clinical practice n engl j med 358 2 www.nejm.org january 10, 2008 171 How should mutation carriers be counseled and treated? Strategies and Evidence Diagnosis Common presentations of the long-QT syndrome are palpitations, presyncope, syncope, and cardiac arrest. In addition, asymptomatic persons may be evaluated because the diagnosis is established or suspected in a family member. The differential diagnosis includes common causes of syncope in the young these causes range from benign conditions such as vasovagal syncope to serious genetic conditions such as hypertrophic cardio- myopathy and catecholaminergic polymorphic ventricular tachycardia.26-28 The history can help with the differential diagnosis and point toward specific subtypes of the long-QT syndrome. The physical examination and echocardiography (or magnetic resonance imaging, if performed) show no abnormalities in patients with this syndrome thus, they are helpful only in ruling out other diagnoses. An abnormal ECG obtained while the patient is at rest is the key to diagnosis. The QT interval, the surface ECG representation of ventricular repolarization, is affected by the patient���s heart rate and sex the upper limits of the QT interval corrected for the heart rate (the QTc) are below 460 msec for women and below 440 msec for men. Yet establishing a diagnosis of the long-QT syndrome may not be straightforward. Physicians may misread the QT interval29 or misdiagnose vasovagal syncope as the long-QT syndrome.26 In addition, mutation carriers may have normal ECGs, although this is unusual in patients with symptoms. The Schwartz scoring system, which includes ECG features and personal and family history, has been widely used,30 but it does not take into account genetic information.31 All per- sons with QT-interval prolongation should be screened for acquired causes such as hypocalce- mia, hypothyroidism, and the use of drugs that can prolong the QT interval these drugs include antiarrhythmic agents such as sotalol and dofet- ilide and noncardiovascular drugs such as halo- peridol, methadone, and pentamidine. Most drugs that cause torsades de pointes block the rapid com- ponent of the delayed rectifier current (IKr), and previously unrecognized long-QT syndrome, of any subtype, can be identified in 5 to 20% of pa- tients with drug-induced torsades de pointes.32-34 A detailed family history is essential. This evaluation should assess not only a history of sudden death, but also other deaths that may have been a manifestation of the long-QT syn- drome, such as drowning, the sudden infant death syndrome,35 and the death of a family member while he or she was driving (a potential manifestation of syncope). Exercise testing can be useful to assess the Table 1. Common Forms of the Long-QT Syndrome.* Variable Genetic Subtype LQT1 LQT2 LQT3 Disease-associated gene KCNQ1 KCNH2 SCN5A In vitro effect Decreased IKs Decreased IKr Increased plateau INa Setting of arrhythmia��� Emotional or physical stress, swimming, diving Emotional or physical stress, sudden loud noise Rest, sleep Typical resting ECG��� Broad T wave Low-amplitude T wave with notching Long isoelectric ST segment ECG at onset of arrhythmia�� No pause Pause Not established QT change with exercise Failure to shorten Normal Supranormal QT shortening with mexiletine�� No No Yes Clinical response to beta-blockers��� Yes Less than LQT1 response Uncertain * ECG denotes electrocardiogram, IKr the rapid component of the delayed rectifier current, IKs the slow component of the cardiac delayed rec- tifier current, and INa the cardiac sodium current. ��� Data are from Schwartz et al.4 ��� These are typical patterns, but exceptions and variants are well recognized. Data are from Moss et al.5 �� Data are from Tan et al.6 �� Data are from Schwartz et al.7 ��� Data are from Priori et al.8 Copyright �� 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on February 15, 2008 .

T h e new england journal o f medicine n engl j med 358 2 www.nejm.org january 10, 2008 172 response of the QT interval (Fig. 1B and Table 1), but arrhythmias are very rare. The epinephrine challenge has been used to identify mutation carriers in families with the LQT1 mutation.22,36 Holter monitoring and electrophysiological test- ing are generally not useful. Genetic Testing The long-QT syndrome is a clinical diagnosis, but genetic testing may provide additional informa- tion. Clinical features such as triggers of syncope and specific QT morphologic attributes5,37 (Fig. 2) in patients in whom the clinical diagnosis has been made can suggest the affected gene in 70 to 90% of patients.38,39 Genetic testing for the com- mon subtypes of the long-QT syndrome is now available commercially, and it can identify a mu- tation in 50 to 75% of probands in whom the di- agnosis appears to be certain on clinical grounds. The lack of detection in the remainder of the pro- bands is probably due to technical difficulties with genotyping,40 noncoding variants,11-13 or as yet unidentified disease-associated genes. Thus, a negative genetic test does not rule out the diag- nosis. There is also the potential for false posi- tive results, since detection of a previously unde- scribed mutation does not establish the diagnosis. Rather, further analysis (e.g., linkage within a family or in vitro studies) may be required to es- tablish the functional significance of any given variant rare DNA variants of little functional con- sequence are well recognized. Genetic testing for the long-QT syndrome is most useful in two settings. First, when a clini- cal diagnosis is relatively certain, knowing the specific gene affected (or the site of the muta- tion within the gene)14,15 may clarify the prog- nosis and guide therapeutic choices. Second, in a family with an affected proband and a known genetic defect, the genotyping of family members can help rule out the diagnosis in some persons. However, a positive test identifies a family mem- ber as being a mutation carrier, even if he or she is asymptomatic, has a normal QT interval, and is unlikely ever to have an event this identification may have attendant consequences for long-term therapies and screening in his or her own family. A positive genetic test also could be used in a discriminatory fashion (e.g., to withdraw health insurance), although the pending Genetic Infor- mation Nondiscrimination Act is meant to rem- edy this situation. Detailed genetic counseling is warranted before proceeding to this testing, par- ticularly for asymptomatic persons for whom the option of not testing must also be recognized. Genetic testing has not been evaluated in pa- tients who present with a borderline QT interval, suspicious symptoms (e.g., syncope), and no rel- evant family history. In these patients, the inci- dence of false positive and false negative results and their implications for management remain unknown. Risk Stratification The most powerful predictor of risk is the QTc duration.20,41-43 In an analysis of 647 LQT1, LQT2, and LQT3 mutation carriers, the incidence of syncope or sudden death by 40 years of age in those with a QTc interval in the lowest quartile (446 msec) was less than 20%, whereas it was 16p6 AUTHOR: FIGURE:the JOB: 4-C H/T RETAKE SIZE ICM CASE EMail Line H/T Combo Revised AUTHOR,uni0020PLEASEuni0020NOTE: Figureuni0020hasuni0020beenuni0020redrawnuni0020anduni0020typeuni0020hasuni0020beenuni0020reset. Pleaseuni0020checkuni0020carefully. REG F Enon 1st 2nd 3rd Roden 2 of 2 01-10-08 ARTIST: ts 35802 ISSUE: LQT1 LQT2 LQT3 Figure 2. Electrocardiographic Patterns in the Three Common Forms of the Long-QT Syndrome. The LQT1 form of long-QT syndrome is associated with a broad T wave without a shortening of the QT interval due to exercise (as shown in Fig. 1C). LQT2 is associated with low-amplitude, often bifid, T waves. LQT3 is associated with a long isoelectric segment and a narrow-based, tall T wave. Although patterns may suggest a specific genotype of the long-QT syndrome,5 many variants have been described.37 Copyright �� 2008 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org at UNIV OF MANITOBA LIBRARIES on February 15, 2008 .