Genetic characteristics of the HHT Italian population: the experience of the three Italian Reference Centres

Objectives: To describe the disease-causing mutations distribution of ENG and ACVRL1 in the HHT Italian population. Methods: Patients were recruited for the clinical screening and the diagnosis in the three main HHT Italian reference centres of Pavia, Crema and Bari. Mutation analyses were performed by DHPLC and/ or Sanger sequencing of ENG and ACVRL1 coding exons. A dedicated mlPA kit (Salsa mlPA Probe mix P093-C2, HHT/PPH1; MRCHolland) was used to detect large deletions and duplications.Results: From 2000 up to October 2016, we collected about 2000 samples from more than 500 families. Until now, we have studied 450 families; a disease-causing mutation was identified in 390 families and about 68% of them have HHT type 2. We found 240 different mutations spread among the whole coding sequence and flanking introns of both genes with the exception of ACVRL1 exon 2 and ENG exons 11 and 15, where no mutation was detected. Noteworthy, about 47% of Patients have a mutation in exons 3, 7 or 8 of ACVRL1. If we consider the geographical origin of the families, a founder effect is suggested for at least 5 mutations. Conclusion: We confirm the peculiar genetic characteristic of the HHT Italian population with a higher incidence of HHT2. In particular, an unexplained 22% of cases carry a mutation in ACVRL1 exon 3. In addition, a founder effect is to be supposed in some geographic regions.