Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.
Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.
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DOI：
10.1186/s13073-021-00855-5
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发表时间：
2021-03-17
期刊：
影响因子：
12.3
通讯作者：
Wedell A
中科院分区：
文献类型：
--
作者：
Stranneheim H;Lagerstedt-Robinson K;Magnusson M;Kvarnung M;Nilsson D;Lesko N;Engvall M;Anderlid BM;Arnell H;Johansson CB;Barbaro M;Björck E;Bruhn H;Eisfeldt J;Freyer C;Grigelioniene G;Gustavsson P;Hammarsjö A;Hellström-Pigg M;Iwarsson E;Jemt A;Laaksonen M;Enoksson SL;Malmgren H;Naess K;Nordenskjöld M;Oscarson M;Pettersson M;Rasi C;Rosenbaum A;Sahlin E;Sardh E;Stödberg T;Tesi B;Tham E;Thonberg H;Töhönen V;von Döbeln U;Vassiliou D;Vonlanthen S;Wikström AC;Wincent J;Winqvist O;Wredenberg A;Ygberg S;Zetterström RH;Marits P;Soller MJ;Nordgren A;Wirta V;Lindstrand A;Wedell A
我们报告了自2015年中期以来在卡罗林斯卡基因组医学中心（GMCK-RD）通过全基因组测序（WGS）分析的4437名个体（3219名患者和1218名亲属）的结果。GMCK-RD代表了卡罗林斯卡大学医院和生命科学实验室之间的长期合作计划，旨在斯德哥尔摩医疗保健环境中建立先进的基于基因组学的诊断。我们的分析涵盖SNV、INDEL、单亲二体、CNV、平衡结构变异和短串联重复扩增的检测和解释。Scout是一个定制开发的决策支持系统，用于临床解释的结果可视化。报告了单胞胎（84%）和三人/家庭（16%）分析的结果。医院的15个专家小组进行不同的解释，其中包括来自三个诊所的工作人员。对于具有复杂表型的患者，数据在团队之间共享。总体而言，40%的患者接受了特定疾病组的分子诊断，范围为19%至54%。致病基因存在异质性（n = 754），其中最常见的是COL 2A 1（n = 12;骨骼发育不良）、SCN 1A（n = 8;癫痫）和TNFRSF 13 B（n = 4;先天性免疫缺陷）。一些致病变异是复发性的，包括先前已知的创始者突变、一些新突变和复发性从头突变。总体而言，GMCK-RD已导致大量患者接受特定的分子诊断。此外，阴性病例已被纳入研究，导致发现了17个已发表的新的致病基因。为了促进新疾病基因的发现，GMCK-RD加入了国际数据共享计划，包括ClinVar，UDNI，Beacon和MatchMaker Exchange。GMCK-RD的临床WGS已经为1200多名患有各种罕见疾病的患者提供了分子诊断。这种临床-学术伙伴关系的巩固和传播将使大规模的国家合作成为可能。在线版本包含补充材料，可通过10.1186/s13073-021-00855-5获得。
We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting. Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout—a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams. Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange. Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration. The online version contains supplementary material available at 10.1186/s13073-021-00855-5.
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影响因子：
64.8
作者：
Gurdasani, Deepti;Carstensen, Tommy;Tekola-Ayele, Fasil;Pagani, Luca;Tachmazidou, Ioanna;Hatzikotoulas, Konstantinos;Karthikeyan, Savita;Iles, Louise;Pollard, Martin O.;Choudhury, Ananyo;Ritchie, GrahamR. S.;Xue, Yali;Asimit, Jennifer;Nsubuga, Rebecca N.;Young, Elizabeth H.;Pomilla, Cristina;Kivinen, Katja;Rockett, Kirk;Kamali, Anatoli;Doumatey, Ayo P.;Asiki, Gershim;Seeley, Janet;Sisay-Joof, Fatoumatta;Jallow, Muminatou;Tollman, Stephen;Mekonnen, Ephrem;Ekong, Rosemary;Oljira, Tamiru;Bradman, Neil;Bojang, Kalifa;Ramsay, Michele;Adeyemo, Adebowale;Bekele, Endashaw;Motala, Ayesha;Norris, Shane A.;Pirie, Fraser;Kaleebu, Pontiano;Kwiatkowski, Dominic;Tyler-Smith, Chris;Rotimi, Charles;Zeggini, Eleftheria;Sandhu, Manjinder S.
通讯作者：
Sandhu, Manjinder S.
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
4
作者：
Freyer, Christoph;Stranneheim, Henrik;Wedell, Anna
通讯作者：
Wedell, Anna
影响因子：
9.8
作者：
Acuna-Hidalgo, Rocio;Schanze, Denny;Zenker, Martin
通讯作者：
Zenker, Martin
影响因子：
11.2
作者：
Hackman, Peter;Sarparanta, Jaakko;Udd, Bjarne
通讯作者：
Udd, Bjarne