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


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Type
Article
Change log
Authors
Turro, Ernest 
Astle, William J 
Megy, Karyn 
Gräf, Stefan 
Greene, Daniel 
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.

Description
Keywords
Actin-Related Protein 2-3 Complex, Adaptor Proteins, Signal Transducing, Alleles, Databases, Factual, Erythrocytes, GATA1 Transcription Factor, Humans, Internationality, National Health Programs, Phenotype, Quantitative Trait Loci, Rare Diseases, Receptors, Thrombopoietin, State Medicine, United Kingdom, Whole Genome Sequencing
Journal Title
Nature
Conference Name
Journal ISSN
0028-0836
1476-4687
Volume Title
583
Publisher
Springer Science and Business Media LLC
Rights
All rights reserved
Sponsorship
Medical Research Council (MR/L019027/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Medical Research Council (MR/K020919/1)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC 2012-2017)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Fondation Botnar (Project 603)
Cystic Fibrosis Trust (IH 001)
Wellcome Trust (109915_A_15_Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust (212219/Z/18/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (BRC)
Cancer Research UK (C20/A20917)
British Heart Foundation (RG/16/4/32218)
Medical Research Council (MR/N025431/2)
British Heart Foundation (None)
Medical Research Council (MC_PC_14089)
Medical Research Council (MC_PC_18030)
Medical Research Council (MR/R002363/1)
Wellcome Trust (206617/Z/17/Z)