The long QT syndrome (LQT) is a dominantly inherited disorder chacterized by delayed cardiac repolarization, recurrent ventricular tachycardia, syncope and sudden death. Since the biochemical basis of LQT is not known, we have chosen a genetic approach to the problem. The long-term goal of this proposal is to enhance our understanding of LQT by characterizing the genetic mutation that causes the syndrome. The first step will be to determine the chromosomal location of the LQT locus using linkage analysis of an extended-Utah family with more than 38 affected individuals sampled. The second step will be to generate a high-resolution genetic map of the genome surrounding the LQT locus by identifying recombinants. In this process we will identify probes that flank the LQT locus. Multilocus linkage analysis will be used to characterize the intervening sequences. A physical map of this region will be generated by orienting large, contiguous cloned segments of DNA. These studies will map the location of the LQT locus to within several million base pairs of well-defined DNA. The third step will be to identify the genes that reside in the DNA between the flanking markers. These genes will be candidates for the LQT locus. Strategies include identification of DNA sequences that are conserved in other mammalian genomes and are thus likely to be coding sequences of genes, identification of sequences that are expressed in the heart and brain, and identification of CpG-islands which are frequently adjacent to genes and may regulate gene expression. Ultimately, the gene that causes LQT will be identified from among these candidate genes. This work will improve presymptomatic diagnosis of LQT, enhance our understanding of cardiac repolarization and stimulate new interest in the mechanisms underlying polyinorphous ventricular tachycardia.
