Introduction

The increasing accessibility of accurate genomic data via next-generation sequencing (NGS) (Shendure and Ji, 2008; L. Metzker, 2010) has opened new avenues to a cost-effective diagnosis of the genetic determinants underlying many rare diseases (RDs) (M. Boycott et al., 2013). Obtaining a molecular diagnosis for a patient with a rare disease constitutes often a challenging task; currently typically less than 50% of patients receive a molecular diagnosis despite strong suspicion of an underlying genetic determinant (E. Soden et al., 2014; Lee et al., 2014; Yang et al., 2014; Stranneheim et al., 2021). However, a powerful approach for disease gene discovery is through identification of other patients with a similar phenotype; by establishing a cohort of similar patients, the likelihood of identifying the shared genomic determinant is strongly increased. The establishment of the MatchMaker Exchange (MME)(A. Philippakis et al., 2015) federated network has dramatically improved the process of “matchmaking” patients across clinical laboratories’ and research centers’ databases(R. Azzariti and Hamosh, 2020). MME APIs(J. Buske et al., 2015) simplify sharing of selected patient data with the purpose of identifying cases with shared phenotypes and genotypic profiles. An MME matching event results in a notification sent to the patients’ data submitters belonging to the two participating centers, so they can evaluate the matching features and eventually establish a gene or variant-disease causality for the given patient features. The obvious advantage of this tool is that single users utilizing the service do not need to worry about different database standards and data formats, as MME nodes communicate via standardized protocols and return results in a common and language-independent data format (JSON).
The Clinical Genomics facility at Science for Life Laboratory (SciLifeLab) Stockholm has been collaborating with the regional healthcare at Karolinska University Hospital to provide whole genome sequencing (WGS) -based rare disease (RD) diagnostics since 2015. Through this collaboration, termed Genomic Medicine Center Karolinska(Stranneheim et al., 2021), to date more than 6000 RD patients corresponding to more than 10,000 samples (6000 at the time PatientMatcher was launched) have been analyzed making this the largest clinical whole genome sequencing effort in Sweden. This collaboration is responsible for the genetic testing of the vast majority of RD cases in the Stockholm region, accounting for ~2500 samples sequenced annually. Clinical Genomics is additionally a founding member of Genomic Medicine Sweden (https://www.genomicmedicine.se) and the Nordic Alliance for Clinical Genomics (http://www.nordicclinicalgenomics.org). In this framework, PatientMatcher was developed by Clinical Genomics as a clinical diagnostic decision support tool to aid clinicians and researchers at partner institutes solving RD cases. PatientMatcher is now being implemented at the Genomic Medicine Center Karolinska in clinical production to establish a controlled, fully integrated data sharing capability as part of the diagnostic workflow.