Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC

Venous malformations with glomus cells are localised cutaneous lesions of v ascular dysmorphogenesis. They are usually sporadic, but sometimes familial . Using five families, we mapped the locus, VMGLOM, to chromosome 1p21-p22. In order to refine this locus, spanning 46 Mbp, we then studied seven addi tional families. They exhibited linkage to VMGLOM and the combined lod scor e for all 12 families was 18.41 at theta = 0.0 for marker D1S188. We found a distinct haplotype shared by seven families, comprising seven alleles whi ch are rare in the general population (P < 0.01). This indicates that the h aplotype is identical by descent in all seven families, and hence the locus can be refined by inferring ancestral crossovers. Using this approach, we position the causative gene between two markers on the same non-chimeric YA C of 1.48 Mbp, a feasible size for positional cloning. As there is no known gene involved in vasculogenesis and/or angiogenesis in this YAC, the ident ification of the causative gene is likely to reveal a novel regulator or va scular development.