Whole-genome Sequencing of Patients with Rare Diseases in a National Health System

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. 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 participants, 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.

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References

Ferreira C . The burden of rare diseases. Am J Med Genet A. 2019; 179(6):885-892. DOI: 10.1002/ajmg.a.61124. View

Bycroft C, Freeman C, Petkova D, Band G, Elliott L, Sharp K . The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018; 562(7726):203-209. PMC: 6786975. DOI: 10.1038/s41586-018-0579-z. View

Boycott K, Rath A, Chong J, Hartley T, Alkuraya F, Baynam G . International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases. Am J Hum Genet. 2017; 100(5):695-705. PMC: 5420351. DOI: 10.1016/j.ajhg.2017.04.003. View

Vissers L, van Nimwegen K, Schieving J, Kamsteeg E, Kleefstra T, Yntema H . A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017; 19(9):1055-1063. PMC: 5589982. DOI: 10.1038/gim.2017.1. View

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

Astle W, Elding H, Jiang T, Allen D, Ruklisa D, Mann A . The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease. Cell. 2016; 167(5):1415-1429.e19. PMC: 5300907. DOI: 10.1016/j.cell.2016.10.042. View

Belkadi A, Bolze A, Itan Y, Cobat A, Vincent Q, Antipenko A . Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci U S A. 2015; 112(17):5473-8. PMC: 4418901. DOI: 10.1073/pnas.1418631112. View

Carss K, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S . Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. Am J Hum Genet. 2017; 100(1):75-90. PMC: 5223092. DOI: 10.1016/j.ajhg.2016.12.003. View

Meyer E, Carss K, Rankin J, Nichols J, Grozeva D, Joseph A . Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2016; 49(2):223-237. DOI: 10.1038/ng.3740. View

10.

Stritt S, Nurden P, Turro E, Greene D, Jansen S, Westbury S . A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood. 2016; 127(23):2903-14. DOI: 10.1182/blood-2015-10-675629. View

11.

Westbury S, Downes K, Burney C, Lozano M, Obaji S, Toh C . Phenotype description and response to thrombopoietin receptor agonist in -related disorder. Blood Adv. 2018; 2(18):2341-2346. PMC: 6156883. DOI: 10.1182/bloodadvances.2018020370. View

12.

Turro E, Greene D, Wijgaerts A, Thys C, Lentaigne C, Bariana T . A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies. Sci Transl Med. 2016; 8(328):328ra30. PMC: 5903547. DOI: 10.1126/scitranslmed.aad7666. View

13.

Tuijnenburg P, Lango Allen H, Burns S, Greene D, Jansen M, Staples E . Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. J Allergy Clin Immunol. 2018; 142(4):1285-1296. PMC: 6148345. DOI: 10.1016/j.jaci.2018.01.039. View

14.

Noris P, Favier R, Alessi M, Geddis A, Kunishima S, Heller P . ANKRD26-related thrombocytopenia and myeloid malignancies. Blood. 2013; 122(11):1987-9. DOI: 10.1182/blood-2013-04-499319. View

15.

Noetzli L, Lo R, Lee-Sherick A, Callaghan M, Noris P, Savoia A . Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015; 47(5):535-538. PMC: 4631613. DOI: 10.1038/ng.3253. View

16.

Song W, Sullivan M, Legare R, Hutchings S, Tan X, Kufrin D . Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999; 23(2):166-75. DOI: 10.1038/13793. View

17.

Evans J, Girerd B, Montani D, Wang X, Galie N, Austin E . BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med. 2016; 4(2):129-37. PMC: 4737700. DOI: 10.1016/S2213-2600(15)00544-5. View

18.

Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmuller P . Phenotypic Characterization of Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension. Circulation. 2017; 136(21):2022-2033. PMC: 5700414. DOI: 10.1161/CIRCULATIONAHA.117.028351. View

19.

Graf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W . Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat Commun. 2018; 9(1):1416. PMC: 5897357. DOI: 10.1038/s41467-018-03672-4. View

20.

Philippakis A, Azzariti D, Beltran S, Brookes A, Brownstein C, Brudno M . The Matchmaker Exchange: a platform for rare disease gene discovery. Hum Mutat. 2015; 36(10):915-21. PMC: 4610002. DOI: 10.1002/humu.22858. View