(Circulation. 2000;102:1178.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Spectrum of Mutations in Long-QT Syndrome Genes
KVLQT1, HERG, SCN5A, KCNE1, and KCNE2
From the Department of Human Genetics (I.S., K.W.T., M.T.K.), Howard Hughes Medical Institute (J.S., M.T.K.), and Division of Cardiology (M.T.K.), University of Utah, and the Department of Medicine, LDS Hospital (G.M.V.), Salt Lake City, Utah; Department of Internal Medicine, University of Michigan, Ann Arbor (M.H.L.); Molecular Cardiology, Fondazione Maugeri (S.P.), and Department of Cardiology, University of Pavia and Policlinico S. Matteo (P.J.S.), IRCCS, Pavia, Italy; Department of Medicine, University of Rochester, Rochester, NY (J.L.R., A.J.M.); and Departments of Pediatrics and Molecular and Human Genetics (J.A.T.), Baylor College of Medicine, Houston, Tex.
Correspondence to Igor Splawski, University of Utah, Eccles Institute of Human Genetics, 15N 2030E Suite 2100, Salt Lake City, UT 84112-5330. E-mail igor.splawski{at}genetics.utah.edu
Background—Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion.
Methods and Results—We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals).
Conclusions—KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.
Key Words: long-QT syndrome • arrhythmia • death, sudden • torsade de pointes • genetics
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