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.

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Item Type: Article
Official URL: https://doi.org/10.1186/s13073-022-01073-3
Journal or Publication Title: Genome Medicine
Volume: 14
Number: 1
Date: 19 July 2022
Divisions: Bioinformatics and Molecular Genetics
Molecular Cardiology
Depositing User: General Admin
Identification Number: 10.1186/s13073-022-01073-3
ISSN: 1756-994X
Date Deposited: 08 Jan 2023 23:11
Abstract:

Background: 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 nine 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 the interpretation of these variants.

Conclusions: 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.

Keywords: Gene regulation; Non-coding variation; Variant interpretation.

Creators:
Creators
Email
Ellingford, Jamie M.
UNSPECIFIED
Ahn, Joo Wook
UNSPECIFIED
Bagnall, Richard D.
UNSPECIFIED
Baralle, Diana
UNSPECIFIED
Barton, Stephanie
UNSPECIFIED
Campbell, Chris
UNSPECIFIED
Downes, Kate
UNSPECIFIED
Ellard, Sian
UNSPECIFIED
Duff-Farrier, Celia
UNSPECIFIED
FitzPatrick, David R.
UNSPECIFIED
Greally, John M.
UNSPECIFIED
Ingles, Jodie
UNSPECIFIED
Krishnan, Neesha
UNSPECIFIED
Lord, Jenny
UNSPECIFIED
Martin, Hilary C.
UNSPECIFIED
Newman, William G.
UNSPECIFIED
O’Donnell-Luria, Anne
UNSPECIFIED
Ramsden, Simon C.
UNSPECIFIED
Rehm, Heidi L.
UNSPECIFIED
Richardson, Ebony
UNSPECIFIED
Singer-Berk, Moriel
UNSPECIFIED
Taylor, Jenny C.
UNSPECIFIED
Williams, Maggie
UNSPECIFIED
Wood, Jordan C.
UNSPECIFIED
Wright, Caroline F.
UNSPECIFIED
Harrison, Steven M.
UNSPECIFIED
Whiffin, Nicola
UNSPECIFIED
Last Modified: 08 Jan 2023 23:11
URI: https://eprints.centenary.org.au/id/eprint/1344

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