Centers for Mendelian Genomics: A decade of facilitating gene discovery

Abstract

Mendelian disease genomic research has undergone a massive transformation over the last decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. Over the last 10 years, the NIH-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Mendelian genomic research extends beyond generating lists of gene-phenotype relationships, it includes developing tools, training the larger community to use these tools and approaches, and facilitating collaboration through data sharing. Thus, the CMGs have also focused on creating resources, tools, and training for the larger community to foster the understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into AnVIL (NHGRIs Genomic Data Science Analysis, Visualization, and Informatics Lab-Space), sharing candidate genes through Matchmaker Exchange (MME) and the CMG website, and sharing variants in Geno2MP and VariantMatcher. The research genomics output remains exploratory with evidence that thousands of disease genes, in which variant alleles contribute to disease, remain undiscovered, and many patients with rare disease remain molecularly undiagnosed. Strengthening communication between research and clinical labs, continued development and sharing of knowledge and tools required for solving previously unsolved cases, and improving access to data sets, including high-quality metadata, are all required to continue to advance Mendelian genomics research and continue to leverage the Human Genome Project for basic biomedical science research and clinical utility.