BMP9 mutations cause a vascular anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. J. McDonald1,2, W. Wooderchak-Donahue3, B. O'Fallon3, P. Upton4, W. Li4, B. Roman5, S. Young5, P. Plant3, G. Fülöp6, C. Langa6, N. Morrell4, L. Botella6, C. Bernabeu6, D. Stevenson7, J. Runo8, P. Bayrak-Toydemir1,3 1) Department of Pathology, University of Utah, Salt Lake City, UT; 2) Department of Radiology, University of Utah, Salt Lake City, UT; 3) ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT; 4) Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, United Kingdom; 5) Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA; 6) Centro de Investigaciones Biologicas, CSIC and Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; 7) Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT; 8) Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.

   Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by telangiectases and arteriovenous malformations (AVMs). Hallmark features are recurrent nosebleeds due to telangiectases of the nasal mucosa; dermal, oral and gastrointestinal tract; and solid organ AVMs, particularly of the lungs, liver, and brain. The dermal telangiectases are typically pinpoint to pinhead size, specifically concentrated on the hands, face and lips, and not diffuse. Telangiectases on the limbs and trunk are not characteristic. Three genes in the transforming growth factor beta (TGF-) signaling pathway (ENG, ACVRL1, and SMAD4) are currently known to cause HHT, but approximately 15% of individuals with clinical features of HHT do not have a mutation in one of these genes. We performed exome and/or Sanger sequencing on 191 unrelated individuals suspected to have HHT, who had tested negative for a mutation in ENG, ACVRL1, and SMAD4. A mutation predicted to be deleterious was identified in three unrelated probands in the BMP9 gene. These three individuals had nosebleeds and dermal lesions described as telangiectases, but which bore resemblance to lesions described in patients with RASA1-related disorders/CM-AVM (capillary malformation-arteriovenous malformation syndrome). Also, vascular liver findings similar to those seen in HHT were reported in one proband. CM-AVM, like HHT, is also characterized by telangiectases and AVMs, but recurrent nosebleeds are not described, and the typical dermal telangiectases differ from HHT in location and appearance. Telangiectases in CM-AVM include the tiny punctate lesions seen in HHT, as well as larger telangiectases referred to as capillary malformations. These punctate telangiectases are commonly diffuse and tend to cluster in a region of the trunk or limbs. Expression analyses were performed which suggest the identified mutations alter BMP9 protein processing and activity. Bmp9 knockdown experiments were performed in zebrafish and suggest BMP9 is involved in angiogenesis, but support the idea that BMP9 mutations might cause a novel vascular phenotype distinct from HHT. We identify a new genetic cause of a hereditary telangiectasia disorder which may overlap clinically with HHT and CM-AVM.

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