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.