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

Genome Medicine

Ulrika von Döbeln¹  Mikael Oscarson¹  Michela Barbaro¹  Karin Naess¹  Carolina Backman Johansson¹  Helene Bruhn²  Christoph Freyer²  Anna Wredenberg²  Tommy Stödberg³  Sofia Ygberg³  Ann-Charlotte Wikström⁴  Sofie Vonlanthen⁴  Sara Lind Enoksson⁴  Per Marits⁴  Ola Winqvist⁴  Anders Jemt⁵  Virpi Töhönen⁵  Eliane Sardh⁶  Rolf H. Zetterström⁶  Martin Engvall⁶  Daphne Vassiliou⁶  Nicole Lesko⁶  Henrik Stranneheim⁷  Anna Wedell⁸  Malin Kvarnung⁹  Maritta Hellström-Pigg⁹  Håkan Thonberg⁹  Giedre Grigelioniene⁹  Anna Lindstrand⁹  Ellika Sahlin⁹  Helena Malmgren⁹  Bianca Tesi⁹  Kristina Lagerstedt-Robinson⁹  Magnus Nordenskjöld⁹  Erik Björck⁹  Emma Tham⁹  Ann Nordgren⁹  Maria Johansson Soller⁹  Peter Gustavsson⁹  Erik Iwarsson⁹  Daniel Nilsson⁹  Anna Hammarsjö⁹  Maria Pettersson⁹  Josephine Wincent⁹  Jesper Eisfeldt⁹  Britt-Marie Anderlid⁹  Måns Magnusson^1,10  Henrik Arnell^1,11  Chiara Rasi^1,12  Valtteri Wirta^1,13  Adam Rosenbaum^1,14  Mikael Laaksonen^1,14 

[1] Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden;Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden;Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden;Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden;Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden;Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden;Science for Life Laboratory, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden;Science for Life Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;Science for Life Laboratory, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden;Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden;Science for Life Laboratory, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden;Science for Life Laboratory, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden;Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institutet of Technology, Stockholm, Sweden;Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institutet of Technology, Stockholm, Sweden;

关键词: Whole genome sequencing;    Monogenic disease;    Single nucleotide variant;    Clinical diagnostics;   

DOI  :  10.1186/s13073-021-00855-5

来源: Springer

【 摘 要 】

BackgroundWe 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.MethodsOur 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.ResultsOverall, 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.ConclusionsClinical 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.

【 授权许可】

CC BY