KVLQT1 C-TERMINAL MISSENSE MUTATION CAUSES A FORME-FRUSTE LONG-QT SYNDROME

Background KVLQT1, the gene encoding the alpha-subunit of a cardiac po tassium channel, is the most common cause of the dominant form of long -QT syndrome (LQT1-type), the Romana-Ward syndrome (RWS). The overall phenotype of RWS is characterized by a prolonged QT interval on the EC G find cardiac ventricular arrhythmias leading to recurrent syncopes a nd sudden death, However, there is considerable variability in the cli nical presentation, and potential severity is often difficult to evalu ate. To analyze the relationship between phenotypes and underlying def ects in KVLQT1, we investigated mutations in this gene in 20 RWS famil ies originating from France. Methods and Results BS PCR-SSCP analysis, 16 missense mutations were identified in KVLQT1, 11 of them being nov el. Fifteen mutations, localized in the transmembrane domains S2-S3, S 4-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-termina l domain in 3 families, was associated with a significantly less prono unced QT prolongation (459+/-33 ms, n=41, Versus 4580+/-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). Mo st of the cardiac events occurring in these 3 families were triggered by drugs known to affect ventricular repolarization. Conclusions Our d ata show a wide KVLQT1 allelic heterogeneity among 20 families in whic h KVLQT1 causes RWS. We describe the first missense mutation in the C- terminal domain of KVLQT1, which is clearly associated with a fruste p henotype, which could be a favoring factor of acquired LQT syndrome.