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

• DOI: 10.1530/ey.18.14.6
• Publication Date: 2021-09-22T02:14:57Z
• Authors: Ernest Turro; William J Astle; Karyn Megy; Stefan Graf; 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; Irene Roberts; Noemi B A Roy; Moin A Saleem; Kenneth G C Smith; Hannah Stark; Rhea Y Y Tan; Andreas C Themist...; Adrian J Thrasher; Hugh Watkins; Andrew R Webster; Martin R Wilkins; Catherine Williamson; James Whitworth; Sean Humphray; David R Bentley; Nathalie Kingston; Neil Walker; John R Bradley; Sofie Ashford; Christopher J Pen...; Kathleen Freson; Kathleen E Stirrups; F Lucy Raymond; Willem H Ouwehand
• Keywords: 0301 basic medicine; Erythrocytes; Internationality; Databases, Factual; National Health Programs; [SDV]Life Sciences [q-bio]; VARIANTS; State Medicine; NIHR BioResource for the 100,000 Genomes Project; Receptors; Genetics research; GATA1 Transcription Factor; 0303 health sciences; Multidisciplinary; Disease genetics; Adaptor Proteins; ASSOCIATION; 3. Good health; Multidisciplinary Sciences; [SDV] Life Sciences [q-bio]; Phenotype; Thrombopoietin; disease genetics; Science & Technology - Other Topics; Receptors, Thrombopoietin; General Science & Technology; Quantitative Trait Loci; 610; DIAGNOSIS; computational biology and bioinformatics; Actin-Related Protein 2-3 Complex; LINKS; Databases; 03 medical and health sciences; Rare Diseases; 616; Humans; Factual; Alleles; Adaptor Proteins, Signal Transducing; Science & Technology; Whole Genome Sequencing; MUTATIONS; THROMBOCYTOPENIA; Signal Transducing; United Kingdom; Computational biology and bioinformatics; MACROTHROMBOCYTOPENIA; genetics research

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.