Germline mutations in BMP9 are not identified in a series of Danish and French patients with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), an inherited vascular disorder, is, in the majority of cases (85%), caused by mutations in one of three genes (ENG, ACVRL1, and SMAD4). In the remaining group of individuals with clinical HHT, mutations have not been identified, suggesting yet undiscovered HHT causative genes. A new vascular-anomaly syndrome caused by mutations in BMP9 has recently been published. Three patients suspected of HHT, with familial nose bleedings and dermal manifestations not characteristic for HHT, were described. Although, it was concluded that these patients probably had a different vascular-anomaly syndrome, the suspicion that BMP9 mutations might cause HHT remained. To evaluate if germline mutations in BMP9 can be identified in HHT patients, we investigated the Danish and the French Lyon cohort of mutation-negative and clinically definite HHT patients. Exons and exon-intron boundaries of BMP9 were analyzed by bi-directional Sanger sequencing in 28 clinical HHT patients (from 28 different families) with no pathogenic mutations in ENG, ACVRL1 or SMAD4. No mutations of potential pathogenicity were identified in BMP9. This study does not suggest that BMP9 mutations causes HHT, although this cannot be fully excluded based on this study. So far, we have been unable to identify any patients with clinical HHT caused by a BMP9 mutation.