Not so long ago, thinking of genetics as a practical, everyday tool in the practice of medicine might have sounded like a scene from a science fiction movie. Now, with advances in understanding the molecular basis of disorders, and rapidly evolving technology dramatically reducing cost, the future is arriving faster than anticipated.
How are recent breakthroughs in genetics and genomics bringing new approaches to the practice of medicine?
In a recent article in the Journal of the American Medical Association, UAB’s Bruce Korf, MD, PhD, a nationally recognized leader in human genetics, neurodevelopmental disorders and neurofibromatosis, addressed the diagnostic side of that question.
“Now that exome sequencing can be done for less than a thousand dollars, and whole genome sequencing, while still several thousand dollars, is rapidly becoming more affordable, the purpose of the article was to assist physicians in recognizing where new approaches may be applied and understanding the principles in interpreting results,” Korf said.
Massively parallel next-generation sequencing and analysis of multiple genes are allowing researchers to identify which genes are contributing to the pathology in diseases and to begin targeting the mechanisms involved.
The protein encoding region of genes, known as the exome, makes up about one to two percent of the genome. It is where most currently interpretable pathogenic mutations are found. There has been significant recent improvement in detecting problems here.
“Sensitivity is much better now. About one-third of patients are likely to get an answer from testing,” Korf said. “If results in previous testing were unclear, physicians may want to consider retesting if indicated.”
Other regions of the genome beyond the exome are not just extra genes or insignificant as was once assumed. Some of these genes seem to play a complex regulatory role in switching exome genes on or off. Changes in response to environmental factors here may explain why diseases occur in one patient and not another. As sequencing of non-protein coding regions becomes more cost effective, clinicians are likely to see a clearer picture of what is happening and why.
“When a physician is deciding whether to order genetic testing, there are four things to consider,” Korf said. “First, is the test reliable and likely to be correct? Does it diagnose the presence or absence of disease? Is it useful in guiding management? Does the result place patients at risk of discrimination, stigma or involve them in social, ethical or legal issues, and if so, what can be done to protect the patient?”
Genetic and genomic testing can help to answer medical questions from several perspectives. For example, if parents have a child with a serious congenital disorder, cytogenetic testing may be able to give them the input they need in deciding whether to have another child.
“High resolution molecular analysis can detect deletions or duplications of DNA much smaller than the light microscope can detect. If the mutation is present in the child but not in the parents, it’s unlikely to recur if they have other children,” Korf said.
Disease-targeted testing can also be ordered based on symptoms and family history. If cystic fibrosis, sickle cell anemia or a similar condition with well described variants is present in a family, when a near relative begins to display symptoms, a test to look for that specific mutation can be ordered. Other family members may also want to be tested to determine whether they carry a recessive gene.
“If a genetic disorder is suspected based on signs and symptoms, but no known single gene condition fits the phenotype, sequencing of the exome or genome may be helpful,” Korf said. “Detecting a pathogenic mutation could help patients avoid a long diagnostic odyssey. There is the potential for incidental findings that are medically significant, as well as other variants whose significance may not yet be understood.”
Korf is working toward establishing a program for undiagnosed diseases based on referral. If, after a review of a patient’s records, it is likely that information can be added, the case will be considered for evaluation.
Recent research in pharmacogenetic testing has also made significant advances, particularly in the areas of blood thinners and cancer therapy.
“Absorption, metabolism and excretion of many drugs are influenced by variants,” Korf said. “DNA testing can identify genetic influences in how a drug interacts with its cellular target, allowing customization of the choice of drug and the dosage that is likely to work best for the individual patient. As we move into the era of personalized medicine, this is likely to be a big part of patient care.”
Perhaps one of the most dramatic benefits we’re likely to see from genetic testing in the near future is in the field of oncology. Tumor testing to identify specific genetic changes in cancer cells can guide therapy choices, surveillance of response to treatment, and give a clearer picture of the prognosis.
Testing can also evaluate inherited cancer risks. Projects are underway mapping all mutations associated with cancer. UAB researchers are studying the genetics of cancer, including breast and ovarian cancer.
With tests assessing the risks for developing common disorders now being marketed directly to consumers, genetic testing for risk assessment has gone main stream. While these tests may answer some questions, they could also create others. If patients follow up with their physician after receiving results of a direct test, they should know that a mutation may not predict development of a disease. They may also need guidance in interpreting what these and other genetic tests mean in their lives and health.
To update physicians on advances in applying genetic and genomic information in medical practice, UAB will be offering a CEU course on the topic August 23. Details are available online under UAB’s Continuing Medical Education program.