BACKGROUND: Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that 
causes sudden death in young, otherwise healthy people. Four genes for LQTS have 
been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3), and 
4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified 
as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel 
gene (SCN5A).
METHODS AND RESULTS: After studying 115 families with LQTS, we used 
single-strand conformation polymorphism (SSCP) and DNA sequence analysis to 
identify mutations in the cardiac potassium channel gene, KVLQT1. Affected 
members of seven LQTS families were found to have new, previously unidentified 
mutations, including two identical missense mutations, four identical splicing 
mutations, and one 3-bp deletion. An identical splicing mutation was identified 
in affected members of four unrelated families (one Italian, one Irish, and two 
American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion 
arose de novo and occurs at an exon-intron boundary. This results in a single 
base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the 
truncation of KVLQT1 protein.
CONCLUSIONS: We have identified LQTS-causing mutations of KVLQT1 in seven 
families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These 
data further confirm that KVLQT1 mutations cause LQTS. The location and 
character of these mutations expand the types of mutation, confirm a mutational 
hot spot, and suggest that they act through a loss-of-function mechanism or a 
dominant-negative mechanism.