Genetic studies became a part of researching Long QT Syndrome (LQTS) about 20 years ago. The first genes that cause LQTS were published on March 10, 1995. Research projects required volunteers with suspected LQTS to give a blood or a tissue sample to the researcher, who would then attempt to find “abnormal” parts of a gene that caused the symptoms. These long and expensive projects were not designed to give each individual the results of testing their sample, but to provide researchers and physicians with more knowledge of LQTS that would benefit everyone.

Clinical genetic testing, however, is designed to aid in an individual’s diagnosis of a disorder. In accordance with federal legislation passed to ensure accuracy and reliability, the results of clinical genetic tests must be obtained or verified in a laboratory that complies with the Clinical Laboratory Improvement Amendment (CLIA) regulations before being released to patients and their doctors. Clinical genetic testing is currently available through many labs in the United States.

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 genetic test cannot determine the cause of LQTS in 100% of patients with the disease. This means that not every family with LQTS will have a mutation in one of the LQTS genes tested. Approximately, one-quarter of families with a LQTS diagnosis will receive negative genetic test results. 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 will occur that do not produce LQTS. Distinguishing the variations that cause LQTS from innocuous ones can be difficult—people can have the genetic mutation but be asymptomatic. A small percentage of tests (~5%) 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. These can be called Variants of Unknown Significance (VUS). 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.

Finally, information about other potential issues, such as  health insurance coverage of genetic testing is always evolving. It seems likely that LQTS genetic testing will be covered given the important clinical role it can play in the evaluation of LQTS. Several commercial payers now have supportive coverage policies specific to the LQTS genetic tests,  Already, the past decade of research has shown why the patient’s underlying genotype is informative. A person’s genotype can help guide treatment strategies in some cases. In addition, if an LQTS-producing genetic variant is discovered in one family member, the less-expensive family specific test (a test that looks for only the specific mutation found in the index case) becomes the diagnostic gold standard for relatives and is far superior to the screening electrocardiogram which may not identify family members who are at risk. Once a diagnosis of LQTS is established in the family, the screening ECG may misclassify many family members. Family member testing for the specific mutation found in the proband is the only way to definitively identify who in the family possesses the LQTS-causing mutation and who does not regardless of the electrocardiogram. With this information, the physician can conduct additional tests on family members who test positive for a disease causing mutation to discern their diagnosis, the appropriate type of treatment, and other preventative measures to recommend.