TY - JOUR
T1 - Centers for Mendelian Genomics
T2 - A decade of facilitating gene discovery
AU - Centers for Mendelian Genomics Consortium
AU - Baxter, Samantha M.
AU - Posey, Jennifer E.
AU - Lake, Nicole J.
AU - Sobreira, Nara
AU - Chong, Jessica X.
AU - Buyske, Steven
AU - Blue, Elizabeth E.
AU - Chadwick, Lisa H.
AU - Coban-Akdemir, Zeynep H.
AU - Doheny, Kimberly F.
AU - Davis, Colleen P.
AU - Lek, Monkol
AU - Wellington, Christopher
AU - Jhangiani, Shalini N.
AU - Gerstein, Mark
AU - Gibbs, Richard A.
AU - Lifton, Richard P.
AU - MacArthur, Daniel G.
AU - Matise, Tara C.
AU - Lupski, James R.
AU - Valle, David
AU - Bamshad, Michael J.
AU - Hamosh, Ada
AU - Mane, Shrikant
AU - Nickerson, Deborah A.
AU - Adams, Marcia
AU - Aguet, François
AU - Akay, Gulsen
AU - Anderson, Peter
AU - Antonescu, Corina
AU - Arachchi, Harindra M.
AU - Atik, Mehmed M.
AU - Austin-Tse, Christina A.
AU - Babb, Larry
AU - Bacus, Tamara J.
AU - Bahrambeigi, Vahid
AU - Balasubramanian, Suganthi
AU - Bayram, Yavuz
AU - Beaudet, Arthur L.
AU - Beck, Christine R.
AU - Belmont, John W.
AU - Below, Jennifer E.
AU - Bilguvar, Kaya
AU - Boehm, Corinne D.
AU - Boerwinkle, Eric
AU - Boone, Philip M.
AU - Bowne, Sara J.
AU - Brand, Harrison
AU - Buckingham, Kati J.
AU - Byrne, Alicia B.
N1 - Funding Information:
Baylor College of Medicine and Miraca Holdings Inc have formed a joint venture with shared ownership and governance of Baylor Genetics, formerly the Baylor Miraca Genetics Laboratories, which performs clinical ES and chromosomal microarray analysis for genome-wide detection of copy number variants. J.R.L. serves on the Scientific Advisory Board of Baylor Genetics. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. H.L.R. receives funding from Illumina to support rare disease gene discovery and diagnosis. Consortium author conflicts of interest are listed in the Supplement. All other authors have no disclosures relevant to the manuscript.We extend our gratitude and respect to our friend and colleague, Dr. Deborah A. Nickerson, who passed away in December of 2021. She was a leader in human genomics research, a passionate advocate for trainees and women in science, and contributed to hundreds of discoveries that have set the stage for precision medicine. The Baylor-Hopkins Center for Mendelian Genomics, Broad Institute of MIT and Harvard Center for Mendelian Genomics, University of Washington Center for Mendelian Genomics, and Yale Center for Mendelian Genomics were funded by the National Human Genome Research Institute (NHGRI) awards UM1HG006542, UM1HG008900, UM1HG006493, and UM1HG006504, respectively. Funds were also provided under the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine Program and the National Eye Institute. The GSP Coordinating Center (U24HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. Aspects of this work were funded by NHGRI K08HG008986 (J.E.P.), NHGRI R01HG009141 (H.L.R. and D.G.M.), the National Institute of Neurological Disorders and Stroke R35NS105078 (J.R.L.), and National Health and Medical Research Council Early Career Fellowship 1159456 (N.J.L.). The Centers for Mendelian Genomics would like to thank all of our collaborators from around the world as well as the families and individuals who contributed their data to this study. Conceptualization: S.M.B. J.E.P. N.J.L. N.S. J.X.C. S.B. E.E.B. L.H.C. K.F.D. C.P.D. M.L. C.W. S.N.J. R.A.G. R.P.L. D.G.M. M.G. T.C.M. J.R.L. D.V. M.J.B. A.H. S.M. D.A.N. H.L.R. A.O.L.; Data Curation: S.M.B. J.E.P. N.J.L. N.S. J.X.C. S.B. A.H. K.F.D.; Formal Analysis: S.M.B. J.E.P. N.J.L. N.S. J.X.C. S.B. Z.H.C. S.N.J. M.J.B. A.H. S.M. D.A.N. H.L.R. A.O.L.; Funding Acquisition: S.B. R.A.G. R.P.L. D.G.M. M.G. T.C.M. J.R.L. D.V. M.J.B. A.H. S.M. D.A.N. H.L.R. K.F.D.; Project Administration: S.B. L.H.C. C.W. T.C.M.; Visualization: S.M.B. S.B. A.O.L.; Writing–original draft: S.M.B. J.E.P. N.J.L. N.S. J.X.C. S.B. M.L. M.J.B. A.H. S.M. H.L.R. A.O.L.; Writing–review & editing: S.M.B. J.E.P, N.J.L. N.S. J.X.C. S.B. E.E.B. L.H.C. K.F.D. C.P.D. M.L. Z.H.C. C.W. S.N.J. R.A.G. R.P.L. D.G.M. M.G. T.C.M. J.R.L. D.V. M.J.B. A.H. S.M. D.A.N. H.L.R. A.O.L. Informed consent was obtained by collaborators for all participants in studies across the Centers for Mendelian Genomics (CMGs), and individual-level data, including genomics and clinical data, were de-identified and coded by our collaborators before submission to the CMGs. The participants’ samples used for this study were obtained from multiple institutions, and each CMG (Baylor-Hopkins, Baylor College of Medicine Institutional Review Board [IRB] and Johns Hopkins Medicine IRB; Broad Institute of MIT and Harvard, Mass General Brigham IRB; University of Washington, University of Washington IRB; Yale, Yale University IRB) was responsible for submitting to their own IRB to receive local approval. There was no central IRB for this consortium; however, the main IRB for this publication is Broad Institute of MIT and Harvard, Mass General Brigham IRB.Alicia B. Byrne was supported by the Australian Government Research Training Program Scholarship, the Australian Genomics Health Alliance & NHMRC (GNT1113531), and the Maurice de Rohan International Scholarship. Laurent C. Francioli was supported by the Swiss National Science Foundation (Advanced Postdoc.Mobility 177853). Vijay S. Ganesh was supported by NIH/NHGRI T32HG010464. Sanna Gudmundsson was supported by the Knut and Alice Wallenberg Foundation. Miriam S. Udler was supported by NIH/NIDDK K23DK114551. Monica H. Wojcik was supported by NIH/NICHD K23HD102589 and by an Early Career Award from the Thrasher Research Fund.
Publisher Copyright:
© 2021 American College of Medical Genetics and Genomics
PY - 2022/4
Y1 - 2022/4
N2 - Purpose: Mendelian disease genomic research has undergone a massive transformation over the past 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. Methods: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. Results: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster 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 the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. Conclusion: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.
AB - Purpose: Mendelian disease genomic research has undergone a massive transformation over the past 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. Methods: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. Results: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster 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 the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. Conclusion: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.
KW - Centers for Mendelian Genomics (CMG)
KW - Data sharing
KW - Mendelian conditions
KW - Novel gene-disease discovery
KW - Rare disease tools
UR - http://www.scopus.com/inward/record.url?scp=85124298361&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2021.12.005
DO - 10.1016/j.gim.2021.12.005
M3 - Review article
C2 - 35148959
AN - SCOPUS:85124298361
SN - 1098-3600
VL - 24
SP - 784
EP - 797
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 4
ER -