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

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.

Keywords: Clinical diagnostics; Monogenic disease; Single nucleotide variant; Whole genome sequencing.

Fig. 1

a Number of individuals whose genomic DNA were sequenced by WGS at GMCK-RD per quarter between years 2015 and 2019. b Turnaround time for sequencing ranged from 2 to 43 days with a median of 13 days

Fig. 2

Massively parallel sequencing (MPS)-based diagnostics at the Genomic Medicine Center Karolinska. Timeline showing the integration of genome sequencing into healthcare by gradually adding novel components to the workflow. Blue = MPS pilots; red = clinical routine analysis; black = bioinformatic softwares developed in-house; green = sequencing instruments; gold = organizational structures/resources. GMCK-RD, Genomic Medicine Center Karolinska-Rare Diseases; LI, low input DNA; MIP, mutation identification pipeline; rWGS, rapid whole genome sequencing; Scilifelab, Science for Life Laboratory; SNV, single nucleotide variant; SMN, copy number identification of SMN1 and SMN2 genes; STR, short tandem repeat; SV, structural variant; UPD, uniparental disomy; WES, whole exome sequencing; WGS, whole genome sequencing

Fig. 3

Schematic illustration of the different components in our current bioinformatic pipeline (MIP 8.2). First (in white), FASTQ data is aligned to the human reference genome. Next, different variant types are called including SNV/INDEL (green), SV (yellow), STR (orange), and SMN (purple). Each variant type is then annotated and prioritized before it is vizualized in Scout