EVIDENCE OF A LONG QT FOUNDER GENE WITH VARYING PHENOTYPIC-EXPRESSIONIN SOUTH-AFRICAN FAMILIES

We report five South African families of northern European descent (pe digrees 161, 162, 163, 164, and 166) in whom Romano-Ward long QT syndr ome (LQT) segregates. The disease mapped to a group of linked markers on chromosome 11p15.5, with maximum combined two point lod scores, all generated at 0=0, of 15.43 for the D11S922, 10.51 for the D11S1318, a nd 14.29 for the tyrosine hydroxylase (TH) loci. Recent studies have s hown that LQT is caused by an A1a212Val mutation in a potassium channe l gene (KVLQT1) in pedigrees 161 to 164. We report that the same mutat ion is responsible for the disease in pedigree 166. Haplotype construc tion showed that all the families shared a common haplotype, suggestin g a founder gene effect. DNA based identification of gene carriers all owed assessment of the clinical spectrum of LQT. The QTc interval was significantly shorter in both carriers and non-carriers in pedigree 16 1 (0.48s and 0.39s, respectively) than the same two groups in pedigree 161 (0.52 s and 0.42 s, respectively). The spectrum of clinical sympt oms appeared more severe in pedigree 162. The possible influence of mo dulating genetic factors, such as HLA. status and sex of family member s, on the expression of an LQT founder gene is discussed.