Mutation analysis of Hereditary Hemorrhagic Telangiectasia disease among eastern Spanish population

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant and age dependent vascular disorder characterized mainly by mutations in the Endoglin (ENG) or activin receptor-like kinase-1 (ACVRL1) genes. Methods: We describe 17 clinically diagnosed HHT patients (Curacao criteria) from our health care area, belonging to unrelated families. Analysis of clinical symptoms was recorded for each patient, with skin and ORL examination, neurovascular imaging, echocardiography, hepatic echo Doppler and thoracic angio CT. Sequencing and MLPA molecular analysis of susceptible genes were carried out in each index patient. Every identified variant was evaluated using functional prediction, familial segregation analysis and data bases. Results: We identified mutations in fourteen of the 17 patients with clinical diagnosis of HHT. 6 HHT1 patients carrying different ENG mutations and 8 HHT2 patients heterozygotes for deleterious variants in ACVRL1 gene; 4 and 5 respectively, had not been previously described. 38 diagnosed patients and 25 presymptomatic individuals were identified as mutation carriers. We found a higher significant presence of pulmonary arteriovenous malformations (36.8%) in HHT1 patients. Hepatic arteriovenous malformations were more prevalent in HHT2 (54.4%). Two patients with ALK-1 mutation presented high output heart failure. Conclusion: ALK1 mutations were predominant over ENG mutations, as has been published in other Mediterranean regions. The finding of 64% patients with mutations never described was unexpected and striking, although it has been described that regionality, as ethnicity, have minimal roles in the clinical presentation of HHT.