Lab Moves Genomic Testing into the Clinic

The earliest symptom of the inherited heart condition hypertrophic cardiomyopathy can be sudden death at a tragically young age. HMS researchers discovered the first human gene underlying the disorder 15 years ago, but clinical genetic testing to identify those people at risk just became available last year.

Photo by Graham Ramsay

Peter Verlander and Heidi Rehm at the Laboratory for Molecular Medicine work to move novel genetic testing from the lab into the clinic for better diagnosis and treatment of common disorders, such as heart disease, cancer, and hearing loss.

About the same time, another genetic test emerged to detect the one in 10 lung cancers susceptible to certain new targeted drugs, within months of reports by two HMS teams that these drug-responsive tumor cells have mutations in a key signaling domain of their epidermal growth factor receptors (EGFRs).

A set of genetic tests to diagnose inherited kidney disorders is in the pipeline. Other genetic tests for a family of liver enzymes that determine how fast people metabolize hundreds of commonly prescribed drugs from beta blockers to codeine are being considered to help doctors titrate doses and predict side effects more precisely than the trial-and-error method favored now.

It may surprise doctors that these genetic tests are not solely for research anymore and that they are available locally. This fast-growing menu displays the efforts of the Laboratory for Molecular Medicine (LMM) in Cambridge to push the fruits of genomic and genetic research into the clinic in hopes of refining the diagnosis and treatment of common diseases, such as heart disease and cancer.

“We want to use the lab as a test bed to show that it is possible to take genetic knowledge discovered by one of our people or someone else around the country and show that testing can actually make a difference in caring for people,” said Raju Kucherlapati, scientific director of the Harvard Medical School–Partners Healthcare Center for Genetics and Genomics and the Paul C. Cabot professor of genetics at HMS.

Opened for business two years ago, the nonprofit clinical diagnostic lab offers more than two dozen tests for genes underlying hearing loss, cardiovascular disease, and cancer. Lab staff add new tests using an informal matrix of perceived clinical usefulness, scientific evidence, and cost. Many tests include genes discovered or studied extensively by HMS faculty advisers, but the lab is increasingly providing more genetic tests of clinical relevance independent of their institutional origin.

“We are driven to a great degree by the needs of clinicians,” said molecular geneticist Peter Verlander, associate director of strategic development for LMM.

“Cardiologists are ready for it,” said lab client Amy Sehnert, a pediatric cardiologist at the University of California, San Francisco. “We’ve known for a decade the genetic basis of some of these diseases,” she said. “What’s been lacking is a clinical laboratory to do the testing.”

Ready or not, genetic testing is here, said lab client Daniel Judge, a cardiologist at Johns Hopkins Hospital in Baltimore, who runs a genetic cardiology clinic. “Genetic testing is rapidly advancing,” he said, “but some people see it as a research tool and are slow to recognize its clinical benefit.”

Extending Molecular Medicine
LMM offers its services to doctors and pathology departments across North America for most of its tests. Now, for example, the lab runs about 35 EGFR tumor tests in-house each month for Partners hospitals, many in the context of a clinical trial. These trials aim to determine whether the targeted therapies, which do not appear to extend people’s lives even if tumors dramatically shrink, can be more effective as a first-line rather than last-chance drug.

“Quite frankly, our intent as a lab for molecular medicine is not necessarily to develop tests and mass market them and be robotic in that sense,” said LMM molecular geneticist Heidi Rehm, HMS instructor in pathology at Brigham and Women’s Hospital. “Our main mission is to push the boundaries of clinical medicine and to get novel discoveries into medicine quickly.”

Protocols for the new genetic tests are more rigorous for the clinic than for research, but the regulatory hurdles are low, Rehm said. Unlike drugs, medical devices, or testing kits, clinical genetic testing labs occupy a niche formally called “homebrew” by the U.S. Food and Drug Administration and “high complexity lab” by the federal Clinical Laboratory Improvement Amendment. Responsibility for the technical validation of the tests developed by a lab lies largely with the lab. LMM is accredited and inspected by the Joint Commission on Accreditation of Healthcare Organizations.

The tests for hypertrophic cardiomyopathy (HCM), likely to remain an LMM exclusive for some time, are a good example of the unique niche the lab occupies in the world of clinical–genetic testing services dominated by commercial labs such as Quest Diagnostics, LabCorp, Genzyme, and a multitude of in-house hospital laboratories.

The tests are packaged as a progressive series, starting at $3,000 for the first panel of five more common genes. The price seems high, but it can be considered a bargain, according to Judge. “In most labs, $1,000 for a single gene is a good price,” he said. If no mutation is found, doctors may request the second panel of three genes and a third panel of two genes.

Like most of the tests now offered, the hypertrophic cardiomyopathy panels rely on time-consuming high-throughput sequencing to read each nucleotide because many different mutations in the same genes can lead to similar phenotypes. In fact, families often carry “private” mutations. And people with mutations in the gene for titin are out of luck. As its name suggests, it is one of the largest genes known and too expensive to test.

Back to the Bench
Besides the diagnosis, the clinical tests add new scientific knowledge. “Now, more than one third of the HCM patients we test have new mutations that have never been seen before,” Rehm said. “A year ago, that was two thirds.” These new mutations are added to a database maintained by Christine Seidman, the Thomas W. Smith professor of medicine at HMS and Brigham and Women’s Hospital (see Bulletin), and Jonathan Seidman, the Henrietta B. and Frederick H. Bugher Foundation professor of genetics at HMS, who discovered the first of a dozen known genes whose mutations can cause the disorder, as well as a distinct and more serious clinical disorder with the same phenotype.

Often, the first genetic test in a family is for a person who already has a tentative diagnosis. Insurance companies may pay for the test at the doctor’s request. LMM has a pre--authorization form letter on its website that has been effective in many cases. Once the mutation is identified, other members of the same family can order a simple genotype test at $250 to confirm or rule out the same genetic predisposition. That is inexpensive enough to pay out of pocket and off the medical record for family members who worry about genetic discrimination in employment, health insurance, and life insurance.

“Until there are clearer regulations, it makes sense to keep the information private,” Sehnert said. “A lot more people [with HCM mutations] live long normal lives than die suddenly.”

Genetic counseling is strongly recommended for all patients considering genetic testing. For those who choose to be tested, one of the most unambiguous clinical benefits may be negative results that let about half of the blood relatives off the hook emotionally and financially from a lifetime of regular echocardiograms. Even if the test comes back positive for the family mutation, it can take 10 to 50 years for symptoms to develop, ranging from mild to severe. There is no cure yet, but doctors can prescribe drugs or implant a defibrillator to stave off the potentially deadly arrhythmias for people who do develop symptoms.

“Recognition of preclinical disease through gene-based diagnosis is such a powerful tool that allows us a huge window to intervene and attenuate disease—if we only knew what to do,” said Christine Seidman. While researchers use increasingly sophisticated genetic approaches to answer that question, people and their doctors can take the first steps toward understanding and treating hypertrophic cardiomyopathy and other disorders starting with the genetic diagnosis.

—Carol Cruzan Morton

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