Experience of an Italian reference laboratory for a rare disease: Hereditary Haemorragic Telangiectasia

Introduction: Hereditary Haemorragic Teleangiectasia (HHT) is an autosomal dominant disorder affecting 1:5000-8000 individuals worldwide. Mucocutaneous telangiectases and Arteriovenous malformations in internal organs (mostly lungs, liver and central nervous system) are the disease hallmarks. HHT is caused by pathogenetic variants in ENG, ACVRL1, SMAD4 and GDF2, belonging to the TGFβ/BMPs pathway. We report the experience of our research laboratory in the last five years (2015-2020), focusing on mutation analysis. Materials and Methods: Patients’ samples were collected by HHT reference centres in Pavia and Crema (CR). Index cases’ samples were analysed by NGS sequencing panel of the four HHT causative genes and MLPA; the molecular investigation in patients’ relatives was performed by Sanger sequencing. Results: We collected 334 patients’ samples; 99/334 were index cases. Results are summarized in the table below. Subjects ACVRL1 ENG SMAD4 Not Found In progress Unaffected Index case 99 39 (39.4%) 26 (26.3%) 1 (1%) 27 (27.3%) 6 (6%) - Patient’s relatives 234 86 60 - - 8 80 Total patients 333 125 86 1 28 13 80 Conclusions: Our data confirm that HHT is mostly underdiagnosed; however, the presence of a reference center enhances the quality of genetic and clinical results. Moreover, we also corroborate the previous observation that in our country ACVRL1 is the major HHT gene. Not found subjects can harbor variants in intronic or regulatory regions rather than in novel genes. However, we are collecting WES data to re-analyse these cases. Grant: CO: Italian Ministry of Education, University and Research to the DMM-University of Pavia “Dipartimenti di Eccellenza (2018-2022)”