期刊
GENOME RESEARCH
卷 27, 期 11, 页码 1895-1903出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.225672.117
关键词
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资金
- SURF Cooperative
- NIH/NINDS [P01 NS084974, R01 NS080882]
- Thierry Latran Foundation
- Netherlands Organization for Health Research and Development
- ALS Foundation Netherlands
- MND Association (UK)
- W.M. Keck Foundation through the grant Finding Genetic Modifiers As Avenues to Developing New Therapeutics
- European Community's Health Seventh Framework Programme (FP7)
- Horizon Programme (H-PHC-two-stage) [633413]
- ZonMW under E-Rare-2, the ERA Net for Research on Rare Diseases (PYRAMID)
- UK, Medical Research Council [MR/L501529/1, ES/L008238/1]
- Ireland, Health Research Board
- Netherlands, ZonMw
- National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London
- W.M. Keck Foundation
- MND Association
- Wellcome Trust
- Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester
- Medical Research Council [MR/L501529/1] Funding Source: researchfish
- Medical Research Foundation [MRF-060-0003-RG-SMITH] Funding Source: researchfish
- Motor Neurone Disease Association [Jones/Oct15/958-799, Smith/Apr16/847-791, McLaughlin/Oct15/957-799, AlChalabi-Dobson/Apr14/829-791] Funding Source: researchfish
- ESRC [ES/L008238/1] Funding Source: UKRI
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.
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