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.