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

• Published in: Genome medicine 2022-07, Vol.14 (1), p.73-19, Article 73
• Main Authors: 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, Nicola
• Format: Article
• Language: English
• Subjects: Binding sites; Diagnostic equipment (Medical); DNA sequencing; Gene expression; Gene regulation; Genetic disorders; Genetic screening; Genetic Variation; Genome; Genome-Wide Association Study; Genomes; Genomics; Guideline; Lubrication and lubricants; Non-coding variation; Nucleotide sequencing; Open Reading Frames; Phenotypes; Protein expression; Proteins; Rare diseases; Regulatory sequences; Regulatory Sequences, Nucleic Acid; Variant interpretation; Whole genome sequencing
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-022-01073-3

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. 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. 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. 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.