Detection of long repeat expansions from PCR-free whole-genome sequence data
Open accessPublished version of a preprint
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.
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Genome sequencing has the potential to detect a wide variety of variant types, including single-nucleotide variants and indels, copy number variants, repeat expansions, and pathogenic nonprotein-coding variation that is missed by other NGS approaches.
“Genome sequencing has the potential to detect a wide variety of variant types, including single‐nucleotide variants and indels (out‐performing exome sequencing in protein‐coding regions), copy number variants (CNV),4 repeat expansions,5 and detection of pathogenic nonprotein‐coding variation that is missed by other NGS approaches.”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [5]
Expansions in 10 genes were confirmed with ExpansionHunter, read pile-ups, gel electrophoresis, and Sanger sequencing.
“We confirmed the tandem repeat expansions in these 10 genes using another tandem repeat detection algorithm, ExpansionHunter47,48, as well as by visualizing read pile-ups and by gel electrophoresis and Sanger sequencing”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [48]
ExpansionHunter estimates allele-specific tandem repeat sizes with high accuracy (precision=0.91, recall=0.99).
“which estimates allele-specific tandem repeat sizes for each genomic coordinate and motif supplied by the user with high accuracy (precision=0.91, recall=0.99)48.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [48]
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Self-citation
- Authors
- Dolzhenko, E., van Vugt, J. J. F. A., Shaw, R. J., Bekritsky, M. A., van Blitterswijk, M., Narzisi, G., Ajay, S. S., Rajan, V., Lajoie, B. R., Johnson, N. H., Kingsbury, Z., Humphray, S. J., Schellevis, R. D., Brands, W. J., Baker, M., Rademakers, R., Kooyman, M., Tazelaar, G. H. P., van Es, M. A., McLaughlin, R., Sproviero, W., Shatunov, A., Jones, A., Al Khleifat, A., Pittman, A., Morgan, S., Hardiman, O., Al-Chalabi, A., Shaw, C., Smith, B., Neo, E. J., Morrison, K., Shaw, P. J., Reeves, C., Winterkorn, L., Wexler, N. S., The US–Venezuela Collaborative Research Group, Housman, D. E., Ng, C. W., Li, A. L., Taft, R. J., van den Berg, L. H., Bentley, D. R., Veldink, J. H., & Eberle, M. A.
- Affiliations
- Illumina (United States) (US)
- Illumina (United Kingdom) (GB)
- New York Genome Center (US)
- Utrecht University (NL)
- Mayo Clinic (US)
- SURFsara (Netherlands) (NL)
- Trinity College Dublin (IE)
- King's College London (GB)
- UCL Queen Square Institute of Neurology (GB)
- University of Southampton (GB)
- University of Sheffield (GB)
- Hereditary Disease Foundation (US)
- Massachusetts Institute of Technology (US)
- ORCID
- Dolzhenko, Egor
- Shaw, Richard J.
- Bekritsky, Mitchell A.
- Narzisi, Giuseppe
- Lajoie, Bryan R.
- Johnson, Nathan H.
- Humphray, Sean J.
- Brands, William J.
- Baker, Matt
- Rademakers, Rosa
- Kooyman, Maarten
- McLaughlin, Russell
- Sproviero, William
- Shatunov, Aleksey
- Jones, Ashley
- Pittman, Alan
- Morgan, Sarah
- Hardiman, Orla
- Smith, Bradley
- Neo, Edmund J.
- Morrison, Karen
- Shaw, Pamela J.
- Reeves, Catherine
- Winterkorn, Lara
- Wexler, Nancy S.
- Housman, David E.
- Ng, Christopher W.
- Taft, Ryan J.
- Veldink, Jan H.
- Eberle, Michael A.
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-09-08
- Volume
- 27
- Issue
- 11
- Pages
- 1895-1903
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC5668946
- OpenAlex
- W2949838248
- Cited by
- 388
- References
- 35
- Citations by year
- 2026: 33 · 2025: 40 · 2024: 62 · 2023: 45 · 2022: 55 · 2021: 45 · 2020: 42 · 2019: 34 · 2018: 26 · 2017: 5 · 2012: 1
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (publishedVersion, cc-by)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Research Portal (King's College London) (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- 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
- “Finding Genetic Modifiers As Avenues to Developing New Therapeutics”
- European Community's Health Seventh Framework Programme (FP7/2007-2013)
- Horizon 2020 Programme (633413)
- ZonMW
- ERA Net for Research on Rare Diseases
- 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
- UK National DNA Bank for MND Research
- MND Association and the Wellcome Trust
- Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- repeat expansion detection, microsatellite markers, C9orf72 repeat expansion, amyotrophic lateral sclerosis, fragile X syndrome, Friedreich's ataxia, Huntington's disease, repeat-primed PCR, precision medicine
- MeSH terms
- Whole Genome Sequencing, C9orf72 Protein, Algorithms, Amyotrophic Lateral Sclerosis, Humans, Sensitivity and Specificity, Software, Databases, Genetic, DNA Repeat Expansion, Precision Medicine
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