After thirty years of research into Rendu-Osler-Weber disease, the authors review the contributions of the three successive approaches used to analyse this rare genetic disorder. First, historical demography sees patients as markers of past migration and population transfers. Starting out from a cluster of cases straddling the Ain and Jura départements, the history of this population group was reconstituted on the basis of civil records, and their migration to other parts of France was studied by looking for family ties between the initial group and the cases observed elsewhere in the country. Second, epidemiology and population genetics give estimates of prevalence by département that are higher than those initially predicted in 1977, the start year of this study. They also provide statistical tools to test hypotheses of a single or multiple origin for the disease by looking for a common ancestor among affected families. Last, molecular biology provides a means to identify the genes responsible for the disease and their various mutations, thus confirming the existence of several different origins. Following the articles published in 1984 and 1989, (Plauchu and Bideau, 1984; Bideau et al., 1989), this article concludes a key phase in the study of Rendu-Osler-Weber disease in France, and opens the way for future international comparisons.
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Rendu-Osler-Weber disease, also known as hereditary hemorrhagic telangiectasia (HHT) is characterized by small vascular malformations. It was first differentiated from haemophilia by the physicians Rendu (1896) and Osler (1901). Diagnosis is based on the simultaneous presence of three parameters: spontaneous nosebleeds (called epistaxis), telangiectasias (abnormal connections between venules and arterioles, with no intervening capillary bed) in specific regions such as the mouth or the fingertips, and a family history of the disease (Plauchu et al., 1992). An international conference in 1999 (Shovlin et al., 2000) confirmed the importance of these three diagnostic criteria, while adding a fourth: the presence of visceral lesions liable to cause life-threatening complications in the lungs, digestive tract, liver and brain (Plauchu et al., 1989). The symptoms of the disease develop gradually, and age at onset may vary. It is a genetic disorder with an autosomal dominant pattern of inheritance, transmitted directly from parents to children without skipping a generation. This means that the offspring of a carrier have a 50% risk of inheriting the mutation.
Demographic and genetic research into HHT in France began in the 1970s, when Professor Robert, head of the genetics department at Hôtel-Dieu in Lyon, identified a cluster of carriers in a region around hundred kilometres to the north-east of Lyon straddling the Ain and Jura départements. Headed by Henri Plauchu (geneticist) and Alain Bideau (historian-demographer), a research team was set up, bringing in students from a range of disciplines, including medicine, genetics, demography and history. The team published data that made it possible to analyse the frequency of the disease at regional and national levels (Bideau et al., 1979 and 1989), and to track its progression among the main affected population group (Bideau et al., 1992), while the study of genealogical networks provided clues about the history of HHT in the region (Heyer, 1991; Brunet, 1998). In association with a genealogical study of families recruited across the Rhône-Alpes region, the medical specialists of the team pursued their in-depth clinical study (Plauchu et al., 1989) to determine the chromosomal location of one of the two major genes whose mutations cause the disease (Vincent et al., 1995). Further key contributions by our team include the description of the gene mutations present in the affected French families (Lesca et al., 2004; Lesca et al., 2006), and the discovery of the mutation affecting the patient cluster in the Ain and Jura départements. …