GREGoR: Accelerating Genomics for Rare Diseases

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[Preprint]. 2024 Dec 18:arXiv:2412.14338v1.

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^{15

16

17}, Richard A Gibbs^{1

2}, James R Lupski^{1

2

18}, Ali Shojaie⁴, Michael E Talkowski^{19

20

21

22

23}, Alex H Wagner^{24

25

26}, Chia-Lin Wei¹⁶, Christopher Wellington²⁷, Matthew T Wheeler⁹; GREGoR Partner Members; Claudia M B Carvalho²⁸, Casey A Gifford^{5

13

29

30}, Susanne May⁴, Danny E Miller^{15

16

31

32}, Heidi L Rehm^{19

20}, Fritz J Sedlazeck^{1

33}, Eric Vilain⁸, Anne O'Donnell-Luria^{19

20

34}, Jennifer E Posey², Lisa H Chadwick³⁵, Michael J Bamshad^{14

15

36}, Stephen B Montgomery^{5

6

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

Affiliations

¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
³ Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.
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, CA, USA.
⁹ Division of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰ Division of Genetics and Metabolism, Children's National Rare Disease Institute, Washington, DC, USA.
¹¹ Center for Genetic Medicine Research, Children's National Rare Disease Institute, Washington, DC, USA.
¹² Department of Genomics and Precision Medicine, George Washington University, Washington, DC, USA.
¹³ Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA, USA.
¹⁴ Department of Pediatrics, Dvision 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 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁰ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, USA.
²¹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²³ Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
²⁴ Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
²⁵ Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
²⁶ Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA.
²⁷ Office of Genomic Data Science, National Human Genome Research Institute, Bethesda, MD, USA.
²⁸ Pacific Northwest Research Institute, Seattle, WA, USA.
²⁹ Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
³⁰ Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
³¹ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
³² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
³³ Department of Computer Science, Rice University, Houston, TX, USA.
³⁴ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
³⁵ Division of Genome Sciences, National Human Genome Research Institute, Bethesda, MD, USA.
³⁶ Department of Pediatrics, Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
³⁷ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.

PMID: 39764392
PMCID: PMC11702807

GREGoR: Accelerating Genomics for Rare Diseases

Moez Dawood et al. ArXiv. 2024.

[Preprint]. 2024 Dec 18:arXiv:2412.14338v1.

Authors

Affiliations

¹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
³ Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.
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, CA, USA.
⁹ Division of Cardiovascular Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
¹⁰ Division of Genetics and Metabolism, Children's National Rare Disease Institute, Washington, DC, USA.
¹¹ Center for Genetic Medicine Research, Children's National Rare Disease Institute, Washington, DC, USA.
¹² Department of Genomics and Precision Medicine, George Washington University, Washington, DC, USA.
¹³ Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA, USA.
¹⁴ Department of Pediatrics, Dvision 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 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁰ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, MA, USA.
²¹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²³ Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
²⁴ Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
²⁵ Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
²⁶ Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USA.
²⁷ Office of Genomic Data Science, National Human Genome Research Institute, Bethesda, MD, USA.
²⁸ Pacific Northwest Research Institute, Seattle, WA, USA.
²⁹ Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
³⁰ Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
³¹ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
³² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
³³ Department of Computer Science, Rice University, Houston, TX, USA.
³⁴ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
³⁵ Division of Genome Sciences, National Human Genome Research Institute, Bethesda, MD, USA.
³⁶ Department of Pediatrics, Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
³⁷ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.

PMID: 39764392
PMCID: PMC11702807

Abstract

Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange 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. Further, all data generated, currently representing ~7500 individuals from ~3000 families, is rapidly made available to researchers worldwide via the Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) to catalyze global efforts to develop approaches for genetic diagnoses in rare diseases (https://gregorconsortium.org/data). The majority of these families have undergone prior 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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Figures

**Figure 1 |. Overview of GREGoR.**
Strategic framework of the GREGoR Consortium for accelerating genomics in rare disease research, highlighting cross-cutting themes, systematic data generation, computational innovations, and endpoints of success.

**Figure 2 |. Overview of Publicly Released GREGoR Data.**
Summary of second public data release (dbGaP:phs003047). (A) Distribution of top 30 phenotypes in GREGoR based on Human Phenotype Ontology descriptions. (B) Table of numbers for probands and total individuals for each sequencing modality. (C) Venn diagram depicting overlap across short-read genomes, RNA-seq, and long-read genomes in data generation. (D) Family structures comprising the overall cohort from a total of n=3059 families. (E) Summary of current solved cases. Data is shared prior to analysis but even the current diagnostic outcomes underscore the challenges and opportunities in resolving rare disease cases that are previously exome negative.

See this image and copyright information in PMC

References

1. Baxter S. M. et al. Centers for Mendelian Genomics: A decade of facilitating gene discovery. Genet. Med. Off. J. Am. Coll. Med. Genet. 24, 784–797 (2022). - PMC - PubMed
1. Taylor J. C. et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat. Genet. 47, 717–726 (2015). - PMC - PubMed
1. Wright C. F. et al. Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland. N. Engl. J. Med. 388, 1559–1571 (2023). - PMC - PubMed
1. Rimmer A. et al. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat. Genet. 46, 912–918 (2014). - PMC - PubMed
1. Monaco L. et al. Research on rare diseases: ten years of progress and challenges at IRDiRC. Nat. Rev. Drug Discov. 21, 319–320 (2022). - PMC - PubMed

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[1] Baxter S. M. et al. Centers for Mendelian Genomics: A decade of facilitating gene discovery. Genet. Med. Off. J. Am. Coll. Med. Genet. 24, 784–797 (2022). - PMC - PubMed

[2] Baxter S. M. et al. Centers for Mendelian Genomics: A decade of facilitating gene discovery. Genet. Med. Off. J. Am. Coll. Med. Genet. 24, 784–797 (2022). - PMC - PubMed

[3] Taylor J. C. et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat. Genet. 47, 717–726 (2015). - PMC - PubMed

[4] Taylor J. C. et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat. Genet. 47, 717–726 (2015). - PMC - PubMed

[5] Wright C. F. et al. Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland. N. Engl. J. Med. 388, 1559–1571 (2023). - PMC - PubMed

[6] Wright C. F. et al. Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland. N. Engl. J. Med. 388, 1559–1571 (2023). - PMC - PubMed

[7] Rimmer A. et al. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat. Genet. 46, 912–918 (2014). - PMC - PubMed

[8] Rimmer A. et al. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat. Genet. 46, 912–918 (2014). - PMC - PubMed

[9] Monaco L. et al. Research on rare diseases: ten years of progress and challenges at IRDiRC. Nat. Rev. Drug Discov. 21, 319–320 (2022). - PMC - PubMed

[10] Monaco L. et al. Research on rare diseases: ten years of progress and challenges at IRDiRC. Nat. Rev. Drug Discov. 21, 319–320 (2022). - PMC - PubMed

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This is a preprint.

GREGoR: Accelerating Genomics for Rare Diseases

Affiliations

GREGoR: Accelerating Genomics for Rare Diseases

Authors

Affiliations

Abstract

Figures

Similar articles

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous

This is a preprint.

Abstract

Figures

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References

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Related information

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