Whole genome sequencing for diagnosis of neurological repeat expansion disorders
Authors: Ibanez Kristina , Polke James , Hagelstrom Tanner , Dolzhenko Egor , Pasko Dorota , Thomas Ellen , Daugherty Louise , Kasperaviciute Dalia , McDonagh Ellen M , Smith Katherine R , Martin Antonio Rueda , Polychronopoulos Dimitris , Angus-Leppan Heather , Bhatia Kailash P , Davison James E , Festenstein Richard , Fratta Pietro , Giunti Paola , Howard Robin , Prasad Korlipara Laxmi Venkata , Laurá Matilde , McEntagart Meriel , Menzies Lara , Morris Huw , Reilly Mary M , Robinson Robert , Rosser Elisabeth , Faravelli Francesca , Schrag Anette , Schott Jonathan M , Warner Thomas T , Wood Nicholas W , Bourn David , Eggleton Kelly , Labrum Robyn , Twiss Philip , Abbs Stephen , Santos Liana , Almheiri Ghareesa , Sheikh Isabella , Vandrovcova Jana , Patch Christine , Taylor Tavares Ana Lisa , Hyder Zerin , Need Anna , Brittain Helen , Baple Emma , Moutsianas Loukas ,   Genomics England Research Consortium, Deshpande Viraj , Perry Denise L , Ajay Shankar , Chawla Aditi , Rajan Vani , Oprych Kathryn , Chinnery Patrick F , Douglas Angela , Wilson Gill , Ellard Sian , Temple Karen , Mumford Andrew , McMullan Dom , Naresh Kikkeri , Flinter Frances , Taylor Jenny C , Greenhalgh Lynn , Newman William , Brennan Paul , Sayer John A. , Raymond F Lucy , Chitty Lyn S , Deans Zandra C , Hill Sue , Fowler Tom , Scott Richard , Houlden Henry , Rendon Augusto , Caulfield Mark J , Eberle Michael A , Taft Ryan J , Tucci Arianna 
Published: November 2020

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 Inc