University of Iowa hopes to better diagnose and treat patients

Some patients with a suspected genetic disorder will go on what medical professionals call a 'diagnostic odyssey' to find the cause of their symptoms.

But those explorations, on occasion, can come up empty, frustrating patients and prompting health care providers to seek outside expertise.

Last month, the Iowa Institute of Human Genetics at the University of Iowa began offering such expertise through 'whole exome sequencing.'

The genetic test, which analyzes a portion of about 20,000 genes in the human genome in hopes of helping practitioners diagnose and treat a patient, is among several initiatives the institute is pursuing to further personalize medicine for patients in Iowa and across the country.

'The research we do here is to develop new tests to bring precision medicine to the state,' said Colleen Campbell, assistant director of the Iowa Institute of Human Genetics and associate with the UI Department of Otolaryngology.

Researchers with the institute also are conducting tests around secondary findings from exome sequencing – the discovery of variants in genes unrelated to a patient's primary condition – and how a person's genes interact with prescribed medication, including pain medication.

The technology is new, but officials with the Iowa institute said genetic sequencing one day could become so widely used that every infant will have it done as part of the standard newborn screen. Then, as a child grows, practitioners will be able to use the information to determine what type of pain medication to prescribe and at what level, for example.

'Our focus is to bring innovation to the state,' Campbell said. 'We want patients to be more informed when they go to the doctor and are offered these new tests. And we want to be able to offer this as a tool to doctors.'

The Iowa Institute of Human Genetics is among only a dozen or so institutions nationally that offer whole exome sequencing to physicians wanting to order the test on behalf of a patient.

The institute just started offering the test to outside providers for a fee last month, but they've had plenty of practice. In the past year, UI researchers have conducted more than 320 exome sequencing analyses in the clinical or research setting.

Results for each test can take up to 12 weeks to process.

'It does not have a fast turnaround time,' Campbell said.

Identifying disorders

Some of the earliest exome sequencing and technology was introduced in 2006, Campbell said. The UI and its researchers became more involved in 2012 through an event called the Clarity Challenge.

The international contest produced approaches in genetic testing aimed at forming a basis of 'best practices' in genome analysis, interpretation and reporting.  The UI team won runner-up distinction in a couple of the challenge's categories, Campbell said, and that work served as a launching pad for the exome sequencing it offers today.

The exome sequencing the institute now offers for practitioners nationally charges a fee to test for specific types of patients. The institute does not offer sequencing as an elective test to patients simply interested in finding out conditions for which they are genetically predisposed.

'This is really to be used to help inform health care providers on the medical management of their patient,' Campbell said.

The most commonly eligible patients for the institute's sequencing include those on a diagnostic odyssey – meaning they're seeking a diagnosis for a suspected genetic disorder – those with a long list of differential diagnoses, and those with atypical symptoms of disease.

Examples of diseases identified through the test include autism spectrum disorder, intellectual disabilities, cardiovascular disorders and pediatric genetic disorders.

The solve rate for patients who order exome sequencing is just 25 percent nationwide, according to Campbell.

'So this is not a slam dunk for everyone,' she said.

But she said that rate will improve as researchers learn more about the cause of human diseases. And, Campbell said, solve rates increase when researchers can test parent-child trios.

Parental samples often are needed to correctly interpret a child's results. That's why the cost to test one person is $4,000 and the cost to test trios is $5,500.

Once the institute conducts a test, a team reviews the results and tries to agree on an interpretation, Campbell said.

'If you find a cause, you can inform on the treatment and understand the chance for recurrence,' she said.

Sometimes, when testing for a specific condition, researchers come across 'incidental findings,' which are variants in the genes associated with the condition that could cause symptoms different from those the patient is experiencing.

Researchers, for example, could be testing a patient for genetic causes of hearing loss when they come across a variant that also could cause infertility. In those cases, patients can choose to learn about those findings or not.

Secondary findings are variants in genes not associated with a patient's primary condition. The Iowa institute doesn't include unrelated genes in its analysis right now because not enough research has been done on patient consent and because it's easier to focus on specific conditions and symptoms.

The institute, however, is putting together a study on secondary findings – looking more closely at whether patients actually want to know about possible disorders identified through their genes.

Personalizing medication

Another test the institute is conducting to further personalize medicine looks at how individual DNA interacts with medication. By swabbing the inside of a person's cheek, researchers can analyze DNA variants to determine how a patient processes a drug.

Someone's genes might reveal that he or she can't metabolize a drug, meaning it wouldn't have the intended effects. Another person's genes might show they metabolize a drug too quickly, increasing its effects.

In the test's initial phase, which launched in January, the institute is looking specifically at how patient genes interact with a drug called Clopidogrel – known by the brand name Plavix, commonly prescribed to prevent heart attacks and strokes in patients with heart disease.

The UIHC has been offering the DNA test to candidates in one of its cardiology clinics. By testing a person's DNA, researchers can determine whether he or she has the enzyme needed to process the medication.

'If you have certain changes in this gene, it doesn't work,' said Anne Kwitek, associate director of the Iowa Institute of Human Genetics and associate professor in the UI Department of Pharmacology. 'Another change makes it work too well. Then you have more than the expected dose in your body.'

The institute eventually plans to build a marker into the hospital's electronic medical record system that would flag patients as possible candidates for the DNA test, Kwitek said.

'Instead of a doctor having to think and remember to offer the test, the (electronic) system will prompt them,' she said.

The institute also plans to expand its screen beyond Plavix to 250 genes and interactions with as many drugs. That would include pain medication – such as hydrocodone. The goal would be to inform providers on which drugs, and how much, to prescribe to maximize effectiveness and patient safety.

Using the example of pain medication, Kwitek said, there have been cases of patients receiving no pain relief due to genetic variants. And, she said, there have been cases of a drug working too well – even leading to morphine overdose.

'So this has big health affects,' she said.

But DNA is not yet widely used to inform medication use and management, she said.

'Our dream would be that every patient who comes through our hospital would have this test,' Kwitek said.

That information would go into the hospital's electronic medical record system, and every time the patient is prescribed a medication affected by genetics, the provider would get an alert. In the long term, Kwitek said, the screen even could be done for every newborn – letting providers know if a child metabolizes one drug faster than normal or not at all.

'The research is really promising,' she said.