Figure 2.

Novel genes published by Care4Rare Canada, by year of publication and primary approach to support of disease causality

Gene discoveries in the early days of Care4Rare Canada relied on analyzing single-RD cohorts (orange) or identifying similarly affected individuals through traditional networking via email or conferences (gray). Starting in 2014, following the launch of the Canadian Rare Diseases: Models and Mechanisms (RDMM) Network, functional assays and model organisms (yellow) became an important approach to providing supporting evidence for disease causality. PhenoTips to capture clinical data as HPO terms came online in 2013 and facilitated the development of PhenomeCentral, a matchmaking data platform, in 2014. Following the launch of Matchmaker Exchange (MME) in 2015, with PhenomeCentral as one of the original three nodes connected, traditional networking was replaced with automated global matchmaking (blue) with researchers beyond our usual collaborations. MME-fueled gene discoveries continue to be the dominant discovery approach. While Care4Rare discovered disease-causing variants in 121 novel genes (listed in Table S2), Figure 2 includes only the 109 novel genes that represent the primary discovery using the described approaches. Of the 12 novel genes not included, seven were the second publication, two used a pilot matchmaking algorithm not yet released, and three were case reports with compelling genetic evidence.