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“Clinical Exome Sequencing Goes Live”—UCSF Hosts Symposium on Delivering Precision Medicine

by Michael A. Goldman, PhD
Professor & Chair, Biology, San Francisco State University
© 2017 by Michael A. Goldman
Harnessing genomics in the diagnosis and treatment of human disease requires moving technologies that have been used primarily in research laboratories into the clinic, on a routine, rather than provisional basis. The University of California at San Francisco (UCSF) launched its clinical exome sequencing laboratory with a symposium entitled "Delivering Precision Medicine at UCSF: Clinical Exome Sequencing Goes Live" in June. The laboratory, directed by a team including co-directors Pui-Yan Kwok, MD, PhD, and Neil Risch, PhD., has received certification from the Clinical Laboratory Improvement Amendments (CLIA), which regulates/certifies testing laboratories. The laboratory is a part of the University's Genomic Medicine Initiative, launched two years ago in the Institute for Human Genetics ( The speakers focused tightly on the elucidation of poorly-understood clinical conditions and rare diseases. Although concerned mainly with the what, where, when, how, and why of providing, delivering, and utilizing the service, the day was peppered with touching stories of the success of clinical exome sequencing in relieving human suffering. The "classic" case is that of Nicholas Volker, whose TWO rare genetic disorders were elucidated using whole exome sequencing (WES) (profiled in the book “One in a Billion”). Patient Jacqui Morgan told her own heart-breaking story of an illness that overcame her in her early twenties. After a fruitless diagnostic odyssey, she came to UCSF, in septic shock, where a consulting geneticist suggested a treatment and a confirming diagnosis involving DNA sequencing. Jacqui didn't have the luxury of waiting for the result, but treatment stabilized her, and put her on the road to a "killer recovery," as she, now in robust health, describes it. Jacqui had GA-2/MADD (Glutaric Acidemia type II or Multiple Acyl Co-A Dehydrogenase Deficiency,, a disease "so rare, they don't even know how rare it is." But it isn't always that easy, if you can call a six-month recovery easy. Sometimes, even exome sequencing doesn't identify the culprit, or, worse yet, gives ambiguous results. Most genomic variants discovered in exome sequencing are of unknown clinical significance. It's possible that a re-analysis of the data later, in light of further discovery, could identify the causative gene--or further DNA sequencing, called whole-genome sequencing, may be required. It is also possible that testing identifies the underlying problem unambiguously, providing a diagnosis, but that there is no cure or treatment. Just knowing what's wrong may be an end in itself for many patients and their families, at least ending long, expensive, and fruitless diagnostic odysseys. One patient had seven MRI’s from seven different medical centers before a less-costly WES provided useful information.

Dr. Gail Jarvik, who is the Arno G. Motulsky Chair of Medical Genetics at the University of Washington, and the Charles & Lois Epstein Visiting Professor at UCSF, spoke of "moving the genome to the clinic." Today, she says, sequencing an exome is cheaper than an MRI, at least if insurance covers it. She also stressed that genetic information is often over-interpreted, citing commercial concerns that claim they can recommend a diet or an ideal mate based on your genotype or blood type. She emphasized the importance of identifying and studying actionable genetic variants, and explained how the University of Washington established its list of genes based on the unanimous agreement of twenty-seven experts. The subject remains controversial, and expert opinions on what constitutes an actionable genetic variant today do not always jive. Some of Dr. Jarvik's concerns are the lack of insurance coverage for panel genetic testing and the lack of general provider knowledge about genetics, both of which must be addressed as we proceed with genomic medicine.

Paraphrasing the age-old Passover question, UCSF Bioethicist Dr. Barbara Koenig, Professor in the Department of Social & Behavioral Sciences, Institute for Health & Aging, and, Deptaetment of Anthropology, History, and Social Medicine, asks what makes genetic testing different from all other medical testing? As an ethicist "embedded" in the Genomic Medicine Initiative, she tries to be circumspect. Genetics still suffers from the historical association with the eugenics of the Twentieth Century. Moreover, no genetic test is ever done on an individual; by nature, the entire extended family is involved. While WES may identify the causative mutation for a previously-unknown condition, it is also likely to produce a number of "incidental" findings, genetic changes that suggest the possibility of conditions not yet manifest in the individual. And there might be no clinical utility to knowing that information. Genetic information doesn't just shed light on the condition of the individual tested, but has implications for all relatives, dead, alive, or as yet unborn. Thus, knowing what to do with the information, and how much of it to share with relatives, presents a serious dilemma. Data privacy is also a concern, and will ultimately need strong regulatory intervention. (I'd actually be quite satisfied if the Emergency Room could just access my own Electronic Health Record at the same institution!) In Dr. Koenig's practical approach to genome ethics, the concerns aren't just theoretical (see, for instance,

Neil Risch, Head of the Institute for Human Genetics at UCSF, thinks that it will soon be practical and sensible to perform WES on every child at or before birth, screening for common and easily-treated diseases that are sometimes missed with deadly consequences, including hemochromatosis and ornithine transcarbamylase (OTCase) deficiency. Health economist Kathryn Phillips, also at UCSF, reminded us that we still have a long way to go in gathering the evidence of efficacy, utility, and cost-effectiveness that health-care payers (like insurance companies, Medicare, and Medicaid) require before these diagnostic technologies can be made available widely. It is crucial that we keep the nuances of genomic medicine in mind as we debate health-care and genetic-discrimination legislation in our society. Nevertheless, the introduction of CLIA-certified laboratories like that at UCSF is a key, and much-anticipated, step in bringing genomic information from bench to bedside.


The author of the above article is Michael A. Goldman (photo), PhD, Professor & Chair, Biology, San Francisco State University. In addition to his academic efforts Dr. Goldman is a published science writer and book review author with articles published in journals such as Science. Dr. Goldman is also a member of the BioQuick News distinguished group of Science & Medicine Advisors ( The above article is © 2017 by Michael A. Goldman.

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