Locus heterogeneity of autosomal dominant long QT syndrome

Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City 84112.
Journal of Clinical Investigation (Impact Factor: 13.22). 09/1993; 92(2):799-803. DOI: 10.1172/JCI116653
Source: PubMed


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.

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Available from: Donald L Atkinson
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    • "Presently four different genetic loci are associated with LQTS: LQT1 on chromosome 11p15.5, LQT2 on chromosome 7q35–36, LQT3 on chromosome 3p21–24, and LQT4 on chromosome 4q25–27 (Keating et al. 1991a, b; Benhorin et al. 1993; Curran et al. 1993; Jiang et al. 1994; Towbin et al. 1994; Schott et al. 1995). Two of these loci, LQT1 and LQT2, encode the cardiac potassium channel genes KVLQT1 and HERG and are thought to be the first and second most common disease genes, respectively (Curran et al. 1995; Wang et al. 1996). "
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    ABSTRACT: Long QT syndrome (LQTS), is an inherited cardiac disorder in which ventricular tachyarrhythmias predispose affected individuals to syncope, seizures, and sudden death. Characteristic electrocardiographic findings include a prolonged QT interval, T wave alternans, and notched T waves. We have screened LQTS patients from 89 families for mutations in the pore region of HERG , the K+ channel gene previously associated with chromosome 7-linked LQT2. In six unrelated LQTS kindreds, single-strand conformation polymorphism analyses identified aberrant conformers in all affected family members. These conformers were not seen in over 100 unaffected, unrelated control individuals, suggesting that they represent pathogenic LQTS mutations. DNA sequence analyses of the aberrant conformers demonstrated that they reflect five different missense mutations: V612L, A614V, N629D, N629S, and N633S. The missense mutation A614V was found in two unrelated families. Further functional studies will be required to determine what effect each of these changes may have on HERG channel function.
    Full-text · Article · Mar 1998 · Human Genetics
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    • "Autosomal dominant LQT was previously thought to be genetically homogeneous, and the first seven families that we studied were linked to 1 lp15.5 (Keating et al., 1991b). In 1993, however, several laboratories , including our group, identified families that were not linked to chromosome 11 p15.5 (Benhorin et al., 1993; Curran et al., 1993a; Towbin et al., 1994). In 1994, we identified two additional LQT loci, LQT2 on chromosome 7q35-36 (nine families) and LQT3 on chromosome 3p21-24 (three families) (Jiang et al., 1994). "
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    ABSTRACT: To identify genes involved in cardiac arrhythmia, we investigated patients with long QT syndrome (LQT), an inherited disorder causing sudden death from a ventricular tachyarrythmia, torsade de pointes. We previously mapped LQT loci on chromosomes 11 (LQT1), 7 (LQT2), and 3 (LQT3). Here, linkage and physical mapping place LQT2 and a putative potassium channel gene, HERG, on chromosome 7q35-36. Single strand conformation polymorphism and DNA sequence analyses reveal HERG mutations in six LQT families, including two intragenic deletions, one splice-donor mutation, and three missense mutations. In one kindred, the mutation arose de novo. Northern blot analyses show that HERG is strongly expressed in the heart. These data indicate that HERG is LQT2 and suggest a likely cellular mechanism for torsade de pointes.
    Preview · Article · Apr 1995 · Cell
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    • "Other individuals are shown only if they were necessary to clarify the genetic relationships of HLA-typed family members. Non-HLA-typed relatives who had a QTc > 0.47 or a sudden, unexplained early death are listed in table 3. Kindred CA004 is the same family reported as K1756 by Curran et al. (1993); siblings are shown in the customary left-to-right birth order in figure 2. Inspection of the pedigrees suggests an approximately dominant pattern of transmission of the LQT syndrome phenotype, using the criteria of Keating et al. (1991a, 1991b), namely QTc > 0.47 in the absence of symptoms or QTc > 0.45 with symptoms. This is apparent, on the basis of clinical status determined from the initial QTc (shown in fig. "
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    ABSTRACT: The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.
    Full-text · Article · Jan 1995 · The American Journal of Human Genetics
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