Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research

doi:10.1016/j.cell.2017.03.005

. 2017 Mar 23;169(1):6-12.

doi: 10.1016/j.cell.2017.03.005.

Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research

Teri A Manolio¹, Douglas M Fowler², Lea M Starita², Melissa A Haendel³, Daniel G MacArthur⁴, Leslie G Biesecker⁵, Elizabeth Worthey⁶, Rex L Chisholm⁷, Eric D Green⁵, Howard J Jacob⁶, Howard L McLeod⁸, Dan Roden⁹, Laura Lyman Rodriguez⁵, Marc S Williams¹⁰, Gregory M Cooper⁶, Nancy J Cox¹¹, Gail E Herman¹², Stephen Kingsmore¹³, Cecilia Lo¹⁴, Cathleen Lutz¹⁵, Calum A MacRae¹⁶, Robert L Nussbaum¹⁷, Jose M Ordovas¹⁸, Erin M Ramos⁵, Peter N Robinson¹⁹, Wendy S Rubinstein²⁰, Christine Seidman²¹, Barbara E Stranger²², Haoyi Wang²³, Monte Westerfield²⁴, Carol Bult²³

Affiliations

¹ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: manolio@nih.gov.
² Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
³ Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR 97239, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
⁷ Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁸ DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, FL 33612, USA.
⁹ Department of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
¹⁰ Genomic Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
¹¹ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
¹² Institute for Genomic Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
¹³ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
¹⁴ Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 1526, USA.
¹⁵ Rare and Orphan Disease Center, Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USA.
¹⁶ Divisions of Cardiovascular Medicine, Network Medicine and Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁷ Invitae Genetics Information and Testing Company, San Francisco, CA 94107, USA.
¹⁸ JM-USDA-Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.
¹⁹ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
²⁰ National Center for Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20892, USA.
²¹ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
²² Section of Genetic Medicine, Department of Medicine, Institute for Genomics and Systems Biology, Center for Data Intensive Science, University of Chicago, Chicago, IL 60637, USA.
²³ The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USA.
²⁴ Department of Biology, University of Oregon, Portland, OR 97403, USA.

PMID: 28340351
PMCID: PMC5511379
DOI: 10.1016/j.cell.2017.03.005

Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research

Teri A Manolio et al. Cell. 2017.

. 2017 Mar 23;169(1):6-12.

doi: 10.1016/j.cell.2017.03.005.

Authors

Affiliations

¹ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: manolio@nih.gov.
² Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
³ Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR 97239, USA.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
⁷ Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
⁸ DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, FL 33612, USA.
⁹ Department of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
¹⁰ Genomic Medicine Institute, Geisinger Health System, Danville, PA 17822, USA.
¹¹ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
¹² Institute for Genomic Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
¹³ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
¹⁴ Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 1526, USA.
¹⁵ Rare and Orphan Disease Center, Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USA.
¹⁶ Divisions of Cardiovascular Medicine, Network Medicine and Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁷ Invitae Genetics Information and Testing Company, San Francisco, CA 94107, USA.
¹⁸ JM-USDA-Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.
¹⁹ The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
²⁰ National Center for Biotechnology Information, National Library of Medicine, NIH, Bethesda, MD 20892, USA.
²¹ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
²² Section of Genetic Medicine, Department of Medicine, Institute for Genomics and Systems Biology, Center for Data Intensive Science, University of Chicago, Chicago, IL 60637, USA.
²³ The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME 04609, USA.
²⁴ Department of Biology, University of Oregon, Portland, OR 97403, USA.

PMID: 28340351
PMCID: PMC5511379
DOI: 10.1016/j.cell.2017.03.005

Abstract

Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.

Published by Elsevier Inc.

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Figures

**Figure 1**
Pathogenicity assertions for 61,169 of 72,472 ClinVar variants as of 9/1/16 (N.B.—no pathogenicity assertions provided for 11,303 variants).

See this image and copyright information in PMC

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References

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1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405–24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. - DOI - PMC - PubMed
1. Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-Salomon R, Rubinstein W, Maglott DR. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016 Jan 4;44(D1):D862–8. doi: 10.1093/nar/gkv1222. Epub 2015 Nov 17. - DOI - PMC - PubMed
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1. Starita LM, Young DL, Islam M, Kitzman JO, Gullingsrud J, Hause RJ, Fowler DM, Parvin JD, Shendure J, Fields S. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. Genetics. 2015 Jun;200(2):413–22. doi: 10.1534/genetics.115.175802. - DOI - PMC - PubMed

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[1] Cooper GM. Parlez-vous VUS? Genome Res. 2015 Oct;25(10):1423–6. doi: 10.1101/gr.190116.115. - DOI - PMC - PubMed

[2] Cooper GM. Parlez-vous VUS? Genome Res. 2015 Oct;25(10):1423–6. doi: 10.1101/gr.190116.115. - DOI - PMC - PubMed

[3] Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405–24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. - DOI - PMC - PubMed

[4] Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405–24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. - DOI - PMC - PubMed

[5] Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-Salomon R, Rubinstein W, Maglott DR. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016 Jan 4;44(D1):D862–8. doi: 10.1093/nar/gkv1222. Epub 2015 Nov 17. - DOI - PMC - PubMed

[6] Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Hoover J, Jang W, Katz K, Ovetsky M, Riley G, Sethi A, Tully R, Villamarin-Salomon R, Rubinstein W, Maglott DR. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016 Jan 4;44(D1):D862–8. doi: 10.1093/nar/gkv1222. Epub 2015 Nov 17. - DOI - PMC - PubMed

[7] Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, Soden SE, Cakici JA, Herd SM, Twist G, Noll A, Creed M, Alba PM, Carpenter SL, Clements MA, Fischer RT, Hays JA, Kilbride H, McDonough RJ, Rosterman JL, Tsai SL, Zellmer L, Farrow EG, Kingsmore SF. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015 May;3(5):377–87. - PMC - PubMed

[8] Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, Soden SE, Cakici JA, Herd SM, Twist G, Noll A, Creed M, Alba PM, Carpenter SL, Clements MA, Fischer RT, Hays JA, Kilbride H, McDonough RJ, Rosterman JL, Tsai SL, Zellmer L, Farrow EG, Kingsmore SF. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015 May;3(5):377–87. - PMC - PubMed

[9] Starita LM, Young DL, Islam M, Kitzman JO, Gullingsrud J, Hause RJ, Fowler DM, Parvin JD, Shendure J, Fields S. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. Genetics. 2015 Jun;200(2):413–22. doi: 10.1534/genetics.115.175802. - DOI - PMC - PubMed

[10] Starita LM, Young DL, Islam M, Kitzman JO, Gullingsrud J, Hause RJ, Fowler DM, Parvin JD, Shendure J, Fields S. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. Genetics. 2015 Jun;200(2):413–22. doi: 10.1534/genetics.115.175802. - DOI - PMC - PubMed

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Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research

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Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research

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