BACKGROUND: The congenital long-QT syndrome (LQTS) is a genetically 
heterogeneous disease characterized by prolonged ventricular repolarization and 
life-threatening arrhythmias. Mutations of the KVLQT1 gene, a cardiac potassium 
channel, generate two allelic diseases: the Romano-Ward syndrome, inherited as a 
dominant trait, and the Jervell and Lange-Nielsen syndrome, inherited as an 
autosomal recessive trait.
METHODS AND 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 recorded with the double 
microelectrode technique. A homozygous missense mutation, leading to an 
alanine-to-threonine substitution at the beginning 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 syncopal episodes during physical exercise. The 
parents of the proband were heterozygous for the mutation and had a normal QT 
interval. The functional evaluation of the mutant channel activity showed 
reduction in total current, a hyperpolarizing shift in activation, and a faster 
activation rate consistent with a mild mutation likely to require homozygosity 
to manifest the phenotype.
CONCLUSIONS: These findings provide the first evidence for a recessive form of 
the Romano-Ward long-QT syndrome and indicate that homozygous mutations on 
KVLQT1 do not invariably produce the Jervell and Lange-Nielsen syndrome. The 
implications of this observation prompt a reconsideration of the penetrance of 
different mutations responsible for LQTS and suggest that mild mutations in LQTS 
genes may be present among the general population and may predispose to 
drug-induced ventricular arrhythmias.