Characterization of Recombination Event Excluding the Harvey-ras-1 (H-ras-1) Locus in Romano-Ward Long QT Syndrome Family Linked to Chromosome 11p15 and Isolation of Polymorphic Repeat Telomeric to H-ras-1

The Romano-Ward Long QT Syndrome (RWLQTS) has been linked to chromosome 11p15.5 in several large families but demonstrates genetic heterogeniety. To date, there has been no published recombination between the Harvey-ras-1 (H-ras-1) locus and the RWLQTS in families linked to 11p15. The one LOD confidence interval for the RWLQTS gene is 3 cM from H-ras-1 (Keating et al, 1992). In large multigenerational family, we demonstrate linkage of the RWLQTS to marker D11S932 on 11p15 with LOD score of 3.14 at thet of 0. The family was genotyped for the following 11p markers: H-ras-1 (2 markers), insulin growth factor II, tyrosine hydroxylase(TH), β-hemoglobin, D11S860, D11-S1363, D11S902, D11S1318, D11S1331, D11S1323, D11S1338, D11S909, D11S932, and D11S922. An unaffected individual and her two unaffected offspring carry the affected haplotype for the H-ras-1 region, spanning from H-ras-1 to TH. All three individuals had QTc ≤ 0.40 seconds and no history of syncope making the diagnosis of RWLQTS extremely unlikely. This suggests that, although the gene for the RWLQTS is linked to chromosome 11p15 in this family, recombination event may have occurred that separated the RWLQTS gene from the affected H-ras-1 region haplotype. Multipoint analysis indicates the most likely location for the RWLQTS gene in this family is near D11S932. To investigate possible telomeric recombination event, cosmids telomeric to H-ras-1 were isolated. From one of these cosmids, repeat marker (78% heterozygosity) was characterized and its location telomeric to H-ras-1 was verified by interphase FISH. Genotyping of the family demonstrated that the same three unaffected individuals had the affected allele for this marker as well. However, due to the genotypes in the family, we could not exclude telomeric recombination event. Based on its degree of heterozygosity, this marker will be extremely useful in the physical and genetic mapping of the 11p telomere. The recombination event in this family should aid the localization of the RWLQTS gene linked to chromosome 11p15. This is the first report of recombination between the H-ras-1 locus and the RWLQTS phenotype in family in which RWLQTS is linked to 11p15.