title: Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.
abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by widespread arteriovenous malformations and caused by mutations in two major genes: ENG and ACVRL1. Two decades ago, a French epidemiological study pointed out that its prevalence was higher than previously thought and that its distribution varied greatly from one area to another, one of the highest concentrations of patients being found in the Haut-Jura mountains. Although germline mutations are usually family specific, some of them have been reported in unrelated patients, especially for ACVRL1. We performed haplotype analysis of 116 French and Italian patients carrying 13 ACVRL1 different mutations. For five of these mutations, we estimated the age of the most recent common ancestors (MRCAs) using the ESTIAGE program. Most mutations were related to both recurrent mutational events and founder effects with age estimates ranging from 100 to 550 years. The c.1112dupG mutation, which is likely to be responsible for the very high concentration of HHT patients found in the former epidemiological study, probably occurred in one inhabitant of the Haut-Jura Mountains more than three centuries ago. The p.Arg374Gln mutation occurred independently in at least two distinct geographical areas, including the area with the second highest prevalence in the epidemiological study and where the MRCA is rather recent (about 100 years ago). Partially shared haplotypes between French and Italian patients were found for three mutations. This suggests a common origin and a possible diffusion of these mutations from Italy to France.
authors.affiliation: Service de Génétique Moléculaire et Clinique, Hôpital Edouard Herriot, Université de Lyon, Université Lyon 1, 5 Place d'Arsonval, Lyon, France. gaetan.lesca@chu-lyon.fr
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Genin
authors.forename: Claire
authors.initials: C
authors.lastname: Blachier
authors.forename: Carla
authors.initials: C
authors.lastname: Olivieri
authors.forename: Florence
authors.initials: F
authors.lastname: Coulet
authors.forename: Guy
authors.initials: G
authors.lastname: Brunet
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupuis-Girod
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Buscarini
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
authors.forename: Alain
authors.initials: A
authors.lastname: Calender
authors.forename: Cesare
authors.initials: C
authors.lastname: Danesino
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.forename: Henri
authors.initials: H
authors.lastname: Plauchu
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D018703:Founder Effect; D005602:France; D006580:Genetic Carrier Screening; D006239:Haplotypes; D006801:Humans; D007558:Italy; D017354:Point Mutation; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics*
chemical_list: D017931:DNA Primers; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II