Whole-genome sequencing of patients with rare diseases in a national health system.
Whole-genome sequencing of patients with rare diseases in a national health system.
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DOI：
10.1038/s41586-020-2434-2
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发表时间：
2020-07
期刊：
影响因子：
64.8
通讯作者：
Ouwehand WH
中科院分区：
文献类型：
--
作者：
Turro E;Astle WJ;Megy K;Gräf S;Greene D;Shamardina O;Allen HL;Sanchis-Juan A;Frontini M;Thys C;Stephens J;Mapeta R;Burren OS;Downes K;Haimel M;Tuna S;Deevi SVV;Aitman TJ;Bennett DL;Calleja P;Carss K;Caulfield MJ;Chinnery PF;Dixon PH;Gale DP;James R;Koziell A;Laffan MA;Levine AP;Maher ER;Markus HS;Morales J;Morrell NW;Mumford AD;Ormondroyd E;Rankin S;Rendon A;Richardson S;Roberts I;Roy NBA;Saleem MA;Smith KGC;Stark H;Tan RYY;Themistocleous AC;Thrasher AJ;Watkins H;Webster AR;Wilkins MR;Williamson C;Whitworth J;Humphray S;Bentley DR;NIHR BioResource for the 100,000 Genomes Project;Kingston N;Walker N;Bradley JR;Ashford S;Penkett CJ;Freson K;Stirrups KE;Raymond FL;Ouwehand WH
大多数罕见病患者没有得到分子诊断，一半以上罕见病的病因变异和介导基因仍有待发现。我们在国家卫生系统中实施了全基因组测序（WGS），以简化诊断并在基因组的编码区和非编码区发现未知的病因变异。在100,000基因组计划的试点研究中，我们生成了13037名参与者的WGS数据，其中9802人患有罕见疾病，并为7065名患者中的1138人提供了详细的表型数据。我们确定了基因与罕见病之间的95种孟德尔关联，其中11种是自2015年以来发现的，至少79种已被确认为病因。利用UK Biobank的WGS，我们发现罕见的等位基因可以解释某些个体在定量红细胞（RBC）性状尾部的存在。最后，我们发现了4个新的非编码变异体，它们通过破坏ARPC1B、GATA1、LRBA和MPL的转录导致疾病。我们的研究表明，在常规医疗保健中，使用WGS进行诊断和病因发现具有协同作用。
Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered. We implemented 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. In a pilot study for the 100,000 Genomes Project, 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 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank, we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we identified 4 novel non-coding variants which 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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影响因子：
64.8
作者：
Jin, Fulai;Li, Yan;Dixon, Jesse R.;Selvaraj, Siddarth;Ye, Zhen;Lee, Ah Young;Yen, Chia-An;Schmitt, Anthony D.;Espinoza, Celso A.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
12.3
作者：
Burren OS;Rubio García A;Javierre BM;Rainbow DB;Cairns J;Cooper NJ;Lambourne JJ;Schofield E;Castro Dopico X;Ferreira RC;Coulson R;Burden F;Rowlston SP;Downes K;Wingett SW;Frontini M;Ouwehand WH;Fraser P;Spivakov M;Todd JA;Wicker LS;Cutler AJ;Wallace C
通讯作者：
Wallace C
影响因子：
16.6
作者：
Gräf S;Haimel M;Bleda M;Hadinnapola C;Southgate L;Li W;Hodgson J;Liu B;Salmon RM;Southwood M;Machado RD;Martin JM;Treacy CM;Yates K;Daugherty LC;Shamardina O;Whitehorn D;Holden S;Aldred M;Bogaard HJ;Church C;Coghlan G;Condliffe R;Corris PA;Danesino C;Eyries M;Gall H;Ghio S;Ghofrani HA;Gibbs JSR;Girerd B;Houweling AC;Howard L;Humbert M;Kiely DG;Kovacs G;MacKenzie Ross RV;Moledina S;Montani D;Newnham M;Olschewski A;Olschewski H;Peacock AJ;Pepke-Zaba J;Prokopenko I;Rhodes CJ;Scelsi L;Seeger W;Soubrier F;Stein DF;Suntharalingam J;Swietlik EM;Toshner MR;van Heel DA;Vonk Noordegraaf A;Waisfisz Q;Wharton J;Wort SJ;Ouwehand WH;Soranzo N;Lawrie A;Upton PD;Wilkins MR;Trembath RC;Morrell NW
通讯作者：
Morrell NW
影响因子：
9.8
作者：
Lopez-Herrera, Gabriela;Tampella, Giacomo;Grimbacher, Bodo
通讯作者：
Grimbacher, Bodo