Dolzhenko, E;
van Vugt, JJFA;
Shaw, RJ;
Bekritsky, MA;
van Blitterswijk, M;
Narzisi, G;
Ajay, SS;
... Eberle, MA; + view all
(2017)
Detection of long repeat expansions from PCR-free whole-genome sequence data.
Genome Research
, 27
(11)
pp. 1895-1903.
10.1101/gr.225672.117.
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Abstract
Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00]) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
| Type: | Article |
|---|---|
| Title: | Detection of long repeat expansions from PCR-free whole-genome sequence data |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1101/gr.225672.117 |
| Publisher version: | http://dx.doi.org/10.1101/gr.225672.117 |
| Language: | English |
| Additional information: | © 2017 Dolzhenko et al.; Published by Cold Spring Harbor Laboratory Press This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biotechnology & Applied Microbiology, Genetics & Heredity, Hexanucleotide Repeat, Variation Discovery, Precision Medicine, C9ORF72, Variants, DNA, Mechanisms, Promoter, Disease, Onset |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10035205 |
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