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Whole genome sequencing for diagnosis of neurological repeat expansion disorders

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

Posted 06 Nov 2020
bioRxiv DOI: 10.1101/2020.11.06.371716

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. ### Competing Interest Statement Genomics 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.

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