Locus heterogeneity of autosomal dominant long QT syndrome

Autosomal dominant long QT syndrome (LQT) is an inherited disorder that causes syncope and sudden death from cardiac arrhythmias. In genetic linkage studies of seven unrelated families we mapped a gene for LQT to the short arm of chromosome 11 (11p15.5), near the Harvey ras-1 gene (H ras-1). To determine if the same locus was responsible for LQT in additional families, we performed linkage studies with DNA markers from this region (H ras-1 and MUC2). Pairwise linkage analyses resulted in logarithm of odds scores of -2.64 and -5.54 for kindreds 1977 and 1756, respectively. To exclude the possibility that rare recombination events might account for these results, we performed multipoint linkage analyses using additional markers from chromosome 11p15.5 (tyrosine hydroxylase and D11S860). Multipoint analyses excluded approximately 25.5 centiMorgans of chromosome 11p15.5 in K1756 and approximately 13 centiMorgans in K1977. These data demonstrate that the LQT gene in these kindreds is not linked to H ras-1 and suggest that mutations in at least two genes can cause LQT. While the identification of locus heterogeneity of LQT will complicate genetic diagnosis, characterization of additional LQT loci will enhance our understanding of this disorder.