Recommendations for clinical interpretation of variants found in non-coding regions of the genome
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Published:2022-07-19
Issue:1
Volume:14
Page:
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ISSN:1756-994X
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Container-title:Genome Medicine
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language:en
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Short-container-title:Genome Med
Author:
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., Harrison Steven M., Whiffin NicolaORCID
Abstract
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.
Funder
Wellcome Trust Rosetrees Trust National Institute for Health Research Medical Research Council National Health and Medical Research Council National Human Genome Research Institute
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine
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