifc 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 identifed genetic confrmation 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 fbrosis (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 confrmed (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 identifed which were missed by panel testing. We identifed 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 confrmed (n=2) or possible (n=1) diagnosis of PCD. We identifed 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 efective 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. Keywords: Primary ciliary dyskinesia, Non-CF bronchiectasis, Whole genome sequencing, Diagnosis, Gene discovery

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Soton PCD and non-CF bronch paper final draft_submitted_2 - Accepted Manuscript
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Accepted/In Press date: 14 September 2021
Published date: 23 September 2021
Additional 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.
Keywords: Diagnosis, Gene discovery, Non-CF bronchiectasis, Primary ciliary dyskinesia, Whole genome sequencing

Identifiers

Local EPrints ID: 451543
URI: http://eprints.soton.ac.uk/id/eprint/451543
PURE UUID: 25a551bf-bc0a-439d-9655-02aa1b927081
ORCID for Gabrielle Wheway: ORCID iD orcid.org/0000-0002-0494-0783
ORCID for Patricia, Mary Goggin: ORCID iD orcid.org/0000-0003-4730-0206
ORCID for Jenny Lord: ORCID iD orcid.org/0000-0002-0539-9343
ORCID for Vito Mennella: ORCID iD orcid.org/0000-0002-4842-9012

Catalogue record

Date deposited: 06 Oct 2021 19:12
Last modified: 19 Nov 2021 02:49

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Contributors

Author: N. Simon Thomas
Author: Mary Carroll
Author: Janice Coles
Author: Regan Doherty
Author: Patricia, Mary Goggin ORCID iD
Author: Ben Green
Author: Amanda Harris
Author: David Hunt
Author: Claire Jackson
Author: Jenny Lord ORCID iD
Author: Vito Mennella ORCID iD
Author: James Thompson
Author: Woolf Walker
Author: Jane Lucas
Corporate Author: Genomics England Research Consortium

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