(Circulation. 1997;96:2778-2781.)
© 1997 American Heart Association, Inc.
Articles |
KVLQT1 C-Terminal Missense Mutation Causes a Forme Fruste Long-QT Syndrome
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.
Correspondence to Pascale Guicheney, INSERM U153, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 47 blvd de l'Hôpital, 75651 Paris Cedex 13, France. E-mail pguichen{at}myologie.infobiogen.fr
Background KVLQT1, the gene encoding the
-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, Arg555Cys, 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.
Key Words: antiarrhythmia agents • tachyarrhythmias • heart defects, congenital • death, sudden
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