Detection of long repeat expansions from PCR-free whole-genome sequence data
- Egor Dolzhenko1,
- Joke J.F.A. van Vugt2,
- Richard J. Shaw3,
- Mitchell A. Bekritsky4,
- Marka van Blitterswijk5,
- Giuseppe Narzisi6,
- Subramanian S. Ajay1,
- Vani Rajan1,
- Bryan Lajoie1,
- Nathan H. Johnson1,
- Zoya Kingsbury4,
- Sean J. Humphray4,
- Raymond D. Schellevis2,
- William J. Brands2,
- Matt Baker5,
- Rosa Rademakers5,
- Maarten Kooyman7,
- Gijs H.P. Tazelaar2,
- Michael A. van Es2,
- Russell McLaughlin8,
- William Sproviero9,
- Aleksey Shatunov9,
- Ashley Jones9,
- Ahmad Al Khleifat9,
- Alan Pittman10,
- Sarah Morgan10,
- Orla Hardiman8,
- Ammar Al-Chalabi9,
- Chris Shaw9,
- Bradley Smith9,
- Edmund J. Neo9,
- Karren Morrison11,
- Pam Shaw12,
- Catherine Reeves6,
- Lara Winterkorn6,
- Nancy S. Wexler13,
- The US-Venezuela Collaborative Research Group14,
- David E. Housman15,
- Christopher W. Ng15,
- Alina L. Li15,
- Ryan J. Taft1,
- Leonard H. van den Berg2,
- David R. Bentley4,
- Jan H. Veldink2 and
- Michael A. Eberle1,16
- 1 Illumina Inc;
- 2 University Medical Center Utrecht;
- 3 Repositive Ltd.;
- 4 Illumina Cambridge Ltd;
- 5 Mayo Clinic;
- 6 New York Genome Center;
- 7 SURFsara;
- 8 Trinity College Dublin;
- 9 King's College London;
- 10 UCL Institute of Neurology;
- 11 University of Southampton;
- 12 Sheffield Institute for Translational Neuroscience;
- 13 Columbia University;
- 14 -;
- 15 Massachusetts Institute of Technology
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 towards integrating WGS into precision medicine. We have 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 3,001 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% (2,786/2,789, 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 where 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. The software is licensed under GPL v3.0 and the source code is freely available on GitHub.
- Received June 1, 2017.
- Accepted August 28, 2017.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
