Title: Centers for Mendelian Genomics: A decade of facilitating gene discovery
Authors: Samantha M. Baxter
1,#
, Jennifer E. Posey
2
, Nicole J. Lake
3,4
, Nara Sobreira
5
, Jessica
X. Chong
6,7
, Steven Buyske
8
, Elizabeth E. Blue
7.9
, Lisa H. Chadwick
10
, Zeynep H.
Coban-Akdemir
2,11
, Kimberly F. Doheny
5
, Colleen P. Davis
6
, Monkol Lek
1,3
, Christopher
Wellington
10
, Shalini N. Jhangiani
12
, Mark Gerstein
13,14
, Richard A. Gibbs
2,12
, Richard P. Lifton
3,15
,
Daniel G. MacArthur
1,16,17
, Tara C. Matise
8
, James R. Lupski
2,12,18
, David Valle
5
, Michael J.
Bamshad
6,7,19
, Ada Hamosh
5
, Shrikant Mane
3
, Deborah A. Nickerson
7,19
, Centers for Mendelian
Genomics Consortium, Heidi L. Rehm
1,20,21,#
, Anne O’Donnell-Luria
1,21,22,#
Affiliations:
1
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge,
MA, USA
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
3
Department of Genetics, Yale School of Medicine, New Haven, CT, USA
4
Murdoch Children’s Research Institute, Melbourne, Australia
5
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
6
Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle
Children's Hospital, Seattle, WA, USA
7
Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
8
Genetics, Rutgers University, Piscataway, NJ, USA
9
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA,
USA
10
Division of Genome Sciences, National Human Genome Research Institute, Bethesda, MD,
USA
11
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental
Sciences, School of Public Health, The University of Texas Health Science Center at Houston,
Houston, Texas, USA
1
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 31, 2021. ; https://doi.org/10.1101/2021.08.24.21261656doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
12
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
13
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
14
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
15
Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA
16
Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney,
Sydney, Australia
17
Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Australia
18
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
19
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA,
USA
20
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
21
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
22
Department of Pediatrics, Division of Genetics and Genomics, Boston Children’s Hospital,
Boston, MA, USA
# Corresponding authors
Contact information for corresponding authors:
Anne O’Donnell-Luria
Heidi Rehm
Samantha Baxter
617-714-8242
617-714-7939
617-714-8012
odonnell@broadinstitute.org
hrehm@broadinstitute.org
samantha@broadinstitute.org
Potential Conflicts of Interest
Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture
2
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 31, 2021. ; https://doi.org/10.1101/2021.08.24.21261656doi: medRxiv preprint
with shared ownership and governance of Baylor Genetics (BG), formerly the Baylor
Miraca Genetics Laboratories (BMGL), which performs clinical exome sequencing and
Chromosomal Microarray Analysis for genome-wide detection of CNV. JRL serves on
the Scientific Advisory Board of BG. JRL has stock ownership in 23andMe, is a paid
consultant for Regeneron Pharmaceuticals, and is a co-inventor on multiple United
States and European patents related to molecular diagnostics for inherited
neuropathies, eye diseases and bacterial genomic fingerprinting. HLR receives funding
from Illumina to support rare disease gene discovery and diagnosis. Consortium author
conflicts of interest are listed in the supplement. Other authors have no disclosures
relevant to the manuscript.
Data Availability statement
Candidate genes identified by the CMG have been submitted to Matchmaker Exchange
(https://www.matchmakerexchange.org/). Variant classifications have been submitted to
ClinVar. De-identified and coded genomic and phenotype data have been shared on the
National Human Genome Research Institute (NHGRI) AnVIL platform. Data access
requests can be made per instructions here
https://anvilproject.org/learn/accessing-data/requesting-data-access#accessing-controll
ed-access-data.
Acknowledgements:
The Baylor Hopkins Center for Mendelian Genomics, Broad Institute 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 (NHLBI) under the Trans-Omics for Precision Medicine
Program (TOPMed), and the National Eye Institute (NEI). 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
3
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 31, 2021. ; https://doi.org/10.1101/2021.08.24.21261656doi: medRxiv preprint
K08HG008986 (JEP), NHGRI R01HG009141 (HLR and DGM), the National Institute of
Neurological Disorders and Stroke (NINDS) R35NS105078 (JRL), and National Health
and Medical Research Council (NHMRC) Early Career Fellowship 1159456 (NJL). The
CMGs 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.
Author Contributions:
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: L.H.C., C.W.; 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.
Ethics Declaration
Informed consent was obtained by collaborators for all participants in studies across the
CMGs, and individual-level data, including genomics and clinical data, was de-identified
and coded by our collaborators prior to submission to the CMGs. The participant’s
samples used for this study were obtained from multiple institutions and each CMG
(Baylor-Hopkins, Broad Institute of MIT and Harvard, University of Washington, Yale)
was responsible for submitting to their own IRB to receive local approval.
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
4
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 31, 2021. ; https://doi.org/10.1101/2021.08.24.21261656doi: medRxiv preprint
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 (NHGRI's 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.
5
. CC-BY 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted August 31, 2021. ; https://doi.org/10.1101/2021.08.24.21261656doi: medRxiv preprint