HUMAN MUTATION Mutation in Brief #892 (2006) Online MUTATION IN BRIEF Received 26 July 2005; accepted revised manuscript 28 February 2006. Distribution of ENG and ACVRL1 (ALK1) Mutations in French HHT Patients Gaëtan Lesca 1,2,3* , Nelly Burnichon 1 , Grégory Raux 4 , Mario Tosi 4 , Stéphane Pinson 1 , Marie- Jeanne Marion 3 , Emmanuel Babin 5 , Brigitte Gilbert-Dussardier 6 , Sophie Rivière 7 , Cyril Goizet 8 , Laurence Faivre 9 , Henri Plauchu 2,10 , Thierry Frébourg 4 , Alain Calender 1,2 , and Sophie Giraud, 1 on Behalf of the French Rendu-Osler Network 1 Service de Génétique Moléculaire et Médicale, Hôpital Edouard Herriot, Lyon, France; 2 Université Claude Bernard, Lyon, France; 3 Inserm U271, Lyon, France; 4 Inserm U614, Faculté de Médecine et de Pharmacie, Rouen, France; 5 Service d’oto-rhino-laryngologie, CHU Clémenceau, Caen, France; 6 Service de Génétique Médicale, Hôpital Jean Bernard, Poitiers, France; 7 Service de Médecine Interne, Hôpital Saint-Eloi, Montpellier, France; 8 Service de Génétique Médicale, CHU Pellegrin-Enfants, Bordeaux, France; 9 Centre de Génétique, Hôpital d’Enfants, Dijon, France; 10 Service de Génétique, Hôpital de l’Hôtel-Dieu, Lyon, France *Correspondence to: Gaëtan Lesca, Service de Génétique Moléculaire et Médicale, Bâtiment 7, Hôpital Edouard Herriot, Place d’Arsonval, 69003 Lyon, France; Tel.: (+33) 4 72 11 73 80; Fax: (+33) 4 72 11 73 81; E-mail: gaetan.lesca@chu-lyon.fr Grant sponsor: This work was supported by the Fondation pour la Recherche Médicale, the Rare Disease Network financed by INSERM and AFM (Association Française contre les Myopathies), and the contract: “Projet Hospitalier de Recherche Clinique 27-2004” (Hospices Civils de Lyon). Communicated by Haig H. Kazazian, Jr. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations and resulting from mutations in two major genes: ENG and ACVRL1. The aim of the present study was to estimate the prevalence of the mutations of ENG and ACVRL1 in HHT, based on the largest series of patients reported so far, recruited through a national network. We previously reported the first mutation screening of both genes, in French HHT patients, using heteroduplex analysis. This previous study, bringing 60 novel mutations, provided a significant improvement to the knowledge of molecular pathology in HHT. However, 32% (n=48) of the patients with a confirmed clinical diagnosis remained without mutation. In these patients, we performed an extensive molecular analysis that included the sequencing of the whole coding sequence, the search for large rearrangements, and screening of the potential 5’ regulatory regions. Additionally, due to the lack of large pedigrees suitable for linkage analysis, and since SMAD4 germline mutations have been reported in families with combined HHT and juvenile polyposis, we screened this gene and five other genes involved in the TGF-β/BMP pathway in the patients without mutation of ENG or ACVRL1. Only a novel SMAD1 non-conservative substitution was found in one patient, changing a poorly conserved methionine to an isoleucin. Twenty- three mutations were found in ACVRL1 and 8 in ENG (including a duplication of exons 4 to 8 and deletions of exons 1 to 3 and 9 to 14). Our results, combined with our previous data, increase the mutation rate to 88% (n=119/136) in French patients with a confirmed clinical diagnosis. Our results also emphasize the higher prevalence of large insertions/deletions in ENG and the predominance of ACVRL1 over ENG mutations. © 2006 Wiley-Liss, Inc. KEY WORDS: hemorrhagic hereditary telangiectasia; ACVRL1; ALK1; ENG INTRODUCTION Hereditary hemorrhagic telangiectasia (HHT, Rendu-Osler-Weber syndrome; MIM# 187300) is an autosomal dominant disease whose primary pathogenic expression is arteriovenous malformation. Common manifestations © 2006 WILEY-LISS, INC. DOI: 10.1002/humu.9421