Rendu-Osler-Weber disease, also known as hereditary hemorrhagic telangiectasia (HHT), has been the focus of several interdisciplinary studies over the last thirty years. An initial epidemiological survey conducted in the 1980s revealed that the prevalence of this hereditary genetic disorder in France is much higher than previously thought, and brought to light several geographical clusters of HHT carriers. The subsequent analysis of the family genealogies of carriers in the main cluster and of the demographic history of the region did not confirm the thesis of a unique founder effect at national level, but provided clues for dating the occurrence of a local mutation. Last, thanks to the recent identification of the genes responsible for HHT, the considerable genetic heterogeneity of the disease has been confirmed and a large number of different mutations existing in France have been identified. Nonetheless, many carriers living in the main geographical cluster studied previously share a single mutation associated with a specific haplotype. At the end of this study, marked by its multi-disciplinary approach and its exceptional duration, the various converging strands confirm the existence of a local founder effect and provide consistent evidence for dating this mutation.