EVIDENCE OF GENETIC-HETEROGENEITY IN ROMANO-WARD LONG-QT-SYNDROME - ANALYSIS OF 23 FAMILIES

Background The Romano-Ward long-QT Syndrome (LQTS) is an autosomal dom inant inherited trait characterized by prolonged QT interval on ECG, l ife-threatening arrhythmias, syncope, and sudden death in affected ind ividuals. A gene responsible for this disorder has been shown to be li nked to the Harvey ras-1 locus (H-ras-1) DNA marker on the short arm o f chromosome 11 (11p) in 7 families. The purpose of this study was to determine, by analyzing 23 families with LQTS for linkage to chromosom e 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, EC Gs, and Holter recordings. Each corrected QT interval (QT(c)) was dete rmined 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 ca rried out using the LINKAGE computer program (v 5.03). Genetic heterog eneity was determined using the HOMOG 2 (v 2.51) computer program. Twe nty-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 usin g pTBB-2 and TH markers was consistent with linkage in 15 of 23 famili es, with the maximum single-family LOD score of +3.038 occurring at Th eta=0. However, 8 of 23 families had negative LOD scores, with the val ues in 4 families being less than -2 at Theta=0, consistent with exclu sion of linkage. Analysis with the HOMOG program was consistent with g enetic heterogeneity (P<.0001). Multipoint linkage data using pTBB-2 a nd TH were also examined for evidence of heterogeneity. HOMOG analysis of multipoint LOD scores from 100 cM surrounding the H-ras-1 locus al so supported heterogeneity (P<.001). Conclusions In the 23 families wi th 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 remai ning 8 of 23 families had negative LOD scores, 4 of which were definit ively excluded from linkage. Thus, genetic heterogeneity is definitive ly (P<.001) demonstrated for this disorder.