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Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Recommendations for clinical interpretation of variants found in non-coding regions of the genome
Recommendations for clinical interpretation of variants found in non-coding regions of the genome
Purpose The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts.

Methods We convened a panel of clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups.

Results We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for these variants.

Conclusion These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
1756-994X
Ellingford, Jamie M.
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Ahn, Joo Wook
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Bagnall, Richard D
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Baralle, Diana
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Barton, Stephanie
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Campbell, Chris
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Downes, Kate
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Ellard, Sian
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Duff-Farrier, Celia
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FitzPatrick, David R.
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Greally, John M
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Ingles, Jodie
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Krishnan, Neesha
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Lord, Jenny
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Martin, Hilary C
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Newman, William G.
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O'Donnell-Luria, Anne
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Ramsden, Simon C.
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Rehm, Heidi L.
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Richardson, Ebony
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Singer-Berk, Moriel
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Taylor, Jenny C.
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Williams, Maggie
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Wood, Jordan C
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Wright, Caroline F.
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Steven M, Harrison
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Whiffin, Nicola
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Ellingford, Jamie M.
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Ahn, Joo Wook
e5bc3cd7-720c-4193-8539-da34ba9371dd
Bagnall, Richard D
ff5dce1a-aa52-48d4-a3bf-cd6a910956a0
Baralle, Diana
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Barton, Stephanie
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Campbell, Chris
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Downes, Kate
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Ellard, Sian
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Duff-Farrier, Celia
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FitzPatrick, David R.
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Greally, John M
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Ingles, Jodie
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Krishnan, Neesha
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Lord, Jenny
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Martin, Hilary C
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Newman, William G.
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O'Donnell-Luria, Anne
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Ramsden, Simon C.
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Rehm, Heidi L.
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Richardson, Ebony
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Singer-Berk, Moriel
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Taylor, Jenny C.
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Williams, Maggie
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Wood, Jordan C
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Wright, Caroline F.
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Steven M, Harrison
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Whiffin, Nicola
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Ellingford, Jamie M., Ahn, Joo Wook, Bagnall, Richard D, Baralle, Diana, Barton, Stephanie, Campbell, Chris, Downes, Kate, Ellard, Sian, Duff-Farrier, Celia, FitzPatrick, David R., Greally, John M, Ingles, Jodie, Krishnan, Neesha, Lord, Jenny, Martin, Hilary C, Newman, William G., O'Donnell-Luria, Anne, Ramsden, Simon C., Rehm, Heidi L., Richardson, Ebony, Singer-Berk, Moriel, Taylor, Jenny C., Williams, Maggie, Wood, Jordan C, Wright, Caroline F., Steven M, Harrison and Whiffin, Nicola (2022) Recommendations for clinical interpretation of variants found in non-coding regions of the genome. Genome Medicine, 14. (doi:10.1186/s13073-022-01073-3).

Record type: Article

Abstract

Purpose The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts.

Methods We convened a panel of clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups.

Results We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for these variants.

Conclusion These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.

Text
2021.12.28.21267792v1.full - Author's Original
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Accepted/In Press date: 17 June 2022
Published date: 19 July 2022

Identifiers

Local EPrints ID: 467630
URI: http://eprints.soton.ac.uk/id/eprint/467630
ISSN: 1756-994X
PURE UUID: ad7d2cb5-7e4b-4e80-8665-ee488a872abc
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833
ORCID for Jenny Lord: ORCID iD orcid.org/0000-0002-0539-9343

Catalogue record

Date deposited: 15 Jul 2022 19:22
Last modified: 21 Jul 2022 01:53

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Contributors

Author: Jamie M. Ellingford
Author: Joo Wook Ahn
Author: Richard D Bagnall
Author: Diana Baralle ORCID iD
Author: Stephanie Barton
Author: Chris Campbell
Author: Kate Downes
Author: Sian Ellard
Author: Celia Duff-Farrier
Author: David R. FitzPatrick
Author: John M Greally
Author: Jodie Ingles
Author: Neesha Krishnan
Author: Jenny Lord ORCID iD
Author: Hilary C Martin
Author: William G. Newman
Author: Anne O'Donnell-Luria
Author: Simon C. Ramsden
Author: Heidi L. Rehm
Author: Ebony Richardson
Author: Moriel Singer-Berk
Author: Jenny C. Taylor
Author: Maggie Williams
Author: Jordan C Wood
Author: Caroline F. Wright
Author: Harrison Steven M
Author: Nicola Whiffin

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