Recommendations for clinical interpretation of variants found in non-coding regions of the genome
Published version
Peer-reviewed
Repository URI
Repository DOI
Type
Change log
Authors
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.
Description
Funder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265
Keywords
Is Part Of
Publisher
Publisher DOI
Sponsorship
Rosetrees Trust (H5R01320)
National Institute for Health Research (RP-2016-07-011, IS-BRC-1215-20007)
National Health and Medical Research Council (#1162929)
National Human Genome Research Institute (U01HG011755, U24HG006834)