Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity

Abstract

Cardiac arrhythmias cause sudden death in 300,000 United States citizens every year. In this study, we describe two new loci for an inherited cardiac arrhythmia, long QT syndrome (LQT). In 1991 we reported linkage of LQT to chromosome 11 p15.5. In this study we demonstrate further linkage to D7S483 in nine families with a combined lod score of 19.41 and to D3S1100 in three families with a combined score of 6.72. These findings localize major LQT genes to chromosomes 7q35–36 and 3p21–24, respectively. Linkage to any known locus was excluded in three families indicating that additional heterogeneity exists. Proteins encoded by different LQT genes may interact to modulate cardiac repolarization and arrhythmia risk.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kannel, W.B., Cupples, A. & D'Agostino, R.B. Sudden death risk in overt coronary heart diseases: The Framingham study. Am. Heart J. 113, 799–804 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. Willich, S.N. et al. Circadian variation in the incidence of sudden cardiac death in the Framingham heart study population. Am. J. Cardiol. 60, 801–806 (1987).

    Article  CAS  PubMed  Google Scholar 

  3. Mason, J. A comparison of electrophysiologic testing with hotter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias. New Engl. J. Med. 329, 445–450 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Mason, J. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. New Engl. J. Med. 329, 452–458 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Myerburg, R.J., Kessler, K.M. & Castellanos, A. Sudden cardiac death: epidemiology, transient risk and intervention assessment. Ann. Intern. Med. 119, 1187–1197 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Brooks, C.M., Gilbert, J.L., Greenspan, M.E., Lange, G. & Mazzella, H.M. Excitability and electrical response of ischemic heart muscle. Am. J. Physiol. 198, 1143–1147 (1960).

    CAS  PubMed  Google Scholar 

  7. Downar, E., Michiel, J.J. & Durrer, D. The effect of acute coronary artery occlusion on subepicardial transmemebrane potentials in the intact porcine heart. Circulation 56, 217–224 (1977).

    Article  CAS  PubMed  Google Scholar 

  8. Penkoske, P.A., Sobel, B.E., & Corr, P.B. Disparate electrophysiological alterations accompanying dysrhythmia due to coronary occasion and reperf usion in the cat. Circulation 58, 1023–1035 (1978).

    Article  CAS  PubMed  Google Scholar 

  9. Schwartz, P.J. & Wolf, S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 57, 1074–1077 (1978).

    Article  CAS  PubMed  Google Scholar 

  10. Barr, C.S., Naas, A., Freeman, M., Lang, C.C. & Struthet, A.D. QT dispersion and sudden unexpected death in chronic heart failure. Lancet 343, 327–329 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Day, C.P., McComb, J.M. & Campbell, R.W.F. QT dispersion: an indication of arrhythmia risk in patients with long QT intervals. Br. Heart J. 63, 342–344 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vincent, G.M., Abildskov, J.A. & Burgess, M.J. Q-T interval syndromes. Prog. cardiovasc. Dis. 16, 523–5230 (1974).

    Article  CAS  PubMed  Google Scholar 

  13. Schwartz, P.J., Periti, M. & Malliani, A. The long Q-T syndrome. Am. Heart J. 109, 378–390 (1975).

    Article  Google Scholar 

  14. Jervell, A. & Lange-Nielson, F. Congenital deaf mutism, functional heart disease with prolongation of the QT interval, and sudden death. Am. Heart J. 54, 59–78 (1957).

    Article  CAS  PubMed  Google Scholar 

  15. Romano, C., Gemme, G. & Pongiglione, R. Aritmie cardiache rare dell'eta' pediatrica. II. Accessi sincopali per fibrillazione ventricolare parossistica. Clin. Pediatr. (Bologna). 45, 656–683 (1963).

    CAS  PubMed  Google Scholar 

  16. Ward, O.C. A new familial cardiac syndrome in children. J. Ir. Med. Assoc. 54, 103–106 (1964).

    CAS  PubMed  Google Scholar 

  17. Zipes, D.P. Proarrhythmic effects of antiarrhythmic drugs. Am. J. Cardiol. 59, 26E–31E (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Keating, M. et al. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 252, 704–706 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Keating, M.T. et al. Consistent linkage of the long-QT syndrome to the Harvey Pas-1 locus on chromosome 11. Am. J. hum. Genet. 49, 1335–1339 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yatani, A. et al. ras p21 and GAP inhibit coupling of muscrinic receptos to atria) potassium channels. Cell 61, 769–776 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Davidenko, J.M., Cohen, L.,, Goodrow, R. & Antzelevitch, C. Quinidine-induced action potential prolongation, early afterdepolarizations, and triggered activity in canine Purkinje fibers. Circulation 79, 674–686 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Philipson, L.H., Eddy, R.L., Shows, T.B. & Bell, G.I. Assignment of human potassium channel gene KCNA4 (Kv1. 4, PCN2) to chromosome 11 q13.4–>q14.1. Genomics 15, 463–464 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Ried, T. et al. Localization of a highly conserved human potassium channel gene (NGK2-KV4; KCNC1) to chromosome 11 p15. Genomics 15, 405–411 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Petronis, A., Van Tol, H.H.M., Lichter, J.B., Livak, K.J. & Kennedy, J.L. The D4 dopamine receptor gene maps on 11 p proximal to HRAS . Genomics 18, 161–163 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Benhorin, J. et al. Evidence of genetic heterogeneity in the long QT syndrome. Science 260, 1960–1962 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Keating, M. Evidence of genetic heterogeneity in the long QT syndrome. Science 260, 1960–1962 (1993).

    Article  Google Scholar 

  27. Curran, M. et al. Locus Heterogeneity of autosomal dominant long QT syndrome. J. clin. Invest. 92, 799–803 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Towbin, J.A. et al. Evidence of genetic heterogeneity in Romano-Ward long-QT syndrome (LQTs): Analysis of 23 families. Circulation (in the press).

  29. Keating, M. Linkage analysis and the long QT syndrome: Using genetics to study cardiovascular disease. Circulation 85, 1973–1986 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Keating, M. Genetics of the long QT syndromes. J. cardiovascular Electrophysiology. 5, 146–153 (1994).

    Article  CAS  Google Scholar 

  31. Lehmann, M. T wave humps as an eletrocardiographic marker of the long QT syndrome. J. Am. coll. Cardiol. (in the press).

  32. Weber, J.L. & May, P.E. Abundant class of human DMA polymorphisms which can be typed using polymerase chain reaction. Am J. hum. Genet. 44, 388–396 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kramer, P. et al. A comprehensive genetic linkage map of the Human Genome/NIH/CEPH collaborative Mapping Group. Science 258, 67–86 (1992).

    Article  Google Scholar 

  34. Weissenbach, J. et al. A second-generation linkage map of the human genome. Nature 359, 794–801 (1992).

    Article  CAS  PubMed  Google Scholar 

  35. Gyapay, G. et al. The 1993–94 Généthon human genetic linkage map. Nature Genet. 7, 246–339 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Green, E.D. et al. Integration of physical, genetic and cytogenetic maps of human chromosome 7: isolation and analysis of yeast artificial chromosome clones for 117 mapped genetic markers. Hum. molec. Genet. 3, 489–501 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Geoge, A.L. Jr., Crackower, M.A., Abdalla, J.A., Hudson, A.J. & Ebers, G.C. Molecular basis of Thomson's disease (autosomal dominant myotonia congenita). Nature Genet. 3, 305–309 (1993).

    Article  Google Scholar 

  38. Koch, M.C. et al. The skeletal muscle chloride channel in dominant and recessive human myotonia. Science 257, 797–800 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Bonner, T.I., Modi, W.S., Seuanez, H.N. & O'Brien, S. Chromosomal mapping of five human genes encoding muscarinic acetylcholine receptors. Cytogenet. cell Genet. 58, 1850–1867 (1991).

    Article  Google Scholar 

  40. Bonner, T.I., Buckley, N.J., Young, A.C. & Brann, M.R. Identification of a family of muscarinic acetylcholine recepor genes. Science 237, 527–532 (1987).

    Article  CAS  PubMed  Google Scholar 

  41. Goyal, R.K. Muscarinic receptors subtypes: Physiology and clinical implications. New Engl. J. Med. 321, 1022–1029 (1989).

    Article  CAS  PubMed  Google Scholar 

  42. Tsukurov, O. et al. A complex bilateral polysyndactyly disease locus maps to chromosome 7q36. Nature Genet. 6, 282–286 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Heutink, P. et al. The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q. Nature Genet. 6, 287–292 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Marks, M.L., Whisler, S.L., Clericuzio, C. & Keating, M. A new form of long QT syndrome associated with syndactyly. J. Am. coll. Cardiol. (in the press).

  45. Garcia, D.K. et al. CA repeat polymorphisms for human chromosme 3. Cytogenet. cell Genet. 58, 1877 (1993).

    Google Scholar 

  46. Chin, H., Kozak, C.A., Kim, H., Mock, B. & McBride, O.W. A brain L-type calcium channel α1 subunit gene (CCHL1A2) maps to mouse chromosome 14 and human chromosome 3. Genomics 11, 914–919 (1991).

    Article  CAS  PubMed  Google Scholar 

  47. Seino, S., Yamada, Y., Espinosa III, R., LeBeau, M.M. & Bell, G.I. Assignments of the gene encoding the a1 subunit of the neuroendocrine/brain-type calcium channel (CACNL1A2) to human chromosome 3, band p14.3. Genomics 13, 1375–1377 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Seino, S. et al. Cloning of the α1 subunit of a voltage-dependent calcium channel expressed in pancreatic β cells. Proc. natn. Acad. Sci. U.S.A. 89, 584–588 (1992).

    Article  CAS  Google Scholar 

  49. Williams, M.E. et al. Structure and functional expression of α1, α2 and β subunit of a novel human neuronal calcium channel subtype. Neuron 8, 71–84 (1992).

    Article  CAS  PubMed  Google Scholar 

  50. January, C.T., Riddle, J.M. & Salata, J.J. A model for early afterdepolarization: induction with the Ca2+ channel agonist Bay K8644. Circ. Res. 62, 563–571 (1988).

    Article  CAS  PubMed  Google Scholar 

  51. January, C.T. & Riddle, J.M. Early afterdepolarizations: mechanism of induction and block, A role for L-type Ca2+ current. Circ. Res. 64, 977–990 (1989).

    Article  CAS  PubMed  Google Scholar 

  52. Vincent, G.M., Timothy, K.W., Leppert, M. & Keating, M. The spectrum of symptoms and QT intervals in carriers of the gene for the Long-QT syndrome. New Engl. J. Med. 327, 846–852 (1992).

    Article  CAS  PubMed  Google Scholar 

  53. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. hum. Genet. 37, 482–498 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Conneally, P.M. et al. Report of the committee on methods of linkage analysis and reporting. Cytogenet. cell Genet. 40, 356–359 (1985).

    Article  CAS  PubMed  Google Scholar 

  55. Ott, J. Linkage analysis and family classification under heterogeneity. Annals hum. Genet. 47, 311–320 (1983).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jiang, C., Atkinson, D., Towbin, J. et al. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet 8, 141–147 (1994). https://doi.org/10.1038/ng1094-141

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1094-141

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing