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

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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.
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*Genetic Variation , Genome , *Genome-Wide Association Study , Open Reading Frames , Regulatory Sequences, Nucleic Acid , Gene regulation , Non-coding variation , Variant interpretation
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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.
Genome Med. 2022 Jul 19;14(1):73. doi: 10.1186/s13073-022-01073-3.
BioMed Central
Genome medicine
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