Sudden Arrhythmia Death Syndromes Foundation
The Role of Genetic Testing in the Diagnosis and Treatment of Long QT Syndrome
Dr. Susan Etheridge; Primary Children’s Medical Center, Salt Lake City, UT
Genetic testing for Long QT Syndrome (LQTS) has been as a research tool for more than a decade. . Originally, long and expensive research projects were performed to provide researchers and physicians with knowledge about LQTS. . These projects identified many genetic abnormalities that result in LQTS and have significantly advanced our understanding of the disease and its variations. Since 2004, advances have enabled LQTS genetic testing to be commercially available, enabling this test to be applied directly to patient care. In patients with a clinical picture consistent with LQTS, genetic testing is helpful to provide information and prognosis and will increasingly be used to guide therapy. In patients where the clinical picture is inconclusive, genetic testing may help confirm or exclude the diagnosis. Combining genetic information and clinical characteristics has shown us that there is a “genotype-phenotype” correlation in LQTS. Simply said, it is possible to better predict a patient’s clinical course once their specific gene defect is known. Increasingly, the genetic information will be applied to therapy.
Thus far, abnormalities in genes that determine the function of potassium, calcium and sodium channels or membrane proteins have been identified on chromosomes 3, 4, 7, 11, 12, 17, and 21 have been associated with LQTS. A large number of specific mutations have been identified. Thus far, a genetic abnormality is identified in approximately 75% of patients with definite LQTS. Thus, in 25% of patients who truly have LQTS, genetic testing fails to identify the LQTS-causing mutation. New technologies are continually being developed to better identify these mutations. As these new defects are characterized and validated, they must be incorporated into the commercially available testing.
In the United States, federal legislation is in place to ensure accuracy and reliability of laboratory testing. The Centers for Medicare and Medicaid Services regulates all laboratory testing performed on humans in the U.S. through the Clinical Laboratory Improvement Amendments (CLIA). PGx Health Pharmaceuticals (New Haven, Connecticut) has introduced FAMILIONTM genetic testing for LQTS. This is a CLIA approved study that examines 5 of the LQTS-causing genes and can detect 75% of LQTS: LQT1 (KCNQ1 or KVLQT1), LQT2 (KCNH2 or HERG), LQT3 (SCN5A), LQT5 (KCNE1 or minK), and LQT6 (KCNE2 or MiRP1).
As with all genetic tests, there are some important limitations to LQTS genetic testing. It is important for families and referring physicians to realize that the currently available genetic test is not 100% accurate. This means that not every family with LQTS will have a mutation in one of the five LQTS genes tested. As stated previously, one-quarter of families that have definite LQTS will receive a negative genetic test result. Thus, if the suspicion for LQTS is high, a negative genetic test cannot and should not be used to “rule out” the diagnosis. In other words, if test results are negative, a patient may still have LQTS—we just do not know the genetic cause.
Another challenge is to know when a DNA change is an LQTS-causing mutation and when is it a polymorphism, or non-disease-causing change. Technically, a “mutation” in a gene is simply a variation in the accepted sequence of DNA code. With the completion of the Human Genome Project, we have learned that the word “normal” no longer has meaning when it comes to a person’s genetic makeup. Genetic variations occur in great numbers in the human genome (our total genetic makeup) and not all the genetic variations produce physical traits (symptoms or disease). This improved understanding of genetic variation means that on those genes that are associated with LQTS, variations can occur that do not produce LQTS. Many gene variations occur without causing LQTS. Distinguishing the variations that cause LQTS from those that do not can be difficult—people can have the genetic mutation but be asymptomatic. Some percentage of tests will return a positive result, i.e. a mutation on one of the known LQTS genes was found, but in fact the mutation is not LQTS-producing. Much research has already taken place to distinguish important DNA changes in the LQTS genes from unimportant ones. For example, Ackerman and colleagues have published a compendium of normal genetic variation, or non-LQTS producing polymorphisms, helpful in the proper interpretation of the LQTS genetic test. More polymorphisms on the LQTS related genes remain to be identified.
2/2006
