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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.

SUBMITTER: Turro E

PROVIDER: S-EPMC7610553 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Turro Ernest E Astle William J WJ Megy Karyn K Gräf Stefan S Greene Daniel D Shamardina Olga O Allen Hana Lango HL Sanchis-Juan Alba A Frontini Mattia M Thys Chantal C Stephens Jonathan J Mapeta Rutendo R Burren Oliver S OS Downes Kate K Haimel Matthias M Tuna Salih S Deevi Sri V V SVV Aitman Timothy J TJ Bennett David L DL Calleja Paul P Carss Keren K Caulfield Mark J MJ Chinnery Patrick F PF Dixon Peter H PH Gale Daniel P DP James Roger R Koziell Ania A Laffan Michael A MA Levine Adam P AP Maher Eamonn R ER Markus Hugh S HS Morales Joannella J Morrell Nicholas W NW Mumford Andrew D AD Ormondroyd Elizabeth E Rankin Stuart S Rendon Augusto A Richardson Sylvia S Roberts Irene I Roy Noemi B A NBA Saleem Moin A MA Smith Kenneth G C KGC Stark Hannah H Tan Rhea Y Y RYY Themistocleous Andreas C AC Thrasher Adrian J AJ Watkins Hugh H Webster Andrew R AR Wilkins Martin R MR Williamson Catherine C Whitworth James J Humphray Sean S Bentley David R DR Kingston Nathalie N Walker Neil N Bradley John R JR Ashford Sofie S Penkett Christopher J CJ Freson Kathleen K Stirrups Kathleen E KE Raymond F Lucy FL Ouwehand Willem H WH

Nature 20200624 7814

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 discovered<sup>1</sup>. 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 ...[more]

PMID: 32581362

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Project description:BackgroundRare diseases are one of the major challenges in the era of precision medicine and reflect the social security level of minority groups. This study aimed to investigate healthcare service utilization and health security of patients with rare diseases in China.MethodsFrom 29 provinces of Mainland China, 7,747 visits with eight common rare diseases who were linked to the national insurance database between 2014 and 2016 were selected as the study population, whose demographic and healthcare service information was collected from China's national monitoring system for health service utilization of patients with healthcare insurance. Univariate analysis was performed to describe the basic statement of healthcare service, such as visit type, institution type, length of stay, healthcare insurance utilization, and the results of disease burden for different groups and its factors were analyzed by multivariate analysis.ResultsMedical treatment from general tertiary hospitals was sought by 61.4% of the patients with rare diseases. Of the total treatment cost (TTC) of 40.18 million Chinese Yuan, 63.3% was paid by basic health insurance, and 54.2% of the medical cost resulted from medicine expenditure. Demography, geography and social-economic factors, security level, and health institution situation had an effect on the TTC. The correlations between these factors and TTC were different for outpatients and inpatients. Reimbursement rate had the highest effect on inpatients' TTC. Basic insurance was effective for providing support for patients with rare diseases that involved high costs; however, the coverage was limited.ConclusionsHealthcare insurance is an effective safeguard for patients with rare diseases; however, affordable and accessible treatment is still lacking for such patients. There remains a need to further improve the diagnostic and treatment technology for rare diseases and expertise among doctors, as well as the security level of healthcare policies.

Dataset Information

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

Publications

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

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