reprinted from Issue 11, Fall 2010 of Frontiers of Medicine (PDF)
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In genetics, we really take care of whole families,” says Robert Nussbaum, MD, chief of the Division of Medical Genetics and a member of the UCSF Institute for Human Genetics.
Since his recruitment from the National Human Genome Research Institute in 2006 to establish the division, Nussbaum has increased genetics services for patients, raised awareness among providers and trainees about how genetics can improve patient care, and fostered information-sharing among UCSF genetic counselors specializing in different areas, such as metabolic disorders and cancer.
Genetics is advancing at an aston-ishing rate, thanks to more affordable technology. “When the human genome was sequenced less than 10 years ago, it cost $3 billion,” says Nussbaum. “One can now sequence a full human genome for around $13,000.”
Yet geneticists are not only focused on genes. “Genes are the dice that fate has thrown for you,” Nussbaum says. “But that doesn’t mean that the result is foretold. In many ways, we have more control over environmental and social factors.” For example, taking a detailed family history is critical for understanding the whole patient, and whether relatives might be at increased risk for certain diseases.
As an internist as well as a geneticist, Nussbaum works to integrate genetics throughout UCSF’s clinical services. “We serve as general internists for people with complicated hereditary disorders,” he says. The division collaborates with Beth Crawford, CGC, director of clinical services for the Cancer Risk Program at the UCSF Helen Diller Family Comprehensive Cancer Center. In addition to providing counseling, test-ing, surveillance and care for breast, ovarian and colon cancer, the program has recently expanded to help patients with many other familial cancers syndromes, such as cancers of the head, neck and endocrine system.
“These are rare syndromes that weren’t being diagnosed previously,” says Crawford. Often, these cancers affect multiple organs. The genetic counseling team can determine whether a patient with one type of cancer is also at risk for developing other related cancers; identify other family members at risk; and develop a prevention plan. For example, if children who inherit a gene mutation for a rare form of thyroid cancer have their thyroid removed at an early age, they can prevent development of cancer. “It can be life-saving for many families,” says Crawford.
In partnership with the Division of Cardiology and the Heart and Vascular Center, the division also launched the Program in Cardiovascular Genetics. “Almost all of these conditions predispose to some form of sudden cardiac death,” says Colleen Brown, a certified genetic counselor with the program. “The opportunities for early diagnosis and prevention are huge in these families.”
Mike and Abby are one such family. Seven years ago, Mike was diagnosed with hypertrophic cardiomyopathy (HCM), caused by one of a handful of genetic mutations. The first symptom is often collapse or sudden death. Mike had a strong family history of HCM; a number of relatives died in their 30s and 40s from the condition.
“We lived in total fear every day,” says Abby. They restricted their three young sons from running, playing strenuous sports, and even eating chocolate, since caffeinated foods could trigger an abnormal heart rhythm. On top of regular checkups and echocardiograms and EKGs twice a year, the family went to urgent care almost every month, any time a child felt dizzy or short of breath. “When you have a family history of HCM, no one takes that lightly,” says Abby.
Mike and Abby were referred to the Program in Cardiovascular Genetics, and an extensive family history was used to piece together a picture of the disease’s likely trail through the family tree. A genetic test for HCM had recently been developed, and Mike decided to take it. The results indicated a previously undiscovered genetic variant. After further research, they were told that testing other family members with HCM could help clarify whether the variant was benign, or related to the cause of Mike’s HCM.
After discussions with some of Mike’s relatives who had HCM, five family members volunteered to have additional genetic testing. All had the same genetic variation, enabling UCSF geneticists to confirm this as the cause of their HCM.
Mike and Abby also decided to test their children; each had a 50 percent chance of inheriting the genetic defect. When the results came in, all three sons were negative. “It was amazing!” Abby recalls. “We were floating on air for a month straight. Our parenting is completely different, now that we know.” Their oldest son now excels at basketball and baseball, and they can let all their children run freely and eat chocolate.
UCSF’s detective work and the willingness of their extended family to participate in the testing means other families can now be tested for this newly discovered genetic variant. Also, Mike and Abby recently gave birth to their fourth son; if he tests positive, UCSF and the family will develop a monitoring plan and continue to discuss new research and treatments.
Abby says that UCSF was as motivated as she and her husband were to find the genetic cause of the disease, and that the experience changed her family’s life. “In the end, we didn’t have to live in fear anymore,” she says.
The Future – Understanding Effects of Multiple Variants
Until now, much of genetics has focused on rare inherited diseases caused by a single genetic variant with large impact, such as HCM. Moving forward, Nussbaum says the field will increasingly focus on more subtle variations that have a large aggregate impact on the general population. For example, men whose mothers or sisters develop heart disease before age 60 are at greatly increased risk for heart disease themselves. “That’s not the result of a single variant somewhere, but rather the accumulated effects of multiple variants which are present in the family,” says Nussbaum.
As full genome sequencing becomes more affordable, researchers at UCSF and other institutions can encourage more patients to contribute genetic samples to large, anonymous databases. By analyzing patterns that develop, investigators can tease out which combinations of variants are associated with particular health outcomes.
This could have significant impacts on fields like pharmacogenetics, in which medication regimens are tailored to a patient’s DNA. “We’re moving to an era where we could predict what drug and starting dose might be best for an individual patient,” says Nussbaum.
He hopes to expand the division’s activities by obtaining funding to expand the testing and counseling capabilities of the division – which will help UCSF continue providing the best care to patients. “Even if families have a rare hereditary disorder, we know what it’s about, and can help them deal with it,” says Nussbaum. “They won’t have to be the ones teaching their doctors.”