Recommendations for Clinical Interpretation of Variants Found in Non-coding Regions of the Genome

Overview

Journal Genome Med

Publisher Biomed Central

Specialty Genetics

Date 2022 Jul 19

PMID 35850704

Authors

Jamie M Ellingford

Joo Wook Ahn

Richard D Bagnall

Diana Baralle

Stephanie Barton

Chris Campbell

Kate Downes

Sian Ellard

Celia Duff-Farrier

David R Fitzpatrick

John M Greally

Jodie Ingles

Neesha Krishnan

Jenny Lord

Hilary C Martin

William G Newman

Anne ODonnell-Luria

Simon C Ramsden

Heidi L Rehm

Ebony Richardson

Moriel Singer-Berk

Jenny C Taylor

Maggie Williams

Jordan C Wood

Caroline F Wright

Steven M Harrison

Nicola Whiffin

Affiliations

Soon will be listed here.

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.

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