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Diagnostic sequencing to support genetically stratified medicine in a tertiary care setting
Authors:Natalie Lippa  Louise Bier  Anya Revah-Politi  Halie May  Sulagna Kushary  Natalie Vena  Jessica L Giordano  Hila Milo Rasouly  Enrico Cocchi  Tristan T Sands  Ronald J Wapner  Kwame Anyane-Yeboa  Ali G Gharavi  David B Goldstein
Institution:1. Institiute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY;2. Precision Genomics Laboratory, Columbia University Irving Medical Center, New York, NY;3. Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, NY;4. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY;5. Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, NY;6. Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY;1. The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA;2. Department of Biostatistics, Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, TN;3. Department of Health Policy, Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, TN;4. Institute for Public Health Genetics, University of Washington School of Public Health, Seattle, WA;5. Department of Health Policy & Behavioral Sciences, School of Public Health, Georgia State University, Atlanta, GA;6. Genomic Medicine Institute, Geisinger, Danville, PA;7. Department of Population Health Sciences, Geisinger, Danville, PA;8. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN;1. Genomics Policy Unit, University of South Wales, Pontypridd, United Kingdom;2. William F. Connell School of Nursing, Boston College, Chestnut Hill, MA;3. Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;4. School of Nursing, University of Northern British Columbia, Prince George, British Columbia, Canada;5. Ross and Carol Nese College of Nursing, The Pennsylvania State University, University Park, PA;6. Genetic Counselling, Genomics England, London, United Kingdom;1. Biological Sciences Division, Department of Human Genetics, The University of Chicago, Chicago, IL;2. National Board of Medical Examiners, Philadelphia, PA;3. Division of Clinical Cytogenetics, Department of Pathology, Brigham and Women''s Hospital, Harvard Medical School, Boston, MA;4. Departmnt of Genetics and Pediatrics, University of Alabama at Birmingham, Birmingham, AL;5. American Board of Medical Genetics and Genomics, Bethesda, MD;6. Division of Human Genetics, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD;1. Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN;2. Division of Health Care Policy and Research, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN;3. School of Medicine, Medical Science Campus, University of Puerto Rico, San Juan, Puerto Rico;4. Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN;5. Department of Medical Oncology, Mayo Clinic, Rochester, MN;6. Department of Clinical Genomics, Mayo Clinic, Rochester, MN;7. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN;1. School of Medicine Greenville, University of South Carolina, Greenville, SC;2. Center for Bioethics, University of South Carolina, Columbia, SC;3. Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY;4. Vanderbilt University Medical Center, Nashville, TN;5. Phoenix Children’s Hospital, College of Medicine, The University of Arizona, Phoenix, AZ;6. Optum, Eden Prairie, MN;7. Color Genomics, Burlingame, CA;8. Patient Advocate, Greenville, SC;9. GeneDx, Gaithersburg, MD;10. Homer Stryker M.D. School of Medicine, Western Michigan University, Kalamazoo, MI;11. Divisions of Medical Genetics and Molecular Diagnostics, Departments of Pathology & Laboratory Medicine, Pediatrics, and Human Genetics, UCLA School of Medicine, Los Angeles, CA;12. The UCLA Institute for Society and Genetics, Los Angeles, CA;13. American College of Medical Genetics and Genomics, Bethesda, MD;1. Faculty of Social Sciences, Business, and Economics, Åbo Akademi University, Turku, Finland;2. Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland;3. Jyväskylä University School of Business and Economics, University of Jyväskylä, Jyväskylä, Finland;4. Labour Institute for Economic Research, Helsinki, Finland;5. IZA Institute of Labor Economics, Bonn, Germany;6. Department of Dermatology and Venereology, Department of Clinical Medicine, Faculty of Medicine, University of Turku, Turku, Finland;7. Department of Dermatology, Turku University Hospital, Turku, Finland;8. Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;9. Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
Abstract:PurposeThe goal of stratified medicine is to identify subgroups of patients with similar disease mechanisms and specific responses to treatments. To prepare for stratified clinical trials, genome-wide genetic analysis should occur across clinical areas to identify undiagnosed genetic diseases and new genetic causes of disease.MethodsTo advance genetically stratified medicine, we have developed and implemented broad exome sequencing infrastructure and research protocols at Columbia University Irving Medical Center/NewYork-Presbyterian Hospital.ResultsWe enrolled 4889 adult and pediatric probands and identified a primary result in 572 probands. The cohort was phenotypically and demographically heterogeneous because enrollment occurred across multiple specialty clinics (eg, epilepsy, nephrology, fetal anomaly). New gene-disease associations and phenotypic expansions were discovered across clinical specialties.ConclusionOur study processes have enabled the enrollment and exome sequencing/analysis of a phenotypically and demographically diverse cohort of patients within 1 tertiary care medical center. Because all genomic data are stored centrally with permission for longitudinal access to the electronic medical record, subjects can be recontacted with updated genetic diagnoses or for participation in future genotype-based clinical trials. This infrastructure has allowed for the promotion of genetically stratified clinical trial readiness within the Columbia University Irving Medical Center/NewYork-Presbyterian Hospital health care system.
Keywords:Exome sequencing  Genetic diagnosis  Precision medicine  Stratified medicine
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