A RECESSIVE VARIANT OF THE ROMANO-WARD-LONG-QT-SYNDROME

Background-The congenital long-QT syndrome (LQTS) is a genetically het erogeneous disease characterized by prolonged ventricular repolarizati on and life-threatening arrhythmias. Mutations of the KVLQT1 gene, a c ardiac potassium channel, generate two allelic diseases: the Romano-Wa rd syndrome, inherited as a dominant trait, and the Jervell and Lange- Nielsen syndrome, inherited as an autosomal recessive trait. Methods a nd Results-A consanguineous family with the clinical phenotype of LQTS was screened for mutations in the KVLQT1 gene. Complementary RNAs for injection into Xenopus oocytes were prepared, and currents were recor ded with the double microelectrode technique. A homozygous missense mu tation, leading to an alanine-to-threonine substitution at the beginni ng of the pore domain of the KVLQT1 channel, was found in the proband, a 9-year-old boy with normal hearing, a prolonged QT interval, and sy ncopal episodes during physical exercise. The parents of the proband w ere heterozygous for the mutation and had a normal QT interval. The fu nctional evaluation of the mutant channel activity showed reduction in total current, a hyperpolarizing shift in activation, and a faster ac tivation rate consistent with a mild mutation likely to require homozy gosity to manifest the phenotype. Conclusions-These findings provide t he first evidence for a recessive form of the Romano-Ward long-QT synd rome and indicate that homozygous mutations on KVLQT1 do not invariabl y produce the Jervell and Lange-Nielsen syndrome. The implications of this observation prompt a reconsideration of the penetrance of differe nt mutations responsible for LQTS and suggest that mild mutations in L QTS genes may be present among the general population and may predispo se to drug-induced ventricular arrhythmias.