@article{472f86baafd9436aa917986d70e6d067,
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 = "{NIHR BioResource for the 100,000 Genomes Project} and 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 Irene Roberts and Roy, {Noemi B.A.} and Saleem, {Moin A.} and Hannah Stark and Tan, {Rhea Y.Y.} and Themistocleous, {Andreas C.} and Thrasher, {Adrian J.} and Hugh Watkins and Webster, {Andrew R.} and Wilkins, {Martin R.} and Catherine Williamson and James Whitworth and Sean Humphray and Bentley, {David R.} and Stephen Abbs and Lara Abulhoul and Julian Adlard and Munaza Ahmed and Aitman, {Timothy J.} and Hana Alachkar and Allsup, {David J.} and Jeff Almeida-King and Philip Ancliff and Richard Antrobus and Ruth Armstrong and Gavin Arno and Sofie Ashford and Astle, {William J.} and Anthony Attwood and Paul Aurora and Christian Babbs and Chiara Bacchelli and Tamam Bakchoul and Siddharth Banka and Tadbir Bariana and Julian Barwell and Joana Batista and Baxendale, {Helen E.} and Beales, {Phil L.} and Bennett, {David L.} and Bentley, {David R.} and Agnieszka Bierzynska and Tina Biss and Bitner-Glindzicz, {Maria A.K.} and Black, {Graeme C.} and Marta Bleda and Iulia Blesneac and Detlef Bockenhauer and Harm Bogaard and Bourne, {Christian J.} and Sara Boyce and Bradley, {John R.} and Eugene Bragin and Gerome Breen and Paul Brennan and Carole Brewer and Matthew Brown and Browning, {Andrew C.} and Browning, {Michael J.} and Buchan, {Rachel J.} and Buckland, {Matthew S.} and Teofila Bueser and Diz, {Carmen Bugarin} and John Burn and Burns, {Siobhan O.} and Burren, {Oliver S.} and Nigel Burrows and Paul Calleja and Carolyn Campbell and Gerald Carr-White and Keren Carss and Ruth Casey and Caulfield, {Mark J.} and Jenny Chambers and John Chambers and Chan, {Melanie M.Y.} and Calvin Cheah and Floria Cheng and Chinnery, {Patrick F.} and Manali Chitre and Christian, {Martin T.} and Colin Church and Jill Clayton-Smith and Maureen Cleary and Brod, {Naomi Clements} and Gerry Coghlan and Elizabeth Colby and Cole, {Trevor R.P.} and Janine Collins and Collins, {Peter W.} and Camilla Colombo and Compton, {Cecilia J.} and Robin Condliffe and Stuart Cook and Cook, {H. Terence} and Nichola Cooper and Corris, {Paul A A.} and Abigail Furnell and Fiona Cunningham and Curry, {Nicola S.} and Cutler, {Antony J.} and Daniels, {Matthew J.} and Mehul Dattani and Daugherty, {Louise C.} and John Davis and {De Soyza}, Anthony and Deevi, {Sri V.V.} and Timothy Dent and Charu Deshpande and Dewhurst, {Eleanor F.} and Dixon, {Peter H.} and Sofia Douzgou and Kate Downes and Drazyk, {Anna M.} and Elizabeth Drewe and Daniel Duarte and Tina Dutt and Edgar, {J. David M.} and Karen Edwards and William Egner and Ekani, {Melanie N.} and Perry Elliott and Erber, {Wendy N.} and Marie Erwood and Estiu, {Maria C.} and Evans, {Dafydd Gareth} and Gillian Evans and Tamara Everington and M{\'e}lanie Eyries and Hiva Fassihi and Remi Favier and Jack Findhammer and Debra Fletcher and Flinter, {Frances A.} and Floto, {R. Andres} and Tom Fowler and James Fox and Frary, {Amy J.} and French, {Courtney E.} and Kathleen Freson and Mattia Frontini and Gale, {Daniel P.} and Henning Gall and Vijeya Ganesan and Michael Gattens and Claire Geoghegan and Gerighty, {Terence S.A.} and Gharavi, {Ali G.} and Stefano Ghio and Ghofrani, {Hossein Ardeschir} and Gibbs, {J. Simon R.} and Kate Gibson and Gilmour, {Kimberly C.} and Barbara Girerd and Gleadall, {Nicholas S.} and Sarah Goddard and Goldstein, {David B.} and Keith Gomez and Pavels Gordins and David Gosal and Stefan Gr{\"a}f and Jodie Graham and Luigi Grassi and Daniel Greene and Lynn Greenhalgh and Andreas Greinacher and Paolo Gresele and Philip Griffiths and Sofia Grigoriadou and Grocock, {Russell J.} and Detelina Grozeva and Mark Gurnell and Scott Hackett and Charaka Hadinnapola and Hague, {William M.} and Rosie Hague and Matthias Haimel and Matthew Hall and Hanson, {Helen L.} and Eshika Haque and Kirsty Harkness and Harper, {Andrew R.} and Harris, {Claire L L.} and Daniel Hart and Ahamad Hassan and Grant Hayman and Alex Henderson and Archana Herwadkar and Jonathan Hoffman and Simon Holden and Rita Horvath and Henry Houlden and Houweling, {Arjan C C.} and Howard, {Luke S.} and Fengyuan Hu and Gavin Hudson and Joseph Hughes and Huissoon, {Aarnoud P.} and Marc Humbert and Sean Humphray and Sarah Hunter and Matthew Hurles and Melita Irving and Louise Izatt and Roger James and Johnson, {Sally A.} and Stephen Jolles and Jennifer Jolley and Ajith Kumar and Smith, {Kenneth G.C.} and Wei Wei",
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 Publishing Group - Macmillan Publishers",
number = "7814",
}