Circulation, Vol 90, 2635-2644, Copyright © 1994 by American Heart Association
JA Towbin, H Li, RT Taggart, MH Lehmann, PJ Schwartz, CA Satler, R Ayyagari, JL Robinson, A Moss and JF Hejtmancik
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
Holter recordings. Each corrected QT interval (QTc) were 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 theta = 0. However, 8 of 23 families had negative LOD
scores, with the values in 4 families being less than -2 at theta = 0,
consistent with exclusion of linkage. Analysis with the HOMOG program was
consistent with genetic heterogeneity (P < .0001). Multipoint linkage
data using pTBB-2 and TH were also examined for evidence of heterogeneity.
HOMOG analysis of multipoint LOD scores from 100 cM surrounding the H-ras-1
locus also supported heterogeneity (P < .001). CONCLUSIONS: In the 23
families with LQTS analyzed for linkage to the H-ras-1 locus on chromosome
11p15.5, 15 of 23 families had LOD scores consistent with linkage. The
remaining 8 of 23 families had negative LOD scores, 4 of which were
definitively excluded from linkage. Thus, genetic heterogeneity is
definitively (P < .001) demonstrated for this disorder.
ARTICLES
Evidence of genetic heterogeneity in Romano-Ward long QT syndrome. Analysis of 23 families
Baylor College of Medicine, Department of Pediatrics, Houston, TX 77030.
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