Detection of long repeat expansions from PCR-free whole-genome sequence data

Egor Dolzhenko; Joke J.f.a. Van Vugt; Richard J. Shaw; Mitchell A. Bekritsky; Marka Van Blitterswijk; Giuseppe Narzisi; Subramanian S. Ajay; Vani Rajan; Bryan Lajoie; Nathan H. Johnson; Zoya Kingsbury; Sean J. Humphray; Raymond D. Schellevis; William J. Brands; Matt Baker; Rosa Rademakers; Maarten Kooyman; Gijs H.p. Tazelaar; Michael A. Van Es; Russell Mclaughlin; William Sproviero; Aleksey Shatunov; Ashley Jones; Ahmad Al Khleifat; Alan Pittman; Sarah Morgan; Orla Hardiman; Ammar Al-chalabi; Chris Shaw; Bradley Smith; Edmund J. Neo; Karren Morrison; Pam Shaw; Catherine Reeves; Lara Winterkorn; Nancy S. Wexler; David E. Housman; Christopher W. Ng; Alina L. Li; Ryan J. Taft; Leonard H. Van Den Berg; David R. Bentley; Jan H. Veldink; Michael A. Eberle

doi:10.1101/gr.225672.117

Detection of long repeat expansions from PCR-free whole-genome sequence data

Egor Dolzhenko, Joke J.f.a. Van Vugt, Richard J. Shaw, Mitchell A. Bekritsky, Marka Van Blitterswijk, Giuseppe Narzisi, Subramanian S. Ajay, Vani Rajan, Bryan Lajoie, Nathan H. Johnson, Zoya Kingsbury, Sean J. Humphray, Raymond D. Schellevis, William J. Brands, Matt Baker, Rosa Rademakers, Maarten Kooyman, Gijs H.p. Tazelaar, Michael A. Van Es, Russell MclaughlinWilliam Sproviero, Aleksey Shatunov, Ashley Jones, Ahmad Al Khleifat, Alan Pittman, Sarah Morgan, Orla Hardiman, Ammar Al-chalabi, Chris Shaw, Bradley Smith, Edmund J. Neo, Karren Morrison, Pam Shaw, Catherine Reeves, Lara Winterkorn, Nancy S. Wexler, David E. Housman, Christopher W. Ng, Alina L. Li, Ryan J. Taft, Leonard H. Van Den Berg, David R. Bentley, Jan H. Veldink, Michael A. Eberle

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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.

Original language	English
Pages (from-to)	1895-1903
Number of pages	9
Journal	Genome Research
Volume	27
Issue number	11
Early online date	8 Sept 2017
DOIs	https://doi.org/10.1101/gr.225672.117
Publication status	Published - Nov 2017

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Detection of long repeat expansions_Dolzhenko_Accepted 28Aug2017_ GOLD AAM (CC BY)Accepted author manuscript, 1.21 MBLicence: CC BY

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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., 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., ... Eberle, M. A. (2017). Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Research, 27(11), 1895-1903. https://doi.org/10.1101/gr.225672.117

@article{1ff1a12cbcae495595ab6adf591615b6,

title = "Detection of long repeat expansions from PCR-free whole-genome sequence data",

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.",

author = "Egor Dolzhenko and {Van Vugt}, {Joke J.f.a.} and Shaw, {Richard J.} and Bekritsky, {Mitchell A.} and {Van Blitterswijk}, Marka and Giuseppe Narzisi and Ajay, {Subramanian S.} and Vani Rajan and Bryan Lajoie and Johnson, {Nathan H.} and Zoya Kingsbury and Humphray, {Sean J.} and Schellevis, {Raymond D.} and Brands, {William J.} and Matt Baker and Rosa Rademakers and Maarten Kooyman and Tazelaar, {Gijs H.p.} and {Van Es}, {Michael A.} and Russell Mclaughlin and William Sproviero and Aleksey Shatunov and Ashley Jones and {Al Khleifat}, Ahmad and Alan Pittman and Sarah Morgan and Orla Hardiman and Ammar Al-chalabi and Chris Shaw and Bradley Smith and Neo, {Edmund J.} and Karren Morrison and Pam Shaw and Catherine Reeves and Lara Winterkorn and Wexler, {Nancy S.} and Housman, {David E.} and Ng, {Christopher W.} and Li, {Alina L.} and Taft, {Ryan J.} and {Van Den Berg}, {Leonard H.} and Bentley, {David R.} and Veldink, {Jan H.} and Eberle, {Michael A.}",

note = "{\textcopyright} 2017 Dolzhenko et al.; Published by Cold Spring Harbor Laboratory Press.",

year = "2017",

month = nov,

doi = "10.1101/gr.225672.117",

language = "English",

volume = "27",

pages = "1895--1903",

journal = "Genome Research",

issn = "1088-9051",

publisher = "Cold Spring Harbor Laboratory Press",

number = "11",

}

Dolzhenko, E, Van Vugt, JJFA, Shaw, RJ, Bekritsky, MA, Van Blitterswijk, M, Narzisi, G, Ajay, SS, Rajan, V, Lajoie, B, Johnson, NH, Kingsbury, Z, Humphray, SJ, Schellevis, RD, Brands, WJ, Baker, M, Rademakers, R, Kooyman, M, Tazelaar, GHP, Van Es, MA, 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, EJ, Morrison, K, Shaw, P, Reeves, C, Winterkorn, L, Wexler, NS, Housman, DE, Ng, CW, Li, AL, Taft, RJ, Van Den Berg, LH, Bentley, DR, Veldink, JH & Eberle, MA 2017, 'Detection of long repeat expansions from PCR-free whole-genome sequence data', Genome Research, vol. 27, no. 11, pp. 1895-1903. https://doi.org/10.1101/gr.225672.117

TY - JOUR

T1 - Detection of long repeat expansions from PCR-free whole-genome sequence data

AU - Dolzhenko, Egor

AU - Van Vugt, Joke J.f.a.

AU - Shaw, Richard J.

AU - Bekritsky, Mitchell A.

AU - Van Blitterswijk, Marka

AU - Narzisi, Giuseppe

AU - Ajay, Subramanian S.

AU - Rajan, Vani

AU - Lajoie, Bryan

AU - Johnson, Nathan H.

AU - Kingsbury, Zoya

AU - Humphray, Sean J.

AU - Schellevis, Raymond D.

AU - Brands, William J.

AU - Baker, Matt

AU - Rademakers, Rosa

AU - Kooyman, Maarten

AU - Tazelaar, Gijs H.p.

AU - Van Es, Michael A.

AU - Mclaughlin, Russell

AU - Sproviero, William

AU - Shatunov, Aleksey

AU - Jones, Ashley

AU - Al Khleifat, Ahmad

AU - Pittman, Alan

AU - Morgan, Sarah

AU - Hardiman, Orla

AU - Al-chalabi, Ammar

AU - Shaw, Chris

AU - Smith, Bradley

AU - Neo, Edmund J.

AU - Morrison, Karren

AU - Shaw, Pam

AU - Reeves, Catherine

AU - Winterkorn, Lara

AU - Wexler, Nancy S.

AU - Housman, David E.

AU - Ng, Christopher W.

AU - Li, Alina L.

AU - Taft, Ryan J.

AU - Van Den Berg, Leonard H.

AU - Bentley, David R.

AU - Veldink, Jan H.

AU - Eberle, Michael A.

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

U2 - 10.1101/gr.225672.117

DO - 10.1101/gr.225672.117

M3 - Article

C2 - 28887402

SN - 1088-9051

VL - 27

SP - 1895

EP - 1903

JO - Genome Research

JF - Genome Research

IS - 11

ER -

Detection of long repeat expansions from PCR-free whole-genome sequence data

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