The genetics underlying acquired long QT syndrome: impact for genetic screening

Abstract

Aims: Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors.

Methods and results: We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7-41%] vs. 64% [95% CI 43-82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations.

Conclusion: A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members.

Keywords: Acquired long QT syndrome; Congenital long QT syndrome; Drug-induced long QT syndrome; Genetics.

Figure 1

Distribution of QTc interval in genotyped congenital long QT syndrome, acquired long QT syndrome, and non-carriers.

Figure 2

Electrocardiograms of true acquired long QT syndrome and unmasked congenital long QT syndrome. (A) A representative case with true long QT syndrome. This 73-year-old female was admitted for the treatment of bacterial pneumonia. Her basal QTc was normal (396 ms, upper panel). Torsades de Pointes and severe QT prolongation appeared 3 days after receiving ciprofloxacin (lower panel) and led to ventricular fibrillation. After cardioversion, the ECG showed marked QT prolongation (613 ms) and atrial fibrillation with hypokalaemia (2.2 mEq/L). (B) A representative case with unmasked congenital long QT syndrome. This 52-year-old alcoholic male was treated with haloperidol i.v. (6 mg) for withdrawal symptoms. Though his control QTc interval was prolonged but not remarkably (466 ms), a monitoring ECG showed Torsades de Pointes and marked QTc prolongation (624 ms) after haloperidol accompanied by hypokalaemia (2.3 mEq/L). Genetic analysis revealed a KCNH2 mutation (R948S) located in the C-terminus.

Figure 3

Distribution of genetic subtypes in acquired long QT syndrome and congenital long QT syndrome. All acquired long QT syndrome mutation carriers are shown in A; they are then subdivided in B as ‘true acquired long QT syndrome’ or ‘unmasked congenital long QT syndrome’, according to the study definitions.

Figure 4

Proportions of mutation carriers/non-mutation carriers among the 188 patients according to increasing score values. Score 0 = age ≥40 years + asymptomatic + QTc ≤ 440 ms; score 3 = age <40 years + symptomatic + QTc >440 ms; Scores 1 and 2 represent the presence of one or of two factors. The number of mutation carriers increases with increasing score values (from 0 in the group with Score 0) and indicates that 89% of mutation carriers (47 of 53) are found within the Scores 2 and 3. Conversely, among the 52 patients with a score of 1, which represent 28% of the entire population, there were six mutation carriers; this means that while within the group with a score of 1, there is an 11% of mutation carriers, when looking at the entire population this percentage drops to 3%. This would be the percentage of mutation carriers missed if genetic screening would be limited to the groups with a score of 2 and 3.

Figure 5

The percentages of mutation carriers, within each value of the probability score, are similar between Japanese and Caucasian acquired long QT syndrome subjects. The figures of 11 and 13% for a score of 1 correspond approximately at a 3% prevalence of mutation carriers on the total population of acquired long QT syndrome.