100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
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DOI：
10.1056/nejmoa2035790
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发表时间：
2021-11-11
期刊：
影响因子：
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通讯作者：
Caulfield M
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作者：
100,000 Genomes Project Pilot Investigators;Smedley D;Smith KR;Martin A;Thomas EA;McDonagh EM;Cipriani V;Ellingford JM;Arno G;Tucci A;Vandrovcova J;Chan G;Williams HJ;Ratnaike T;Wei W;Stirrups K;Ibanez K;Moutsianas L;Wielscher M;Need A;Barnes MR;Vestito L;Buchanan J;Wordsworth S;Ashford S;Rehmström K;Li E;Fuller G;Twiss P;Spasic-Boskovic O;Halsall S;Floto RA;Poole K;Wagner A;Mehta SG;Gurnell M;Burrows N;James R;Penkett C;Dewhurst E;Gräf S;Mapeta R;Kasanicki M;Haworth A;Savage H;Babcock M;Reese MG;Bale M;Baple E;Boustred C;Brittain H;de Burca A;Bleda M;Devereau A;Halai D;Haraldsdottir E;Hyder Z;Kasperaviciute D;Patch C;Polychronopoulos D;Matchan A;Sultana R;Ryten M;Tavares ALT;Tregidgo C;Turnbull C;Welland M;Wood S;Snow C;Williams E;Leigh S;Foulger RE;Daugherty LC;Niblock O;Leong IUS;Wright CF;Davies J;Crichton C;Welch J;Woods K;Abulhoul L;Aurora P;Bockenhauer D;Broomfield A;Cleary MA;Lam T;Dattani M;Footitt E;Ganesan V;Grunewald S;Compeyrot-Lacassagne S;Muntoni F;Pilkington C;Quinlivan R;Thapar N;Wallis C;Wedderburn LR;Worth A;Bueser T;Compton C;Deshpande C;Fassihi H;Haque E;Izatt L;Josifova D;Mohammed S;Robert L;Rose S;Ruddy D;Sarkany R;Say G;Shaw AC;Wolejko A;Habib B;Burns G;Hunter S;Grocock RJ;Humphray SJ;Robinson PN;Haendel M;Simpson MA;Banka S;Clayton-Smith J;Douzgou S;Hall G;Thomas HB;O'Keefe RT;Michaelides M;Moore AT;Malka S;Pontikos N;Browning AC;Straub V;Gorman GS;Horvath R;Quinton R;Schaefer AM;Yu-Wai-Man P;Turnbull DM;McFarland R;Taylor RW;O'Connor E;Yip J;Newland K;Morris HR;Polke J;Wood NW;Campbell C;Camps C;Gibson K;Koelling N;Lester T;Németh AH;Palles C;Patel S;Roy NBA;Sen A;Taylor J;Cacheiro P;Jacobsen JO;Seaby EG;Davison V;Chitty L;Douglas A;Naresh K;McMullan D;Ellard S;Temple IK;Mumford AD;Wilson G;Beales P;Bitner-Glindzicz M;Black G;Bradley JR;Brennan P;Burn J;Chinnery PF;Elliott P;Flinter F;Houlden H;Irving M;Newman W;Rahman S;Sayer JA;Taylor JC;Webster AR;Wilkie AOM;Ouwehand WH;Raymond FL;Chisholm J;Hill S;Bentley D;Scott RH;Fowler T;Rendon A;Caulfield M
英国10万基因组计划正在调查未被诊断的罕见疾病患者在常规护理后进行基因组测序的作用，以及研究与英国国家医疗服务体系医疗保健实施的一致性。(该项目的其他部分侧重于癌症和感染患者。)我们招募了参与者，收集了具有人类表型本体术语的临床特征，进行了基因组测序，并应用基于虚拟基因面板(PanelApp)和表型(Exomiser)的自动变异优先顺序，同时通过研究分析识别新的致病变异。我们报告了一项对来自2183个家庭、161个疾病的4660名参与者的初步研究结果，涵盖了广泛的罕见疾病。诊断结果因家系结构不同而不同，在三个家系和较大的家系中最高。可能的单基因疾病对智力残疾、听力和视力障碍的诊断收益率要高得多(35%)，收益率在40%到55%之间。那些病因较复杂的患者总体收益率为25%。研究和自动化方法的结合对14%的诊断至关重要，在这些诊断中，我们发现外显子组测序覆盖不佳的病因性非编码、结构和线粒体基因组变异和编码变异。对57,000个基因组进行全队列负担测试，发现了3个新的疾病基因和19个新的关联。在我们做出的基因诊断中，24%对患者或他们的亲属的临床决策有直接影响。我们在国家医疗保健系统中进行的基因组测序试点研究表明，对一系列罕见疾病的诊断能力有所提高。(由国家卫生研究所和其他机构资助)
The UK 100,000 Genomes Project is in the process of investigating the role of genome sequencing of patients with undiagnosed rare disease following usual care, and the alignment of research with healthcare implementation in the UK’s national health service. (Other parts of this Project focus on patients with cancer and infection.) We enrolled participants, collected clinical features with human phenotype ontology terms, undertook genome sequencing and applied automated variant prioritization based on virtual gene panels (PanelApp) and phenotypes (Exomiser), alongside identification of novel pathogenic variants through research analysis. We report results on a pilot study of 4660 participants from 2183 families with 161 disorders covering a broad spectrum of rare disease. Diagnostic yields varied by family structure and were highest in trios and larger pedigrees. Likely monogenic disorders had much higher diagnostic yields (35%) with intellectual disability, hearing and vision disorders, achieving yields between 40 and 55%. Those with more complex etiologies had an overall 25% yield. Combining research and automated approaches was critical to 14% of diagnoses in which we found etiologic non-coding, structural and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohort-wide burden testing across 57,000 genomes enabled discovery of 3 new disease genes and 19 novel associations. Of the genetic diagnoses that we made, 24% had immediate ramifications for the clinical decision-making for the patient or their relatives. Our pilot study of genome sequencing in a national health care system demonstrates diagnostic uplift across a range of rare diseases. (Funded by National Institute for Health Research and others)