College of American Pathologists
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  Whole exome sequencing and pharmacogenomics


CAP Today




January 2013
Feature Story

A striking example of the interrelation between pharmacogenomics and next-generation sequencing is provided by a Clinical Sequencing Exploratory Research (CSER) grant awarded to Karen Weck, MD, and her colleagues at the University of North Carolina, one of six such grants awarded by the National Human Genome Research Institute. In this work, whole exome sequencing will be done on 750 patients with a likely genetic etiology to their disease to look for diagnostic results. The conditions to be included are cardiomyopathy, seizures, neuromuscular disorders, inherited or familial cancer, and microencephaly and developmental delay.

“The study is designed so we can study characteristics of genomic information that patients want and study its impact on medical treatment and behavior,” says Dr. Weck, professor of pathology and laboratory medicine and genetics at UNC and director of molecular genetics. “If you do whole genome sequencing or whole exome sequencing, what information do you find that is useful to patients?

“We will also be returning so-called incidental information not related to that patient’s disease,” Dr. Weck says. Study subjects are randomized to receive only diagnostic information or diagnostic information with the choice to receive incidental information. “I am particularly excited about pharmacogenomic information that we will glean from this study, which is a big part of personalized medicine,” Dr. Weck says. Patients can decide whether they want pharmacogenomic information along with information about their risk of future disease. “We will have the opportunity to study how patients and physicians deal with pharmacogenomic information and whether they find it useful, and to see what effect it has on medical treatment and diseases,” Dr. Weck says. “This is a huge issue. That’s why we designed the study this way.” They have divided incidental genomic information into different risk categories or “bins,” she says, based on the potential harms and benefits to the patient, including whether information is medically actionable.

Information about pharmacogenomics is considered fairly low risk, while information about diseases such as Huntington’s is fairly high risk. Information about the apolipoprotein E gene, which affects the risk for Alzheimer’s disease, would be considered intermediate risk.

For high-risk information, patients go through a series of counseling steps. “Our approach is to have a conversation with the patient upfront,” Dr. Weck says. “We will tell them, ‘This is the type of information we might get.’ And to have the patient be the driver. My guess is that most patients will say, Yes, I want to know it all, but that they haven’t thought about all the ramifications. So having a serious conversation about that is very important.”

“If information is potentially life-threatening and treatable or medically actionable, we will return it to people even in the control arm,” Dr. Weck says. A genetic variant for long QT syndrome falls into this category. It is associated with an increased risk of sudden death, and there is something you can do about it. “That’s why I think pharmacogenomic variants will be of extreme interest to patients,” she says. “By definition it will affect their response to a drug if the patient ever needs that drug.”

—William Check, PhD


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