GREGoR: accelerating genomics for rare diseases

Moez Dawood^{1

2

3}, Ben Heavner⁴, Marsha M Wheeler⁴, Rachel A Ungar^{5

6

7}, Jonathan LoTempio⁸, Laurens Wiel^{5

6

9}, Seth Berger^{10

11

12}, Jonathan A Bernstein¹³, Jessica X Chong^{14

15}, Emmanuèle C Délot⁸, Evan E Eichler^{16

17}, James R Lupski^{18

19

20}, Ali Shojaie^{4

21}, Michael E Talkowski^{22

23

24

25

26}, Alex H Wagner^{27

28

29}, Chia-Lin Wei¹⁶, Christopher Wellington³⁰, Matthew T Wheeler⁹; GREGoR Partner Members; Claudia M B Carvalho³¹, Richard A Gibbs^{18

19}, Casey A Gifford^{5

32

33

34}, Susanne May⁴, Danny E Miller^{15

16

35

36}, Heidi L Rehm^{22

23}, Kaitlin E Samocha^{22

23}, Fritz J Sedlazeck^{18

19

37}, Eric Vilain⁸, Anne O'Donnell-Luria^{22

23

38}, Jennifer E Posey^{19

39

40}, Lisa H Chadwick⁴¹, Michael J Bamshad^{14

15

42}, Stephen B Montgomery^{43

44

45}; Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium

Collaborators, Affiliations

Collaborators

Affiliations

¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. mdawood@bcm.edu.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. mdawood@bcm.edu.
³ Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA. mdawood@bcm.edu.
⁴ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁵ Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
⁶ Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.
⁷ Stanford Center for Biomedical Ethics, School of Medicine, Stanford University, Stanford, CA, USA.
⁸ Institute for Clinical and Translational Science, University of California, Irvine, Irvine, CA, USA.
⁹ Division of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰ Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.
¹¹ Center for Precision Medicine and Genomics Research, Children's National Hospital, Washington, DC, USA.
¹² Department of Genomics and Precision Medicine, George Washington University, Washington, DC, USA.
¹³ Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, USA.
¹⁴ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
¹⁵ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA, USA.
¹⁶ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
¹⁷ Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
¹⁸ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
²⁰ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
²¹ Department of Statistics, University of Washington, Seattle, WA, USA.
²² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²³ Program in Medical and Population Genetics, Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁶ Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
²⁷ Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
²⁸ Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
²⁹ Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA.
³⁰ Office of Genomic Data Science, National Human Genome Research Institute, Bethesda, MD, USA.
³¹ Pacific Northwest Research Institute, Seattle, WA, USA.
³² Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA, USA.
³³ Basic Science and Engineering (BASE) Initiative, Betty Irene Moore Children's Heart Center, Stanford Medicine Children's Health, Stanford, CA, USA.
³⁴ Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
³⁵ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
³⁶ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
³⁷ Department of Computer Science, Rice University, Houston, TX, USA.
³⁸ Department of Pediatrics, Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
³⁹ Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁴⁰ Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁴¹ Division of Genome Sciences, National Human Genome Research Institute, Bethesda, MD, USA.
⁴² Department of Pediatrics, Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
⁴³ Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA. smontgom@stanford.edu.
⁴⁴ Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA. smontgom@stanford.edu.
⁴⁵ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. smontgom@stanford.edu.

PMID: 41224980
DOI: 10.1038/s41586-025-09613-8

GREGoR: accelerating genomics for rare diseases

Moez Dawood et al. Nature. 2025 Nov.

. 2025 Nov;647(8089):331-342.

doi: 10.1038/s41586-025-09613-8. Epub 2025 Nov 12.

Authors

Collaborators

Affiliations

¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. mdawood@bcm.edu.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. mdawood@bcm.edu.
³ Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA. mdawood@bcm.edu.
⁴ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁵ Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
⁶ Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.
⁷ Stanford Center for Biomedical Ethics, School of Medicine, Stanford University, Stanford, CA, USA.
⁸ Institute for Clinical and Translational Science, University of California, Irvine, Irvine, CA, USA.
⁹ Division of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰ Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.
¹¹ Center for Precision Medicine and Genomics Research, Children's National Hospital, Washington, DC, USA.
¹² Department of Genomics and Precision Medicine, George Washington University, Washington, DC, USA.
¹³ Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, USA.
¹⁴ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, USA.
¹⁵ Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA, USA.
¹⁶ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
¹⁷ Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
¹⁸ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
²⁰ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
²¹ Department of Statistics, University of Washington, Seattle, WA, USA.
²² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²³ Program in Medical and Population Genetics, Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁶ Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
²⁷ Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
²⁸ Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
²⁹ Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA.
³⁰ Office of Genomic Data Science, National Human Genome Research Institute, Bethesda, MD, USA.
³¹ Pacific Northwest Research Institute, Seattle, WA, USA.
³² Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA, USA.
³³ Basic Science and Engineering (BASE) Initiative, Betty Irene Moore Children's Heart Center, Stanford Medicine Children's Health, Stanford, CA, USA.
³⁴ Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
³⁵ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
³⁶ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
³⁷ Department of Computer Science, Rice University, Houston, TX, USA.
³⁸ Department of Pediatrics, Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
³⁹ Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁴⁰ Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁴¹ Division of Genome Sciences, National Human Genome Research Institute, Bethesda, MD, USA.
⁴² Department of Pediatrics, Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
⁴³ Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA. smontgom@stanford.edu.
⁴⁴ Department of Pathology, School of Medicine, Stanford University, Stanford, CA, USA. smontgom@stanford.edu.
⁴⁵ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. smontgom@stanford.edu.

PMID: 41224980
DOI: 10.1038/s41586-025-09613-8

Abstract

Rare diseases are collectively common, affecting approximately 1 in 20 individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in next-generation sequencing, development of new computational and functional genomics approaches to prioritize genes and variants and increased global sharing of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Furthermore, all data generated, currently representing over 7,500 individuals from over 3,000 families, are rapidly made available to researchers worldwide through the Analysis, Visualization and Informatics Lab-space (AnVIL) to catalyse global efforts to develop approaches for genetic diagnoses in rare diseases. Most of these families have undergone previous clinical genetic testing but remained unsolved, with most being exome-negative. Here we describe the collaborative research framework, datasets and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics.

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Conflict of interest statement

Competing interests: R.A.G. declares that Baylor Genetics is a Baylor College of Medicine affiliate that derives revenue from genetic testing. BCM and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs clinical microarray analysis and other genomic studies (exome and genome sequencing) for patient and family care. F.J.S. has received research support from Illumina, Pacific Biosciences and Genentech. J.E.P. is an advisor to MaddieBio. S.B.M. is an advisor to MyOme, PhiTech and Valinor Therapeutics. F.J.S. and D.E.M. have received research support and/or consumables from ONT and have received travel funding to speak on behalf of ONT. D.E.M. has received travel support from Pacific Biosciences. D.E.M. is on an advisory board at ONT, a scientific advisory board at Basis Genetics and holds stock options in both MyOme and Basis Genetics. M.J.B. is the chair of the scientific advisory board of GeneDx and receives funding from the American Society of Human Genetics as the editor-in-chief of HGG Advances. J.X.C. receives funding from the American Society of Human Genetics as the Deputy Editor of HGG Advances. D.P. consults for Ionis Pharmaceuticals. H.L.R. and K.E.S. have received rare-disease research funding from Microsoft. H.L.R. has received research funding from Illumina and compensation as a past member of the scientific advisory board of Genome Medical. A.O.-L. was a paid consultant to Tome Biosciences, Ono Pharma USA, Addition Therapeutics, Congenica and receives research funding from Pacific Biosciences. E.E.E. is a scientific advisory board member of Variant Bio. M.P.S. is a cofounder and scientific advisor of Xthera, Exposomics, Filtricine, Fodsel, iollo, InVu Health, January AI, Marble Therapeutics, Mirvie, Next Thought AI, Orange Street Ventures, Personalis, Protos Biologics, Qbio, RTHM and SensOmics. M.P.S. is a scientific advisor of Abbratech, Applied Cognition, Enovone, Jupiter Therapeutics, M3 Helium, Mitrix, Neuvivo, Onza, Sigil Biosciences, Captify Inc, WndrHLTH, Yuvan Research and Ovul. A.A. and A.C. are employees and shareholders of Illumina, Inc.

Update of

GREGoR: Accelerating Genomics for Rare Diseases.
Dawood M, Heavner B, Wheeler MM, Ungar RA, LoTempio J, Wiel L, Berger S, Bernstein JA, Chong JX, Délot EC, Eichler EE, Gibbs RA, Lupski JR, Shojaie A, Talkowski ME, Wagner AH, Wei CL, Wellington C, Wheeler MT; GREGoR Partner Members; Carvalho CMB, Gifford CA, May S, Miller DE, Rehm HL, Sedlazeck FJ, Vilain E, O'Donnell-Luria A, Posey JE, Chadwick LH, Bamshad MJ, Montgomery SB; Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium. Dawood M, et al. ArXiv [Preprint]. 2024 Dec 18:arXiv:2412.14338v1. ArXiv. 2024. Update in: Nature. 2025 Nov;647(8089):331-342. doi: 10.1038/s41586-025-09613-8. PMID: 39764392 Free PMC article. Updated. Preprint.

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GREGoR: accelerating genomics for rare diseases

Collaborators

Affiliations

GREGoR: accelerating genomics for rare diseases

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous