Results

PhenomeCentral presently has 1,615 users that have entered 12,292 cases (Figure 2 ) from all over the world. PhenomeCentral has become a major data repository for several large scale rare disease research programs, which have collectively contributed approximately 69% of the total cases within PhenomeCentral. PhenomeCentral is endorsed by multiple rare disease consortia and initiatives and is a recommended resource by the International Rare Diseases Research Consortium (IRDiRC; ). The Care for Rare Canada Consortium (C4R; ) has a user base of 159 accounts which have deposited over 2,900 of their cases into PhenomeCentral. Other groups contributing a significant number of cases and using PhenomeCentral regularly include the Genetics of Development Disorders Team (GAD; ), the NIH Undiagnosed Diseases Program and Network (UDN; ), and the Telethon Institute of Genetics and Medicine (TIGEM; ). The last two are members of the Undiagnosed Diseases Network International (UDNI; ), which has endorsed PhenomeCentral as a data sharing solution. Collectively, the RD research programs mentioned above bring together 389 users that have contributed over 8,400 cases to date.
Currently, 5,554 cases in PhenomeCentral have a manually curated candidate gene listed, spanning a total of 3,234 unique genes. Most cases have a single candidate gene, with only 12% of cases listing two or more genes as candidates. Additional genotypic data in the form of VCF files are available in 1901 cases, which can be used to generate matches between candidate genes and variants in genomic sequencing data.
The majority of cases in PhenomeCentral also have some degree of computer-readable phenotyping (10250/12292, 83%). Of these cases, 94% have two or more phenotypes documented, with a median of 8 phenotypic terms per case. In total, 118,059 HPO annotations are documented across this dataset, spanning across 7,938 unique HPO terms. When grouped into general phenotypic categories, abnormalities of the nervous system are the most commonly reported type of HPO term, followed by abnormalities of the head or neck and abnormalities of the skeletal system (Figure 3a) . More specifically, the most prevalent HPO terms within this dataset (Figure 3b ) include global developmental delay (2867/12292, 23%), seizures (1572/12292, 13%), and short stature (1531/12292, 12%). In addition to HPO terms, many cases have additional information entered, including growth charts (3005/12292, 24%), a pedigree (2555/12292, 21%), and additional medical history information (1972/12292, 16%).
A total of 4,665 matches have been made internally between PhenomeCentral cases. In addition to internal matchmaking with other PhenomeCentral cases, currently 70% of PhenomeCentral cases (8479/12292) have been consented for matching with the other MME nodes. Such cases submitted queries for over 2,900 unique candidate genes, and these 8,479 cases collectively contained over 98,500 HPO annotations. Queries involving PhenomeCentral as a node in the MME have resulted in 61,362 matches with other nodes, with the majority of these originating from cases in GeneMatcher (40701/61362, 66%) and DECIPHER (17097/61362, 28%).
In collaboration with the MME, PhenomeCentral has enjoyed success in facilitating matches leading to gene discovery (e.g., Chelban et al., 2019; den Hoed et al., 2021; Faden et al., 2015; Ito et al., 2018; Johnstone et al., 2017; Kernohan et al., 2017; Y.-R. Lee et al., 2020; Lessel et al., 2020; Martinelli et al., 2018; Oud et al., 2017; Salpietro et al., 2019; Simons et al., 2017; Skraban et al., 2017; Stray-Pedersen et al., 2016; Vavassori et al., 2021), and, ultimately, answers for families.