In this article, author Dr. Kathy Glatter discusses the use of genetic testing for finding cardiac syndromes such as long QT syndrome. Case History A 34-year-old female with long QT syndrome (LQTS) was referred to our institution for evaluation. Starting at age 19, she had experienced four documented cardiac arrests, all of when she was several months postpartum with each of her four children. Her cardiac catheterization and echocardiogram results were normal. However, an electrocardiogram (ECG) showed a prolonged QTC (corrected QT interval) of 480 ms. Her mother was healthy and had a QTC on ECG of 460 ms, but the patient’s maternal aunt had died suddenly at five months postpartum. A normal QTC interval for a female is 450 or less and 440 or less for a male. The diagnosis of LQTS was made, and the patient received an implantable cardioverter-defibrillator (ICD). ECGs were also performed on her four children. Her 7-year-old son had a QTC interval of 450 ms. He was started on beta-blocker therapy and restricted from playing any sports, with the concern that he might have LQTS too. Should this family be referred for genetic testing of LQTS? What would that entail? This article will explore the pros and cons of genetic testing. Background on LQTS Long QT syndrome is a fascinating disease that represents one of the more common genetic causes of sudden death (at least 1 in 5,000 carry an LQTS mutation).1-3 Most patients with LQTS suffer from the autosomal dominant type, although a very rare, more virulent form called Jervell and Lange-Nielsen Syndrome (JLNS) can be seen, which also has autosomal recessive congenital deafness. Mutations in different genes coding for cardiac ion channels have been identified to cause LQTS (Table 1). Most such mutations prolong ventricular repolarization in the heart and affect the potassium ion channel. Diagnosis of LQTS can be very difficult, since up to one-third of affected patients may have normal or only borderline prolonged QT intervals.1-3 Each of the different genetic subtypes of LQTS have different clinical courses and triggers to their symptoms, which include sudden death, aborted cardiac arrest, and syncope.1-4 Treatment for symptomatic LQTS patients includes beta-blocker therapy as well as possible defibrillator implantation in the high-risk patient.1-4 Medical treatment for asymptomatic LQTS patients is controversial, but can include therapy with beta-blocker medications and restriction from intense physical activity. The critical point in terms of genetic testing is that half of the offspring from an affected patient will also have the LQTS mutation. It is a dominant disease that does not skip generations. Overview of Genetic Testing for LQTS Genetic testing for LQTS was restricted for many years to large research labs, and only under the rubric of enrolling in a research study. Some LQTS patients had their genes discovered, but were never informed of the results in a timely fashion. Even those who were told of the genetic results could only rarely get their children or first-degree relatives tested. Since inheritance occurs in a dominant fashion for LQTS, half of the children from an affected LQTS proband will receive the “bad” LQTS gene, although they may have no symptoms. For many affected LQTS patients, learning about the genetic fate of their children or relatives is the impetus to get genetic testing. In today’s world, it has become much easier to get genetic testing for cardiac channelopathies like LQTS, Brugada syndrome, hypertrophic cardiomyopathy (HCM), and other genetic cardiac syndromes. For example, a commercial blood test called FAMILION® (PGx Health, a division of Clinical Data, Inc., New Haven, CT) allows screening of the major LQTS genes in just a few weeks. The company will screen the five major LQTS genes, which they estimate account for up to 75% of all LQTS cases.5 Patients simply provide a blood sample (in two 4-mL purple-top EDTA tubes) and then receive their results in approximately six weeks. However, there are a few limitations to consider in the genetic testing of LQTS patients, as outlined below. Limitations of Genetic Testing for LQTS 1. It’s expensive. The test costs $5,400 to screen each proband,5 and payment is due regardless if the gene is found or not. Furthermore, if the patient’s LQTS gene is found, it will cost $900 per additional family member screened. Therefore, if we screened all four of my patient’s children, which would be the ultimate goal, that would be $3,600 total. Fortunately, PGx Health does work with insurance companies to cover genetic testing. In my patient’s case, the insurance company ultimately paid $3,000, leaving the patient to pay a reduced sum ($2,400) out of pocket. 2. They may find genetic polymorphisms, not disease-causing mutations. The human genome is filled with genetic polymorphisms, which are little base-pair mutations that, in the end, do not affect how the gene functions. It has to do with where your ancestor’s DNA came from. So for example, if thousands of years ago your DNA originally came from Africa and mine came from Europe, our ion channels may vary a little in their DNA content, but, in the end, our channels work just fine either way. However, this information is critical when you do genetic screening. My colleagues and I studied this question several years ago when looking at genetic testing in two unrelated Chinese-American women who had LQTS.6 Both were initially found to have the P448R-KVLQT1 gene mutation. A large research lab had previously published this gene as being a disease-causing mutation, meaning if you had this bad gene, you indeed had LQTS.7 We tested the two sons of the first woman and found that her younger son had the bad LQTS gene. He started taking beta-blocker medications to treat LQTS, he was told not to participate in sports, and the parents considered an ICD for him. However, we still found it strange that two totally unrelated women had the same LQTS mutation, so we took it a step further. We obtained DNA on 300 healthy controls who didn’t have LQTS. None of the 150 white and 100 African-American volunteers had this P448R mutation, but 14% of our healthy Chinese (descent) volunteers had this “mutation.” We went back and tested the P448R “mutation” in the test tube and found that it didn’t affect how the LQTS ion channel worked — it was just fine. This was just a benign polymorphism that some Asians have.8 We ultimately found the unique LQTS mutations the women had, which they didn’t share. We showed that their mutations did affect the LQTS ion channel and was causing their disease. Ultimately, we cleared the younger son of LQTS but found that the older child did have the bad gene. Thus, one pitfall of genetic testing for LQTS can be that sometimes the company or lab will not generally do patch-clamp analysis to document that the purported mutation really causes the disease. They compare the found “mutation” with matched controls and draw conclusions from there. However, FAMILION® (PGx Health) does try to control this pitfall by asking the ethnic background of the person being tested. Yield of Genetic Screening for LQTS Bai et al outlined these issues in an elegant study published in 2009.9 They looked at 546 patients referred to their large consortium of LQTS research labs for genetic testing between 2001-2006. Their author list included Dr. Silvia Priori and others who have been instrumental in setting up the International LQTS Registry. Their findings were very interesting. Of the 304 patients who had a long QTC interval on ECG (and thus likely had a high pre-test probability of having LQTS), they found the gene in 64% of these patients. This ultimately cost $8,418 for each positive patient identified. For patients with a borderline QTC interval, they only identified an LQTS gene in 14% of the patients. This ultimately cost $37,565 for each positive patient found. Finally, in those patients with normal QTC intervals but who were family members of sudden cardiac death victims, they only identified an LQTS gene in 2%, which cost $221,400 for each one found.9 Thus, like so many tests in cardiology or electrophysiology, genetic testing for LQTS seems to be more useful as the pre-test probability or likelihood that you have the disease increases. It is probably not cost-effective to randomly screen everyone for an LQTS gene. The authors in this study recommend that priority for LQTS testing be given to those with a “conclusive diagnosis” of LQTS. Utility of Genetic Testing for LQTS In summary, genetic testing for LQTS is a useful tool. However, a key point to remember with genetic testing for LQTS is that a negative LQTS genetic test doesn’t mean that you do not have the disease. Since only 64-75% of LQTS patients will ultimately have their gene identified, the other 25-36% will not have their gene found.3,9,10 These patients still may have LQTS, but there is no blood test yet available to screen their family members. If you have a patient (the “proband”) who definitely has LQTS, it is worthwhile to send their blood in for genetic testing. They may have family members or children who can be tested if the proband’s gene mutation is found. If the proband’s mutation isn’t found, then the only way to screen family members is by getting a yearly ECG to see if their QTC interval looks long. Case Study Follow-up Our 34-year-old mother of four opted for the FAMILION® test. The test results came four weeks later and unfortunately did not find any mutations for her. Since her test came back negative, we recommended that her other three children get yearly ECGs to see if a long QTC interval is ever found for them. She was understandably disappointed and continues to wonder if her 7-year-old son “really” has LQTS.