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Dec 1, 2011 (Vol. 31, No. 21)

Sequencing Alters Medical Genetics

Use of NGS in Medicine Contributing to Improvements in Human Health

  • Click Image To Enlarge +
    Next-generation sequencing technology is rapidly moving toward the clinical diagnostic arena while remaining a critical basic research tool. [iStockphoto]

    A plenary debate, entitled “Current and Emerging Sequencing Technologies: Changing the Practice of Medical Genetics,” provoked strong and divergent opinions at the combined American Society of Human Genetics (ASHG) and International Congress of Human Genetics (ICHG) conference held recently in Montreal.

    Han Brunner, M.D., Ph.D., a clinical geneticist and professor of human genetics at University Hospital and Radboud University, moderated the debate, which in the end generated more questions than answers, highlighting the strong opinions and emotions surrounding the role of genome sequencing in medicine today and into the future.

    The panelists represented a range of viewpoints, expressing the perspectives of industry, researchers, clinicians, and patient advocates. They included Joris Veltman, Ph.D., associate professor, department of human genetics, Radboud University; Radoje Drmanac, Ph.D., co-founder and CSO at Complete Genomics, Ségolène Aymé, a medical geneticist and epidemiologist, director of research at INSERM and coordinator of the Orphanet platform for rare disease registries; Louanne Hudgins, M.D., professor and chief, division of medical genetics in the department of pediatrics at Stanford University School of Medicine; Michael Hayden, Ph.D., director and senior scientist, Centre for Molecular Medicine and Therapeutics, and University Killam professor, department of medical genetics, University of British Columbia; and Ming Qi, Ph.D., director and professor, Zhejiang University Center for Genetic and Genomic Medicine, China.

    The panelists each had an opportunity to respond to four statements, and then to discuss and debate each others’ responses: 1) Targeted sequencing will remain the norm for diagnostic medical genetics because whole exome and whole-genome sequencing (WGS) will yield an excess of information that is useless, counterproductive, and possibly damaging to the patient. 2) Personal genome sequencing creates an unacceptable risk to the privacy of people. 3) Cytogenetics will cease to be. Sequencing is the only future technology in diagnostic labs. 4) Personal genomes will be incorporated in the standard of care for all medicine. Therefore, medical genetics will disappear as a separate medical specialty.

    Han Brunner summed up the main challenge implicit in all of these statements, asking the panelists, “How do we take this beast of a new technology and use it for the advantage of our patients?” And that, above all else—how to use WGS to improve human health—was the facet on which the panelists could all agree, that ultimately, the use of next-generation sequencing (NGS) technology in clinical medicine had to benefit patients and their families.

    Notwithstanding that the ability to do targeted DNA sequencing, exome sequencing, or whole-genome sequencing accurately and cost effectively is a remarkable scientific achievement and is here today, or that the data generated has incalculable value from a scientific and research perspective, are we ready to share this information with clinicians and patients, do we really know what it means in terms of predicting inherited disease risk, diagnosing disease predisposition, providing reproductive counseling, or managing disease, and do we know how to interpret and apply sequence information to impact prognosis, treatment, or quality of life?

    The areas of consensus were quite clear, the points of disagreement less so, as the panelists debated: whether genome sequencing technology should be implemented simply because it is available; whether it is immoral not to gather the most information you possibly can about a patient’s disease; who “owns” and has a responsibility to store, protect, and reanalyze individuals’ genomic data; what do patients want to know; and where is the line (and how do you keep it from blurring) between clinical research and clinical medicine and when is it appropriate to cross the line from applying NGS information for scientific discovery to using it to guide clinical decision making; and how do we maintain a clear distinction between disease-related sequencing and screening, and should clinicians handle incidental findings.

  • Where We Can Agree

    Several main areas of consensus emerged from the discussions, including: the directive to proceed carefully and, as in all aspects of medicine, first do no harm; to continue to emphasize hope for what NGS can provide, but without all the hype; and to acknowledge that whole-genome sequencing is here now and is here to stay. Overall, the panelists agreed that, with the exception of diagnosing and providing genetic counseling on Mendelian diseases, sequence data is “not ready for prime time” and it is far too early to share the information with patients, and perhaps even with clinicians.

  • Exome Sequencing Finds Sweet Spot: At least in terms of sharing information, the panel said, the gold standard remained targeted sequencing for identification of specific genetic diseases. But somewhere between targeted sequencing and likely uninformative whole sequence data lies exome sequencing, a technique that selectively targets the most functionally relevant DNA sequences that encode proteins. You can get the scoop on how scientists are leveraging exome sequencing here.

  • Three overarching and urgent needs emerged from the debate: unified strategies for storing and interpreting genomic sequence data; mechanisms to protect patient privacy and prevent misuse of genetic data to stigmatize or discriminate against individuals; and the need for education—for physicians, medical geneticists, genetic counselors, and patients—on how to present and share sequence data and what it may or may not mean.

    There was general support for the creation of an international, curated genotype/phenotype database to help accelerate and standardize data interpretation and understand differences based on ethnicity, and for an international, multidisciplinary body of experts that would establish underlying principles, monitor the field as it advances and evolves, help determine what filters are needed between sequence information and clinicians/patients, and devise strategies to protect individual privacy.

    There was no consensus or definitive answers to several issues raised, such as how to pay for testing and what it will take to convince payers that whole-genome sequencing is cost-effective; what constitutes true informed consent; and who should have access to a patient’s sequence information.

    The panelists challenged each other to delineate the point at which DNA sequence data has clinical utility—when it is “actionable” and how to define what actionable even means. Does it have to guide treatment decisions for a patient with a diagnosed disorder or is it actionable if it can simply improve quality of life and perhaps impact a person’s risk of developing a disease?

    For example, would it be valuable to be able to tell patients they have a genetic trait associated with an increased risk of high cholesterol if it might encourage them to change their lifestyle and behavior to modulate that risk?

    Another complex question arose: for WGS data collected now and stored for future use, who is responsible for maintaining, updating, and re-analyzing the data as new knowledge becomes available? And is there, in fact, a moral obligation to reanalyze the information and report the results to patients?

    Where clear differences of opinion emerged was in discussions comparing the short-term and long-term value of targeted genomic sequencing, whole-genome sequencing, and exome sequencing. Should the focus be on collecting WGS data because there is more of it and because we can or is it more appropriate and cost-effective to redo targeted sequencing as needed?

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