A 2ND LOCUS FOR HEREDITARY HEMORRHAGIC TELANGIECTASIA MAPS TO CHROMOSOME-12

Hereditary hemorrhagic telangiectasia [HHT] or Osler-Rendu-Weber [ORW] disease is an autosomal dominant vascular dysplasia. Initial linkage studies identified an ORW gene localized to 9q33-q34 but with some fam ilies clearly excluding this region. A probable correlation in clinica l phenotype between the 9q3-linked families and unlinked families was described with a significantly lower incidence of pulmonary arterioven ous malformations observed in the unlinked families. In this study we examined four unrelated ORW families for which linkage to chromosome 9 q33-q34 has been previously excluded. Linkage was established for all four families to markers on chromosome 12, with a combined maximum lod score of 10.77 [theta = 0.04] with D12S339. Mapping of crossovers usi ng haplotype analysis indicated that the candidate region lies in an 1 1-CM interval between D12S345 and D12S339, in the pericentromeric regi on of chromosome 12. A map location for a second ORW locus is thus est ablished that exhibits a significantly reduced incidence of pulmonary involvement.