100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.


Damian Smedley
Katherine R Smith
Antonio Martin
Ellen A Thomas
Ellen M McDonagh
Valentina Cipriani
Jamie M Ellingford
Gavin Arno
Arianna Tucci
Jana Vandrovcova
Georgia Chan
Hywel J Williams
Thiloka Ratnaike
Wei Wei
Kathleen Stirrups
Kristina Ibanez
Loukas Moutsianas
Matthias Wielscher
Anna Need
Michael R Barnes
Letizia Vestito
James Buchanan
Sarah Wordsworth
Sofie Ashford
Karola Rehmström
Emily Li
Gavin Fuller
Philip Twiss
Olivera Spasic-Boskovic
Sally Halsall
R Andres Floto
Kenneth Poole
Annette Wagner
Sarju G Mehta
Mark Gurnell
Nigel Burrows
Roger James
Christopher Penkett
Eleanor Dewhurst
Stefan Gräf
Rutendo Mapeta
Mary Kasanicki
Andrea Haworth
Helen Savage
Melanie Babcock
Martin G Reese
Mark Bale
Emma Baple
Christopher Boustred
Helen Brittain
Anna de Burca
Marta Bleda
Andrew Devereau
Dina Halai
Eik Haraldsdottir
Zerin Hyder
Dalia Kasperaviciute
Christine Patch
Dimitris Polychronopoulos
Angela Matchan
Razvan Sultana
Mina Ryten
Ana L T Tavares
Carolyn Tregidgo
Clare Turnbull
Matthew Welland
Suzanne Wood
Catherine Snow
Eleanor Williams
Sarah Leigh
Rebecca E Foulger
Louise C Daugherty
Olivia Niblock
Ivone U S Leong
Caroline F Wright
Jim Davies
Charles Crichton
James Welch
Kerrie Woods
Lara Abulhoul
Paul Aurora
Detlef Bockenhauer
Alexander Broomfield
Maureen A Cleary
Tanya Lam
Mehul Dattani
Emma Footitt
Vijeya Ganesan
Stephanie Grunewald
Sandrine Compeyrot-Lacassagne
Francesco Muntoni
Clarissa Pilkington
Rosaline Quinlivan
Nikhil Thapar
Colin Wallis
Lucy R Wedderburn
Austen Worth
Teofila Bueser
Cecilia Compton
Charu Deshpande
Hiva Fassihi
Eshika Haque
Louise Izatt
Dragana Josifova
Shehla Mohammed
Leema Robert
Sarah Rose
Deborah Ruddy
Robert Sarkany
Genevieve Say
Adam C Shaw
Agata Wolejko
Bishoy Habib
Gavin Burns
Sarah Hunter
Russell J Grocock
Sean J Humphray
Peter N Robinson, The Jackson LaboratoryFollow
Melissa Haendel
Michael A Simpson
Siddharth Banka
Jill Clayton-Smith
Sofia Douzgou
Georgina Hall
Huw B Thomas
Raymond T O'Keefe
Michel Michaelides
Anthony T Moore
Sam Malka
Nikolas Pontikos
Andrew C Browning
Volker Straub
Gráinne S Gorman
Rita Horvath
Richard Quinton
Andrew M Schaefer
Patrick Yu-Wai-Man
Doug M Turnbull
Robert McFarland
Robert W Taylor
Emer O'Connor
Janice Yip
Katrina Newland
Huw R Morris
James Polke
Nicholas W Wood
Carolyn Campbell
Carme Camps
Kate Gibson
Nils Koelling
Tracy Lester
Andrea H Németh
Claire Palles
Smita Patel
Noemi B A Roy
Arjune Sen
John Taylor
Pilar Cacheiro
Julius O Jacobsen
Eleanor G Seaby
Val Davison
Lyn Chitty
Angela Douglas
Kikkeri Naresh
Dom McMullan
Sian Ellard
I Karen Temple
Andrew D Mumford
Gill Wilson
Phil Beales
Maria Bitner-Glindzicz
Graeme Black
John R Bradley
Paul Brennan
John Burn
Patrick F Chinnery
Perry Elliott
Frances Flinter
Henry Houlden
Melita Irving
William Newman
Shamima Rahman
John A Sayer
Jenny C Taylor
Andrew R Webster
Andrew O M Wilkie
Willem H Ouwehand
F Lucy Raymond
John Chisholm
Sue Hill
David Bentley
Richard H Scott
Tom Fowler
Augusto Rendon
Mark Caulfield

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Publication Title

The New England journal of medicine


JGM, Adolescent, Adult, Child, Child, Preschool, Family Characteristics, Female, Genetic Variation, Genome, Human, Humans, Male, Middle Aged, Pilot Projects, Polymerase Chain Reaction, Rare Diseases, Sensitivity and Specificity, State Medicine, United Kingdom, Whole Genome Sequencing, Young Adult

JAX Source

N Engl J Med 2021 Nov 11; 385(20):1868-1880





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BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.

METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.

RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.

CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).