GENETIC-HETEROGENEITY IN HEREDITARY HEMORRHAGIC TELANGIECTASIA - POSSIBLE CORRELATION WITH CLINICAL PHENOTYPE

Hereditary haemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu synd rome is an autosomal dominant vascular dysplasia characterised by recu rrent haemorrhage. Our initial linkage studies found an HHT gene to be localised to 9q3 in two large kindreds. In the present study, we exam ine an additional five unrelated HHT families. Linkage analysis in thi s region resulted in a peak multipoint location score of 13.03, 10 cM proximal of D9S60. We found significant evidence for heterogeneity of HHT. Multipoint analysis supports the family specific two point studie s with odds of 3 000 000:1 showing Linkage and heterogeneity over link age and homogeneity. Four of the seven families give a posterior proba bility of >99% of being of the linked type, and three families appear unlinked to this region of 9q, and by multipoint analysis completely e xclude the candidate region for HHT. Two new crossovers in affected pe rsons in one of the linked families further define the proximal border of the candidate region on 9q3. A possible correlation in clinical ph enotype between the 9q3 linked families and unlinked families is descr ibed. Although six of the seven families clearly meet the clinical cri teria for HHT diagnosis, a significant absence of pulmonary arterioven ous malformations is seen in all three 9q3 unlinked families. Genetic heterogeneity of HHT and its potential correlation with a clinical phe notype may have a significant impact on the clinical management and tr eatment of HHT patients.