Affiliation:
1. From INSERM U153, Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris (C.D., M.B., N.N., M.B., K.S., P.G.) and Service de Cardiologie, Hôpital Lariboisière (I.D., N.N., P.C.) Paris; Château des Côtes, Les Loges en Josas (I.D.); Généthon-CNRS URA 1922, Evry (C.C.); and Service de Cardiologie, Hôpital de Brabois, Nancy (G.C.), France.
Abstract
Background
KVLQT1
, the gene encoding the α-subunit of a cardiac potassium channel, is the most common cause of the dominant form of long-QT syndrome (LQT1-type), the Romano-Ward syndrome (RWS). The overall phenotype of RWS is characterized by a prolonged QT interval on the ECG and cardiac ventricular arrhythmias leading to recurrent syncopes and sudden death. However, there is considerable variability in the clinical presentation, and potential severity is often difficult to evaluate. To analyze the relationship between phenotypes and underlying defects in
KVLQT1
, we investigated mutations in this gene in 20 RWS families originating from France.
Methods and Results
By PCR-SSCP analysis, 16 missense mutations were identified in
KVLQT1
, 11 of them being novel. Fifteen mutations, localized in the transmembrane domains S2-S3, S4-S5, P, and S6, were associated with a high percentage of symptomatic carriers (55 of 95, or 58%) and sudden deaths (23 of 95, or 24%). In contrast, a missense mutation, Arg
555
Cys, identified in the C-terminal domain in 3 families, was associated with a significantly less pronounced QT prolongation (459±33 ms, n=41, versus 480±32 ms, n=70,
P
=.0012), and significantly lower percentages of symptomatic carriers (7 of 44, or 16%,
P
<.001) and sudden deaths (2 of 44, or 5%,
P
<.01). Most of the cardiac events occurring in these 3 families were triggered by drugs known to affect ventricular repolarization.
Conclusions
Our data show a wide KVLQT1 allelic heterogeneity among 20 families in which KVLQT1 causes RWS. We describe the first missense mutation in the C-terminal domain of KVLQT1, which is clearly associated with a fruste phenotype, which could be a favoring factor of acquired LQT syndrome.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine