Evidence of genetic heterogeneity in Romano-Ward long QT Syndrome: Analysis of 23 families

J. A. Towbin, H. Li, R. T. Taggart, M. H. Lehmann, P. J. Schwartz, C. A. Satler, R. Ayyagari, J. L. Robinson, A. Moss, J. F. Hejtmancik

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Abstract

Background: The Romano-Ward long-QT Syndrome (LQTS) is an autosomal dominant inherited trait characterized by prolonged QT interval on ECG, life- threatening arrhythmias, syncope, and sudden death in affected individuals. A gene responsible for this disorder has been shown to be linked to the Harvey ras-1 locus (H-ras-1) DNA marker on the short arm of chromosome 11 (11p) in 7 families. The purpose of this study was to determine, by analyzing 23 families with LQTS for linkage to chromosome 11p, whether evidence exists for more than one gene causing LQTS (ie, locus heterogeneity). Methods and Results: Twenty-three families (262 family members) were clinically evaluated using medical histories, ECGs, and Holier recordings. Each corrected QT interval (QT(c)) was determined using Bazett's formula. Blood for DNA extraction and cell line immortalization was obtained after informed consent. Southern blotting and polymerase chain reaction were performed, and linkage analysis carried out using the LINKAGE computer program (v 5.03). Genetic heterogeneity was determined using the HOMOG 2 (v 2.51) computer program. Twenty-three families were studied for evidence of linkage to chromosome 11p using the H-ras-1 locus probe pTBB-2 and multiple flanking markers, including tyrosine hydroxylase (TH). Two-point linkage analysis using pTBB-2 and TH markers was consistent with linkage in 15 of 23 families, with the maximum single-family LOD score of +3.038 occurring at Θ=0. However, 8 of 23 families had negative LOD scores, with the values in 4 families being less than -2 at Θ=0, consistent with exclusion of linkage. Analysis with the HOMOG program was consistent with genetic heterogeneity (P

Original languageEnglish
Pages (from-to)2635-2644
Number of pages10
JournalCirculation
Volume90
Issue number6
Publication statusPublished - 1994

Keywords

  • genetics
  • long QT syndrome

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Towbin, J. A., Li, H., Taggart, R. T., Lehmann, M. H., Schwartz, P. J., Satler, C. A., Ayyagari, R., Robinson, J. L., Moss, A., & Hejtmancik, J. F. (1994). Evidence of genetic heterogeneity in Romano-Ward long QT Syndrome: Analysis of 23 families. Circulation, 90(6), 2635-2644.