RT Journal Article
SR Electronic
T1 Whole genome sequencing for diagnosis of neurological repeat expansion disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.06.371716
DO 10.1101/2020.11.06.371716
A1 Kristina Ibanez
A1 James Polke
A1 Tanner Hagelstrom
A1 Egor Dolzhenko
A1 Dorota Pasko
A1 Ellen Thomas
A1 Louise Daugherty
A1 Dalia Kasperaviciute
A1 Ellen M McDonagh
A1 Katherine R Smith
A1 Antonio Rueda Martin
A1 Dimitris Polychronopoulos
A1 Heather Angus-Leppan
A1 Kailash P Bhatia
A1 James E Davison
A1 Richard Festenstein
A1 Pietro Fratta
A1 Paola Giunti
A1 Robin Howard
A1 Laxmi Venkata Prasad Korlipara
A1 Matilde Laurá
A1 Meriel McEntagart
A1 Lara Menzies
A1 Huw Morris
A1 Mary M Reilly
A1 Robert Robinson
A1 Elisabeth Rosser
A1 Francesca Faravelli
A1 Anette Schrag
A1 Jonathan M Schott
A1 Thomas T Warner
A1 Nicholas W Wood
A1 David Bourn
A1 Kelly Eggleton
A1 Robyn Labrum
A1 Philip Twiss
A1 Stephen Abbs
A1 Liana Santos
A1 Ghareesa Almheiri
A1 Isabella Sheikh
A1 Jana Vandrovcova
A1 Christine Patch
A1 Ana Lisa Taylor Tavares
A1 Zerin Hyder
A1 Anna Need
A1 Helen Brittain
A1 Emma Baple
A1 Loukas Moutsianas
A1 Genomics England Research Consortium
A1 Viraj Deshpande
A1 Denise L Perry
A1 Shankar Ajay
A1 Aditi Chawla
A1 Vani Rajan
A1 Kathryn Oprych
A1 Patrick F Chinnery
A1 Angela Douglas
A1 Gill Wilson
A1 Sian Ellard
A1 Karen Temple
A1 Andrew Mumford
A1 Dom McMullan
A1 Kikkeri Naresh
A1 Frances Flinter
A1 Jenny C Taylor
A1 Lynn Greenhalgh
A1 William Newman
A1 Paul Brennan
A1 John A. Sayer
A1 F Lucy Raymond
A1 Lyn S Chitty
A1 Zandra C Deans
A1 Sue Hill
A1 Tom Fowler
A1 Richard Scott
A1 Henry Houlden
A1 Augusto Rendon
A1 Mark J Caulfield
A1 Michael A Eberle
A1 Ryan J Taft
A1 Arianna Tucci
YR 2020
UL http://biorxiv.org/content/early/2020/11/06/2020.11.06.371716.abstract
AB Background Repeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach.Methods WGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders.Findings WGS RE detection showed minimum 97·3% sensitivity and 99·6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate.Interpretation We show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England.Funding Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina IncCompeting Interest StatementGenomics England Ltd is a wholly owned Department of Health and Social Care company created in 2013 to introduce WGS into healthcare in conjunction with NHS England. All Genomics England affiliated authors are, or were, salaried by or seconded to Genomics England. RJT, ME, ED, RTH are employees and shareholders of Illumina Inc.