Efficient Genotyping for Congenital Long QT Syndrome

Within the past decade, investigators have uncovered the genetic basis for multiple long QT syndromes (LQTSs). These include LQT1, in which mutations in the gene KCNQ1 lead to abnormal I_Ks, a slow delayed-rectifier potassium current; LQT2, in which mutations in the gene KCNH2 lead to abnormal I_Kr, a rapid delayed-rectifier potassium current; and LQT3, in which mutations in the gene SCN5A lead to abnormal I_Na, a sodium channel current.^{1 - 2} After genetic testing was made available, it became clear that clinical evaluation based on the resting electrocardiogram was inadequate to detect many cases of LQTS.³ In fact, there is a considerable overlap between QT intervals of unaffected individuals and those with LQTS.⁴ Thus, in many instances, genetic testing adds important information beyond clinical evaluation in determining which patients are at risk both of personal cardiac events and of transmitting LQTS to their offspring.

Furthermore, the availability of genetic testing has led to an understanding of important clinical differences between the individual genetic disorders (LQT1 vs LQT2 vs LQT3). Patients with LQT1 are at particularly high risk of cardiac events during physical exercise, especially swimming.⁵ Patients with LQT2 are susceptible to cardiac events during emotional or auditory stimuli⁵ and during the postpartum period.⁶ Patients with LQT3 may have cardiac events during rest or sleep.⁵ Differences in the LQTS subtypes have implications for risk assessment^{7 - 8} and for clinical treatment decisions.^{9 - 10}

Knowledge of a patient's genotype is important because it can guide a clinician's decision whether to diagnose a patient as having LQTS (especially when the electrocardiographic phenotype is borderline), whether to restrict activity in a young athlete, whether to treat with medication or consider implantable cardioverter-defibrillator therapy, and how to counsel patients about the risks of LQTS in potential offspring. Once the abnormal genotype has been discovered within a family, it is relatively easy to screen additional family members for the involved mutation. In this regard, negative genotype results are as important as positive results because negative results allow asymptomatic family members with a borderline-normal QT interval to be informed that they do not carry the LQTS gene that runs in their family and that they do not require further restriction, medication, or screening of their children.

Despite hope that the major advances in the understanding of the genetics of LQTS would have simplified clinical care and routinely informed treatment decisions, genetic test results often are not available to the clinician. In previous years, access to genetic test results depended on establishing a relationship with an LQTS research laboratory. Even then, the labor-intensive nature of the genotyping process, the high volume of tests requested, and the small number of qualified research laboratories resulted in long delays before results would become available.

Since May 2004, the genotyping situation has changed, at least in the United States. With the emergence of a commercial LQTS genetic laboratory, genetic research laboratories have welcomed the opportunity to give up the burden of routine LQTS testing and to focus on uncharted territories. Screening for LQT1, 2, 3, 5, and 6 (genes KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) can be completed with a turn-around time of approximately 6 weeks, but the cost is $5400 for comprehensive testing of the proband.¹¹ If a mutation is found, the cost is $900 for each additional family member, limited to checking for the mutation found in the proband. Insurance often does not cover the cost of genotyping. Thus, genetic testing remains out of reach for many families. Ironically, in many practices, this has led to a decrease in the number of patients for whom genetic test results are available.

What can be done to remedy this situation? In this issue of JAMA, Napolitano et al¹² propose a streamlined process for genetic testing in LQTS, designed to reduce cost and make genetic testing more widely available. Among 430 LQTS probands, Napolitano et al identified genetic mutations in 310 (72%), mostly on KCNQ1 or KCNH2. Of the 310 genotyped probands, 180 (58%) could be genotyped on 64 “repeated” codons and 14 probands (4.5%) had multiple mutations. The authors then examined 75 additional probands and found that 52% could be genotyped on the 64 repeated codons. The authors propose an efficient strategy for screening for LQTS mutations: first, test the 64 repeated codons; if no mutations are found, test the entire coding region of genes KCNQ1 and KCNH2; if still no positive results, screen for mutations in other genes, namely SCN5A, KCNE1, and KCNE2. Such an approach could make genetic analysis more efficient, affordable, and accessible.

The problem with this approach, as the authors acknowledge, is evident from their own data set. That is, 4.5% of probands had 2 or more mutations. If genetic analysis had been terminated with discovery of the first abnormal mutation in one of these probands, their family members with a different mutation might have been given false reassurance that they were unaffected, did not require prophylactic β-blocker treatment, and did not require that their children be followed up closely. Without genetic information, these individuals would be treated according to the clinician's best judgment. With inaccurate genetic information, these individuals (or their children) might be at risk of fatal arrhythmias due to lack of treatment. In this situation, no information arguably is better than inaccurate information.

Napolitano et al¹² have provided important new information about the yield of genetic testing and about the distribution of mutations, and their proposed efficient genotyping strategy could make genetic testing accessible to more families with LQTS but at the cost of some accuracy. As the authors note, “the more complete the screening process the higher the accuracy of the results of genetic analysis. . . . [T]he ideal screening should include the evaluation of the entire coding region of each disease-related gene of each patient. However, this comprehensive approach may be neither possible nor cost-effective” everywhere based on current technology.¹² Novel technologies for rapid and efficient DNA sequencing are on the horizon.¹³ Until these technologies are developed further, the medical community will have to decide how much accuracy is reasonable to sacrifice to make genetic testing more accessible.