From the Telethon Institute of Genetics and Medicine (TIGEM), San
Raffaele Biomedical Science Park, Milan (S.G.P., C.N., M.D.F., G.C.); the
Molecular Cardiology and Electrophysiology Laboratory, Fondazione "S.
Maugeri" IRCCS, Pavia (S.G.P., C.N.); the Department of Cardiology,
University of Pavia and Policlinico S. Matteo IRCCS, Pavia (S.G.P., P.J.S.);
the Centro di Fisiologia Clinica e Ipertensione, University of Milan, Ospedale
Maggiore IRCCS, Milan (P.J.S., C.N.), Italy; and the Rammelkamp Research
Center, Case Western Reserve University, Cleveland, Ohio (L.B., A.D., A.M.B.).
Correspondence to Giorgio Casari, PhD, Research Unit Coordinator, Telethon Institute of Genetics and Medicine, S. Raffaele Biomedical Science Park, Via Olgettina 58, 20132 Milan, Italy. E-mail casari{at}tigem.it
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.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
A Recessive Variant of the Romano-Ward Long-QT Syndrome?
Key Words: arrhythmia • genetics • molecular biology • torsade de pointes • death, sudden
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