Original functionality
The PhenomeCentral web portal is based on the PhenoTips software (Girdea et al., 2013), which is used in both clinical and genomics research applications across the world. Clinicians or researchers (users) can create detailed patient records (cases) which enables the sharing of both genotypic and phenotypic information with other PhenomeCentral cases and across the MME. When a case is first created, users are prompted to select what level of data sharing a patient has consented for, which can include medical and family history, genome-wide sequencing data, or photographs. Genotypic information can be entered as manually curated gene entries and/or uploaded variant call format (VCF) files. Any VCF data is processed by the Exomiser software to produce a computationally prioritized list of candidate genes (Smedley et al., 2015). Case phenotypes are entered as lists of phenotypic terms, which are then mapped to a standardized phenotype vocabulary known as the Human Phenotype Ontology (HPO; Köhler et al., 2021). These HPO terms can be used to generate a list of “Suggested Genes”, which lists all known gene associations for each of a case’s terms. Finally, users have the ability to provide additional clinical information including a pedigree, growth charts and measurements, and other medical history details using free text boxes.
Once a case has been added to PhenomeCentral, internal matching is automatically performed and a list of similar PhenomeCentral cases is displayed. Users also have the option to indicate that their case has consented to share across the MME, which adds similar matches from other rare disease repositories in the MME (called nodes) to the results.
The matchmaking philosophy of PhenomeCentral is that phenotypic data is a valuable, but often overlooked resource (Baynam et al., 2015), and can lead to higher quality matches and decrease time spent exploring false positives (potential matches that are disproven with further exploration). Without phenotypic data, gene level matching may yield many false positive matches (Osmond et al., in press). Consequently, matches in PhenomeCentral are evaluated based on both phenotypic similarity and genotypic similarity. A score for phenotypic similarity is generated using the simGIC algorithm, a semantic similarity measure capable of comparing multiple lists of HPO terms (Pesquita et al., 2008). Genotypic similarity between cases is denoted either as having the same manually curated candidate gene, or in situations where a PhenomeCentral case had VCF data, a match between a manually entered gene and VCF file data with a variant identified in the matching gene (Buske et al., 2015a). After reviewing the matches for a PhenomeCentral case, users are given the option to send an introductory email through PhenomeCentral to other users who have matches of interest.
Any case deposited in PhenomeCentral remains available for future cases to match against. New matches with other PhenomeCentral cases are updated automatically on the web portal, and users can manually refresh their case to identify new matches across the MME.