Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients

被引：179

作者：

Stranneheim, Henrik ^{[1
,2
,3
]}

Lagerstedt-Robinson, Kristina ^{[1
,4
]}

Magnusson, Mans ^{[1
,3
]}

Kvarnung, Malin ^{[1
,4
]}

Nilsson, Daniel ^{[1
,4
]}

Lesko, Nicole ^{[1
,2
]}

Engvall, Martin ^{[1
,2
]}

Anderlid, Britt-Marie ^{[1
,4
]}

Arnell, Henrik ^{[5
]}

Johansson, Carolina Backman ^{[2
]}

Barbaro, Michela ^{[2
]}

Bjorck, Erik ^{[1
,4
]}

Bruhn, Helene ^{[2
,6
]}

Eisfeldt, Jesper ^{[1
,4
]}

Freyer, Christoph ^{[2
,6
]}

Grigelioniene, Giedre ^{[1
,4
]}

Gustavsson, Peter ^{[1
,4
]}

Hammarsjo, Anna ^{[1
,4
]}

Hellstrom-Pigg, Maritta ^{[1
,4
]}

Iwarsson, Erik ^{[1
,4
]}

Jemt, Anders ^{[1
]}

Laaksonen, Mikael ^{[7
]}

Enoksson, Sara Lind ^{[8
]}

Malmgren, Helena ^{[1
,4
]}

Naess, Karin ^{[2
]}

Nordenskjold, Magnus ^{[1
,4
]}

Oscarson, Mikael ^{[2
]}

Pettersson, Maria ^{[1
,4
]}

Rasi, Chiara ^{[3
]}

Rosenbaum, Adam ^{[7
]}

Sahlin, Ellika ^{[1
,4
]}

Sardh, Eliane ^{[1
,2
]}

Stodberg, Tommy ^{[2
,5
]}

Tesi, Bianca ^{[1
,4
]}

Tham, Emma ^{[1
,4
]}

Thonberg, Hakan ^{[1
,4
]}

Tohonen, Virpi ^{[1
]}

von Dobeln, Ulrika ^{[2
]}

Vassiliou, Daphne ^{[1
,2
]}

Vonlanthen, Sofie ^{[5
,8
]}

Wikstrom, Ann-Charlotte ^{[8
]}

Wincent, Josephine ^{[1
,4
]}

Winqvist, Ola ^{[8
]}

Wredenberg, Anna ^{[2
,6
]}

Ygberg, Sofia ^{[2
]}

Zetterstrom, Rolf H. ^{[1
,2
]}

Marits, Per ^{[8
]}

Soller, Maria Johansson ^{[1
,4
]}

Nordgren, Ann ^{[1
,4
]}

Wirta, Valtteri ^{[3
,7
]}

机构：

[1] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[2] Karolinska Univ Hosp, Ctr Inherited Metab Dis, Stockholm, Sweden

[3] Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Sci Life Lab, Stockholm, Sweden

[4] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden

[5] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden

[6] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden

[7] KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Sci Life Lab, Stockholm, Sweden

[8] Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden

[9] Karolinska Inst, Dept Mol Med & Surg, Sci Life Lab, Stockholm, Sweden

来源：

GENOME MEDICINE | 2021年 / 13卷 / 01期

基金：

瑞典研究理事会;

关键词：

Whole genome sequencing; Monogenic disease; Single nucleotide variant; Clinical diagnostics; INTELLECTUAL DISABILITY; MUTATIONS; DEFICIENCY; IDENTIFICATION; VARIANTS; MYOPATHY; ABSENCE;

D O I：

10.1186/s13073-021-00855-5

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background 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. Methods 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. Results 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. Conclusions 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.

引用

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