Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients
Authors: Stranneheim Henrik , Lagerstedt-Robinson Kristina , Magnusson Måns , Kvarnung Malin , Nilsson Daniel , Lesko Nicole , Engvall Martin , Anderlid Britt-Marie , Arnell Henrik , Johansson Carolina Backman , Barbaro Michela , Björck Erik , Bruhn Helene , Eisfeldt Jesper , Freyer Christoph , Grigelioniene Giedre , Gustavsson Peter , Hammarsjö Anna , Hellström-Pigg Maritta , Iwarsson Erik , Jemt Anders , Laaksonen Mikael , Enoksson Sara Lind , Malmgren Helena , Naess Karin , Nordenskjöld Magnus , Oscarson Mikael , Pettersson Maria , Rasi Chiara , Rosenbaum Adam , Sahlin Ellika , Sardh Eliane , Stödberg Tommy , Tesi Bianca , Tham Emma , Thonberg Håkan , Töhönen Virpi , von Döbeln Ulrika , Vassiliou Daphne , Vonlanthen Sofie , Wikström Ann-Charlotte , Wincent Josephine , Winqvist Ola , Wredenberg Anna , Ygberg Sofia , Zetterström Rolf H. , Marits Per , Soller Maria Johansson , Nordgren Ann , Wirta Valtteri , Lindstrand Anna , Wedell Anna 
Published: March 2021

Abstract
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.