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


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.

Type Journal
ISBN 1756-994X (Electronic) 1756-994X (Linking)
Authors Ellingford, J. M.; Ahn, J. W.; Bagnall, R. D.; Baralle, D.; Barton, S.; Campbell, C.; Downes, K.; Ellard, S.; Duff-Farrier, C.; FitzPatrick, D. R.; Greally, J. M.; Ingles, J.; Krishnan, N.; Lord, J.; Martin, H. C.; Newman, W. G.; O'Donnell-Luria, A.; Ramsden, S. C.; Rehm, H. L.; Richardson, E.; Singer-Berk, M.; Taylor, J. C.; Williams, M.; Wood, J. C.; Wright, C. F.; Harrison, S. M.; Whiffin, N.
Publisher Name Genome Medicine
Published Date 2022-07-19
Published Volume 14
Published Issue 1
Published Pages 73
Status Published in-print
DOI 10.1186/s13073-022-01073-3
URL link to publisher's version