Characterizing genetic variants for clinical action

Authors

  • Erin M. Ramos,

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    • Dr. Erin Ramos is a genetic epidemiologist and Program Director in the Division of Genomic Medicine, National Human Genome Research Institute (NHGRI). She manages a portfolio of research in genomic medicine and population genomics, including the Clinical Genome Resource (ClinGen), and was the lead organizer for the Characterizing and Displaying Genetic Variants for Clinical Action (ClinAction) Workshop.
    • * Correspondence to: Erin M. Ramos, Ph.D., M.P.H., Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, 5635 Fishers Lane, Suite 4076, MSC 9305, Bethesda, MD 20892-9307. E-mail: ramoser@nih.gov
  • Corina Din-Lovinescu,

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    • Corina Din-Lovinescu was a program analyst for the Genetic Association Information Network Data Access Committee and the Genomics and Randomized Trials Network (GARNET), two programs of the NHGRI. She was instrumental in the planning of the ClinAction Workshop and is now a medical student at the Touro College of Osteopathic Medicine.
  • Jonathan S. Berg,

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    • Dr. Jonathan Berg is an Assistant Professor in the Department of Genetics at UNC Chapel Hill, where he maintains an active clinical practice in Cancer and Adult Genetics and pursues research related to the application of genomic sequencing in different aspects of clinical medicine. He is a co-PI or investigator on grants that explore the use of next-generation sequencing as a diagnostic tool, for augmented newborn screening, and for population screening of healthy adults.
  • Lisa D. Brooks,

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    • Dr. Lisa D. Brooks manages the Genetic Variation Program in the Division of Genome Sciences at the NHGRI. She manages computational studies of genetic variation and its relation to phenotype, as well as the 1,000 Genomes Project, ClinGen, and BD2K.
  • Audrey Duncanson,

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    • Dr. Audrey Duncanson is a Senior Portfolio Developer, Wellcome Trust. She helps develop and implement strategic funding initiatives in genetics, genomics and the molecular sciences, and oversees the portfolio in these areas. Her current responsibilities include the Wellcome Trust Case Control Consortium, the UK10K sequencing project and H3 Africa.
  • Michael Dunn,

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    • Dr. Michael Dunn is Head of the Genetic and Molecular Sciences team in Science Funding. Having obtained a PhD in biochemistry at the University of Cambridge, he went on to work on the genetics of type 1 diabetes at the Wellcome Trust Centre for Human Genetics in Oxford. Michael joined the Trust in 2000 where he manages and develops its scientific portfolio and community of investigators to enable the Trust to achieve its mission.
  • Peter Good,

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    • Dr. Peter Good is the deputy director for the Division of Genomic Sciences, NHGRI where he advises NHGRI leaders on bioinformatics as a key component of genomic research. Dr. Good oversaw development of UniProt, a database of protein sequence and functional information derived from genome sequencing projects and guided other NHGRI projects including The Cancer Genome Atlas, the Knockout Mouse Project, and the ENCyclopedia of DNA Elements (ENCODE).
  • Tim J.P. Hubbard,

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    • Dr. Tim Hubbard is Head of Department of Medical & Molecular Genetics, King's College London and Director of Bioinformatics, King's Health Partners. Dr. Hubbard is also Head of Bioinformatics at Genomics England which is implementing the UK 100,000 Genomes project. Previously, he was Head of Informatics at the Wellcome Trust Sanger Institute.
  • Gail P. Jarvik,

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    • Gail Jarvik, M.D., Ph.D., is an Internist, Medical Geneticist, Head of Medical Genetics, the Arno G. Motulsky Endowed Chair of Medicine, Professor of Genome Sciences at the University of Washington, and the Director of the Northwest Institute for Genetic Medicine. She is a practicing physician in both Internal Medicine and Medical Genetics with research focuses on the genetics of complex disease and the utility of high-throughput genomic data in clinical medicine.
  • Christopher O'Donnell,

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    • Dr. Christopher O'Donnell, a cardiologist and genetic epidemiologist, serves as the Senior Advisor for Genome Research to the Director of the National Heart, Lung and Blood Institute (NHLBI). He is a Tenured Senior Investigator in the NHLBI Division of Intramural Research, where he serves as Chief of the Cardiovascular Epidemiology and Human Genomics Branch and Associate Director of the Framingham Heart Study.
  • Stephen T. Sherry,

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    • Dr. Steve Sherry serves as the Chief of the Reference Collections Section, Information Engineering Branch at National Center for Biotechnology Information.
  • Naomi Aronson,

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    • Dr. Naomi Aronson is the Executive Director of the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Dr. Aronson has overseen TEC's development as a nationally recognized technology assessment program and an Evidence-based Practice Center (EPC) of the Agency for Healthcare Research and Quality (AHRQ).
  • Leslie G. Biesecker,

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    • Dr. Leslie Biesecker is a clinical and molecular geneticist with expertise in highly penetrant genetic and genomic disorders. He has been in the intramural research program of the NIH for 20 years and is a member of numerous editorial and advisory boards.
  • Bruce Blumberg,

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    • Dr. Bruce Blumberg is a clinical geneticist and Institutional Director of Graduate Medical Education at Kaiser Permanente Northern California. He is a Clinical Professor of Pediatrics at UCSF and an Adjunct Clinical Professor of Pediatrics at Stanford University School of Medicine.
  • Ned Calonge,

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    • Ned Calonge, MD, serves as President and CEO of The Colorado Trust and has worked closely with nonprofit organizations in every county across the state to improve health and well-being or all Coloradans. Dr. Calonge is a member and past President of the Colorado Medical Board, which licenses and regulates physicians. He teaches epidemiology, biostatistics and research methods at the University of Colorado Schools of Medicine and Public Health.
  • Helen M. Colhoun,

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    • Dr. Helen Colhoun is a professor of public health at the University of Dundee, Scotland, UK. Her research includes studies that involve large scale linkage of electronic health record data to biospecimen resources used for genetic analyses of determinants of diabetes and diabetic complications.
  • Robert S. Epstein,

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    • Dr. Robert Epstein is an epidemiologist and faculty member at University of Maryland Medical System, Department of Epidemiology and Public Health. Prior to his current role Dr. Epstein was Medco's Chief Medical Officer for 13 years, where he led formulary development, clinical guideline development, drug information services, personalized medicine programs, and client analytics and reporting.
  • Paul Flicek,

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    • Dr. Paul Flicek leads the Vertebrate Genomics Team at the European Bioinformatics Institute and heads the cluster of resources focused on genes, genomes, and variation. He is a senior scientist of the European Molecular Biology Laboratory.
  • Erynn S. Gordon,

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    • Erynn S. Gordon, M.S., LCGC is a board certified genetic counselor with over 12 years of clinical and research experience in neurology, oncology, and genetics. Before joining Invitae, Erynn managed the Coriell Personalized Medicine Collaborative, examining the utility of personalized medicine.
  • Eric D. Green,

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    • Eric D. Green, M.D., Ph.D., became the third Director of the NHGRI in December 2009. He is responsible for providing overall leadership of the NHGRI's research portfolio and other initiatives. Immediately prior to this appointment, he was the Scientific Director of NHGRI, a position he had held since 2002, and Director of the NIH Intramural Sequencing Center (NISC).
  • Robert C. Green,

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    • Robert C. Green, M.D., M.P.H., is a medical geneticist at Brigham and Women's Hospital and Harvard Medical School. Dr. Green leads a research program in translational genomics and leads and co-leads respectively the NIH funded MedSeq and BabySeq Projects, research projects exploring the integration of genome sequencing into the practice of medicine.
  • Matthew Hurles,

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    • Dr. Matthew Hurles earned his degree in biochemistry at Oxford University, UK, and PhD in Leicester, UK. He was a Research Fellow at the McDonald Institute for Archaeological Research at Cambridge University, UK, analyzing genetic variation with the aim of improving our understanding of the human past. He is now at the Wellcome Trust Sanger Institute near Cambridge, UK, investigating the unusual evolutionary dynamics of recently duplicated genomic regions.
  • Kensaku Kawamoto,

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    • Kensaku Kawamoto, M.D., Ph.D., is Associate Chief Medical Information Officer for the University of Utah Health Sciences Center. He is also its Director of Knowledge Management and Mobilization and an Assistant Professor of Biomedical Informatics.
  • William Knaus,

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    • Dr. William A. Knaus is the Director of the Applied Genomics Research and Health Heritage Family Medical History Project, Center for Biomedical Research Informatics NorthShore University Health Systems, Evanston, Illinois.
  • David H. Ledbetter,

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    • Dr. Ledbetter is a board-certified Clinical Cytogeneticist whose research interest is in the development and application of new genetic/genomic technologies to improve early diagnosis for neurodevelopmental disorders such as autism and intellectual disabilities. He currently serves as Executive Vice President and Chief Scientific Officer at Geisinger Health Systems where he is investigating the clinical utility of genomic medicine in an integrated healthcare “laboratory.”
  • Howard P. Levy,

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    • Howard P. Levy, M.D., Ph.D., is an Assistant Professor at Johns Hopkins University. He is board certified in Internal Medicine and Clinical Genetics, and specializes in general primary care medicine, genetics of common complex disease, and the care of adults with Mendelian genetic disease.
  • Elaine Lyon,

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    • Dr. Elaine Lyon is an associate professor of Pathology at the University of Utah School of Medicine. In addition, she is a medical director of Genetics/Genomics at ARUP Laboratories, a national reference laboratory owned by the University of Utah.
  • Donna Maglott,

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    • Dr. Donna Maglott has been a staff scientist at NCBI since 1998 where she contributed to diverse projects such as RefSeq, Gene, OMIM, Map Viewer, Eukaryotic Genome Annotation, UniGene, UniSTS, dbSNP, GTR, ClinVar, and MedGen.
  • Howard L. McLeod,

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    • Dr. Howard McLeod is the Medical Director of the DeBartolo Family Personalized Medicine Institute at the Moffitt Cancer Center in Tampa, Florida. He is also a Senior Member of the Division of Population Sciences and an Endowed Research Chair of the state of Florida.
  • Nazneen Rahman,

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    • Dr. Nazneen Rahman, M.D., Ph.D., is Professor of Human Genetics at Institute of Cancer Research, London and Head of Clinical Cancer Genetics Unit at the Royal Marsden Hospital. Her research is focused on the identification and clinical translation of disease predisposition genes.
  • Gurvaneet Randhawa,

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    • Gurvaneet S. Randhawa, M.D., M.P.H., is a past director of the U.S. Preventive Services Task Force program. He provides scientific direction to AHRQ grants that are building an clinical electronic infrastructure to collect prospective, patient-centered outcomes data used for comparative effectiveness research, patient-centered outcomes research and quality improvement of clinical care. He is also a senior AHRQ adviser on clinical genomics and personalized medicine.
  • Catherine Wicklund,

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    • Catherine Wicklund is an Associate Professor and Director of the Graduate Program in Genetic Counseling at Northwestern University Feinberg School of Medicine, Center for Genetic Medicine. She is the National Society of Genetic Counselors representative on the IOM Roundtable on Translating Genomic-Based Research for Health and is an appointed member of the Discretionary Advisory Committee on Heritable Disorders in Newborns and Children.
  • Teri A. Manolio,

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    • Dr. Teri Manolio, a physician and epidemiologist, serves as the Director of the Division of Genomic Medicine, NHGRI. Dr. Manolio is leading efforts to support research translating genomic discoveries into more effective diagnoses, preventive measures, and treatments.
  • Rex L. Chisholm,

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    • Dr. Rex L. Chisholm is the Adam and Richard Lind Professor of Human Genetics at Northwestern University Feinberg School of Medicine. His research focuses on biomedical informatics and the contributions of genetic variation to human disease and therapeutic outcomes.
  • Marc S. Williams

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    • Dr. Williams is the director of the Genomic Medicine Institute (GMI) for Geisinger Health System. The GMI is responsible for implementation of genomic medicine for the system. Dr. Williams was co-chair of the Characterizing and Displaying Genetic Variants for Clinical Action Workshop.

Abstract

Genome-wide association studies, DNA sequencing studies, and other genomic studies are finding an increasing number of genetic variants associated with clinical phenotypes that may be useful in developing diagnostic, preventive, and treatment strategies for individual patients. However, few variants have been integrated into routine clinical practice. The reasons for this are several, but two of the most significant are limited evidence about the clinical implications of the variants and a lack of a comprehensive knowledge base that captures genetic variants, their phenotypic associations, and other pertinent phenotypic information that is openly accessible to clinical groups attempting to interpret sequencing data. As the field of medicine begins to incorporate genome-scale analysis into clinical care, approaches need to be developed for collecting and characterizing data on the clinical implications of variants, developing consensus on their actionability, and making this information available for clinical use. The National Human Genome Research Institute (NHGRI) and the Wellcome Trust thus convened a workshop to consider the processes and resources needed to: (1) identify clinically valid genetic variants; (2) decide whether they are actionable and what the action should be; and (3) provide this information for clinical use. This commentary outlines the key discussion points and recommendations from the workshop. © 2014 Wiley Periodicals, Inc.

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