Whole-genome sequencing of patients with rare diseases in a national health system

Ernest Turro; William J. Astle; Karyn Megy; Stefan Gräf; Daniel Greene; Olga Shamardina; Hana Lango Allen; Alba Sanchis-Juan; Mattia Frontini; Chantal Thys; Jonathan Stephens; Rutendo Mapeta; Oliver S. Burren; Kate Downes; Matthias Haimel; Salih Tuna; Sri V.V. Deevi; Timothy J. Aitman; David L. Bennett; Paul Calleja; Keren Carss; Mark J. Caulfield; Patrick F. Chinnery; Peter H. Dixon; Daniel P. Gale; Roger James; Ania Koziell; Michael A. Laffan; Adam P. Levine; Eamonn R. Maher; Hugh S. Markus; Joannella Morales; Nicholas W. Morrell; Andrew D. Mumford; Elizabeth Ormondroyd; Stuart Rankin; Augusto Rendon; Sylvia Richardson; David L. Bennett; Teofila Bueser; Gerald Carr-White; Frances A. Flinter; Melita Irving; Dragana Josifova; Ania Koziell; Shehla N. Mohammed; Ellen Thomas; Matthew Traylor; Richard Trembath; Catherine Williamson; NIHR BioResource for the 100,000 Genomes Project

doi:10.1038/s41586-020-2434-2

Whole-genome sequencing of patients with rare diseases in a national health system

Ernest Turro
, William J. Astle
, Karyn Megy
, Stefan Gräf
, Daniel Greene
, Olga Shamardina
, Hana Lango Allen
, Alba Sanchis-Juan
, Mattia Frontini
, Chantal Thys
, Jonathan Stephens
, Rutendo Mapeta
, Oliver S. Burren
, Kate Downes
, Matthias Haimel
, Salih Tuna
, Sri V.V. Deevi
, Timothy J. Aitman
, David L. Bennett
, Paul Calleja

Keren Carss, Mark J. Caulfield, Patrick F. Chinnery, Peter H. Dixon, Daniel P. Gale, Roger James, Ania Koziell, Michael A. Laffan, Adam P. Levine, Eamonn R. Maher, Hugh S. Markus, Joannella Morales, Nicholas W. Morrell, Andrew D. Mumford, Elizabeth Ormondroyd, Stuart Rankin, Augusto Rendon, Sylvia Richardson, David L. Bennett, Teofila Bueser, Gerald Carr-White, Frances A. Flinter, Melita Irving, Dragana Josifova, Ania Koziell, Shehla N. Mohammed, Ellen Thomas, Matthew Traylor, Richard Trembath, Catherine Williamson, NIHR BioResource for the 100,000 Genomes Project

Cambridge University Hospitals NHS Foundation Trust
University of Cambridge
NHS Blood and Transplant
KU Leuven
Jeffrey Cheah Biomedical Centre
Imperial College London
Medical Schoo
University of Oxford
Oxford University Hospitals Trust
Genomics England Ltd.
Barts and The London Queen Mary's School of Medicine and Dentistry
MRC Mitochondrial Biology Unit
King's College London
UCL University College London
UK Renal Registry
Department of Paediatric Nephrology
GSTT Guy's and St Thomas' NHS Foundation Trust
NIHR Cambridge Biomedical Research Centre
CRUK Cancer Research UK
European Molecular Biology Laboratory Cambridge
University of Bristol
University Hospital Bristol NHS Foundation Trust
NIHR Oxford Biomedical Research Centre (BRC)
Clinical Genetics Department

Research output: Contribution to journal › Article › peer-review

463 Citations (Scopus)

2525 Downloads (Pure)

Abstract

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered¹. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants², we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Original language	English
Pages (from-to)	96-102
Number of pages	7
Journal	Nature
Volume	583
Issue number	7814
Early online date	24 Jun 2020
DOIs	https://doi.org/10.1038/s41586-020-2434-2
Publication status	Published - 2 Jul 2020

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Turro, E., Astle, W. J., Megy, K., Gräf, S., Greene, D., Shamardina, O., Allen, H. L., Sanchis-Juan, A., Frontini, M., Thys, C., Stephens, J., Mapeta, R., Burren, O. S., Downes, K., Haimel, M., Tuna, S., Deevi, S. V. V., Aitman, T. J., Bennett, D. L., ... NIHR BioResource for the 100,000 Genomes Project (2020). Whole-genome sequencing of patients with rare diseases in a national health system. Nature, 583(7814), 96-102. https://doi.org/10.1038/s41586-020-2434-2

@article{d47d5d4ee42c4314901e21a27f68c082,

title = "Whole-genome sequencing of patients with rare diseases in a national health system",

abstract = "Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.",

author = "Ernest Turro and Astle, \{William J.\} and Karyn Megy and Stefan Gr{\"a}f and Daniel Greene and Olga Shamardina and Allen, \{Hana Lango\} and Alba Sanchis-Juan and Mattia Frontini and Chantal Thys and Jonathan Stephens and Rutendo Mapeta and Burren, \{Oliver S.\} and Kate Downes and Matthias Haimel and Salih Tuna and Deevi, \{Sri V.V.\} and Aitman, \{Timothy J.\} and Bennett, \{David L.\} and Paul Calleja and Keren Carss and Caulfield, \{Mark J.\} and Chinnery, \{Patrick F.\} and Dixon, \{Peter H.\} and Gale, \{Daniel P.\} and Roger James and Ania Koziell and Laffan, \{Michael A.\} and Levine, \{Adam P.\} and Maher, \{Eamonn R.\} and Markus, \{Hugh S.\} and Joannella Morales and Morrell, \{Nicholas W.\} and Mumford, \{Andrew D.\} and Elizabeth Ormondroyd and Stuart Rankin and Augusto Rendon and Sylvia Richardson and Bennett, \{David L.\} and Teofila Bueser and Gerald Carr-White and Flinter, \{Frances A.\} and Melita Irving and Dragana Josifova and Ania Koziell and Mohammed, \{Shehla N.\} and Ellen Thomas and Matthew Traylor and Richard Trembath and Catherine Williamson and \{NIHR BioResource for the 100,000 Genomes Project\}",

year = "2020",

month = jul,

day = "2",

doi = "10.1038/s41586-020-2434-2",

language = "English",

volume = "583",

pages = "96--102",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7814",

}

Turro, E, Astle, WJ, Megy, K, Gräf, S, Greene, D, Shamardina, O, Allen, HL, Sanchis-Juan, A, Frontini, M, Thys, C, Stephens, J, Mapeta, R, Burren, OS, Downes, K, Haimel, M, Tuna, S, Deevi, SVV, Aitman, TJ, Bennett, DL, Calleja, P, Carss, K, Caulfield, MJ, Chinnery, PF, Dixon, PH, Gale, DP, James, R, Koziell, A, Laffan, MA, Levine, AP, Maher, ER, Markus, HS, Morales, J, Morrell, NW, Mumford, AD, Ormondroyd, E, Rankin, S, Rendon, A, Richardson, S, Bennett, DL, Bueser, T , Carr-White, G , Flinter, FA , Irving, M , Josifova, D , Koziell, A , Mohammed, SN , Thomas, E , Traylor, M , Trembath, R , Williamson, C & NIHR BioResource for the 100,000 Genomes Project 2020, 'Whole-genome sequencing of patients with rare diseases in a national health system', Nature, vol. 583, no. 7814, pp. 96-102. https://doi.org/10.1038/s41586-020-2434-2

TY - JOUR

T1 - Whole-genome sequencing of patients with rare diseases in a national health system

AU - Turro, Ernest

AU - Astle, William J.

AU - Megy, Karyn

AU - Gräf, Stefan

AU - Greene, Daniel

AU - Shamardina, Olga

AU - Allen, Hana Lango

AU - Sanchis-Juan, Alba

AU - Frontini, Mattia

AU - Thys, Chantal

AU - Stephens, Jonathan

AU - Mapeta, Rutendo

AU - Burren, Oliver S.

AU - Downes, Kate

AU - Haimel, Matthias

AU - Tuna, Salih

AU - Deevi, Sri V.V.

AU - Aitman, Timothy J.

AU - Bennett, David L.

AU - Calleja, Paul

AU - Carss, Keren

AU - Caulfield, Mark J.

AU - Chinnery, Patrick F.

AU - Dixon, Peter H.

AU - Gale, Daniel P.

AU - James, Roger

AU - Koziell, Ania

AU - Laffan, Michael A.

AU - Levine, Adam P.

AU - Maher, Eamonn R.

AU - Markus, Hugh S.

AU - Morales, Joannella

AU - Morrell, Nicholas W.

AU - Mumford, Andrew D.

AU - Ormondroyd, Elizabeth

AU - Rankin, Stuart

AU - Rendon, Augusto

AU - Richardson, Sylvia

AU - Bennett, David L.

AU - Bueser, Teofila

AU - Carr-White, Gerald

AU - Flinter, Frances A.

AU - Irving, Melita

AU - Josifova, Dragana

AU - Koziell, Ania

AU - Mohammed, Shehla N.

AU - Thomas, Ellen

AU - Traylor, Matthew

AU - Trembath, Richard

AU - Williamson, Catherine

AU - NIHR BioResource for the 100,000 Genomes Project

PY - 2020/7/2

Y1 - 2020/7/2

N2 - Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

AB - Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

UR - https://www.scopus.com/pages/publications/85086777024

U2 - 10.1038/s41586-020-2434-2

DO - 10.1038/s41586-020-2434-2

M3 - Article

C2 - 32581362

AN - SCOPUS:85086777024

SN - 0028-0836

VL - 583

SP - 96

EP - 102

JO - Nature

JF - Nature

IS - 7814

ER -

Whole-genome sequencing of patients with rare diseases in a national health system

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