The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome

Abstract

Background: The familial long-QT syndrome is characterized by a prolonged QT interval on the electrocardiogram, ventricular arrhythmias, and sudden death. It is not certain, however, that the length of the QT interval is a sensitive or a specific diagnostic criterion. Recently, we identified genetic markers on chromosome 11 that distinguished between carriers and noncarriers of the gene for the long-QT syndrome in three families. In this study, we compared the clinical features of carriers and noncarriers and assessed the diagnostic accuracy of the QT interval.

Methods: We obtained medical histories and electrocardiograms from 199 family members. QT intervals corrected for heart rate (QTc) were determined independently by two blinded investigators. Carriers of the long-QT gene (83 subjects) and noncarriers (116 subjects) were distinguished by genetic-linkage analysis.

Results: Fifty-two of the carriers of the long-QT gene (63 percent) had a history of syncope, whereas four (5 percent) had a history of aborted sudden death. The QTc intervals of the gene carriers ranged from 0.41 to 0.59 second (mean, 0.49). By contrast, the QTc intervals of the noncarriers ranged from 0.38 to 0.47 second (mean, 0.42). On average, carriers of the gene for the long-QT syndrome had longer QTc intervals than noncarriers, but there was substantial overlap (in 126 of the 199 subjects, or 63 percent). The use of a QTc interval above 0.44 second as a diagnostic criterion resulted in 22 misclassifications among the 199 family members (11 percent). QTc intervals of 0.47 second or longer in males and 0.48 second or longer in females were completely predictive but resulted in false negative diagnoses in 40 percent of the males and 20 percent of the females.

Conclusions: In families affected by the long-QT syndrome, measurement of the QTc interval may not permit an accurate diagnosis. DNA markers make it possible to make a genetic diagnosis in some families, but not all gene carriers have symptoms.