Arrhythmias and conduction disturbance
Mutation-Specific Risk in Two Genetic Forms of Type 3 Long QT Syndrome

https://doi.org/10.1016/j.amjcard.2009.08.676Get rights and content

The clinical course of patients with 2 relatively common long QT syndrome type 3 mutations has not been well described. In the present study, we investigated the mutational-specific risk in patients with deletional (ΔKPQ) and missense (D1790G) mutations involving the SCN5A gene. The study population involved 50 patients with the ΔKPQ mutation and 35 patients with the D1790G mutation. The cumulative probability of a first cardiac event (syncope, aborted cardiac arrest, or long QT syndrome-related sudden death) was evaluated using the Kaplan-Meier method. The Cox proportional hazards survivorship model was used to determine the independent contribution of clinical and genetic factors to the first occurrence of cardiac events from birth through 40 years of age. The Andersen-Gill proportional intensity regression model was used to analyze the factors associated with recurrent syncope. Patients with a ΔKPQ mutation had a significantly greater probability of a first cardiac event from birth through 40 years of age (34%) than those with the D1790G mutation (20%; p <0.001). Multivariate analysis demonstrated an increased risk of cardiac events among ΔKPQ carriers compared to D1790G carriers (hazard ratio 2.42, p <0.0001) after adjustment for gender and QTc duration. Patients with ΔKPQ mutations also had an increased risk of recurrent syncope (hazard ratio 5.20, p <0.001). In conclusion, the clinical course of patients with long QT syndrome type with ΔKPQ mutations was shown to be more virulent than those with D1790G mutations, and this effect was independent of QTc duration. The findings highlight the importance of knowing the specific mutation in risk stratification of patients with long QT syndrome type 3.

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Methods

The study population of 85 patients was drawn from the International LQTS Registry. The 85 patients included 50 affected subjects from 3 unrelated families carrying the ΔKPQ mutation and 35 from 2 unrelated families from Israel carrying the D1790G mutation. The patients carrying the D1790G mutation were either from a large multigenerational kindred originating from Tunisia or a family from Israel. The SCN5A mutations were identified using standard genetic tests performed in academic

Results

The clinical characteristics of the patients with ΔKPQ and D1790G mutations are listed in Table 1. Patients with ΔKPQ mutations were more likely to be treated with β blockers, implanted defibrillators, left cervicothoracic sympathetic ganglionectomy, and pacemakers than were patients with D1790G mutations. Patients with D1790G mutations were primarily treated with flecainide. This medication was discontinued in 3 patients after new onset of a Brugada-type pattern on the electrocardiogram. Only

Discussion

This is the first study to investigate the clinical course of patients with the LQTS with 2 different LQT3 mutations. The findings demonstrated meaningful differences in the clinical severity between patients affected with the ΔKPQ and D1790G mutations, with ΔKPQ patients at a considerably greater risk of first cardiac events and recurrent syncope than those with the D1790 mutation.

LQT3 results from mutations of the SCN5A gene on chromosome 3p21 that affect the structure of the cardiac α

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  • Cited by (0)

    This study was supported in part by research grants HL-33843 and HL-51618 (to Dr. Moss) from the National Institutes of Health, Bethesda, Maryland.

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