Care4Rare Canada: Outcomes from a decade of network science for rare disease gene discovery

Abstract

The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs. We achieved a diagnostic yield of 34% (623/1,806 of participating families), including the discovery of deleterious variants in 121 genes not previously associated with disease, and we continue to study candidate variants in novel genes for 145 families. The Consortium has made significant contributions to RD research, including development of platforms for data collection and sharing and instigating a Canadian network to catalyze functional characterization research of novel genes. The Consortium was instrumental to implementing genome-wide sequencing as a publicly funded test for RD diagnosis in Canada. Despite the successes of the past decade, the challenge of solving all RDs remains enormous, and the work is far from over. We must leverage clinical and 'omic data for secondary use, develop tools and policies to support safe data sharing, continue to explore the utility of new and emerging technologies, and optimize research protocols to delineate complex disease mechanisms. Successful approaches in each of these realms is required to offer diagnostic clarity to all families with RDs.

Keywords: Care4Rare Canada; FORGE Canada; exome sequencing; gene discovery; genome sequencing; rare diseases.

Figure 1

A decade of rare disease (RD) gene discovery and diagnosis via the Care4Rare Canada Consortium RD gene discoveries and diagnoses span three eras of the Care4Rare Canada program: FORGE, Care4Rare, and Care4Rare-SOLVE were a continuous series of large-scale pan-Canadian RD sequencing projects. For each era (colored boxes), the time frame, types of RDs studied, and number of families agreeing to participate is summarized. The outcomes, to date, from each era (gray box) display the diagnostic yield (in known and novel genes), compelling VUSs and GUSs, and novel genes published. Note that the outcomes (diagnosis or discovery) may have occurred at any point during the 10-year Care4Rare Canada program. A list of our candidate GUSs can be found in the Open Access Data webpage of the Genomics4RD website (https://www.genomics4rd.ca/openaccess). Families whose RD remains unsolved following clinical exome sequencing are eligible to participate in our research protocol for unsolved RDs. VUS, variant of uncertain significance; GUS, gene of uncertain significance.

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.