title: Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a rare, progressive, fatal vascular disorder. Genetic predisposition plays vital roles in the development of PAH, with most mutations being identified in genes involved in the transforming growth factor beta (TGF-β) signaling pathways. Defects in the BMP9 gene have been documented in hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, which is occasionally associated with PAH. Selective enhancement of endothelial BMPR2 with BMP9 reverses pulmonary arterial hypertension.
  
  
  METHODS
  We report the case of a 5-year-old Hispanic boy who was diagnosed with severe PAH and right heart failure at 3 years of age. During his stay in the pediatric intensive care unit, treatment was initiated with inhaled nitric oxide and intravenous epoprostenol; he subsequently was transitioned to treprostinil, sildenafil, and prophylactic enoxaparin. Now, two years later, the child is asymptomatic on sildenafil, bosentan, subcutaneous treprostinil, and warfarin. Genetic screening revealed a novel homozygous nonsense mutation in the BMP9 gene (c.76C > T; p.Gln26Ter). The child had no telangiectasias or arteriovenous malformations; family history also was negative. Subsequent parental testing showed both parents were heterozygous for the same mutation, indicating that the child inherited the BMP9 mutant allele from each parent.
  
  
  CONCLUSIONS
  To our knowledge, this is the first report of a BMP9 mutation in a patient with PAH. The homozygous nonsense mutation may account for the early onset and severity of PAH in this patient and also fit the 'two-hit' model we proposed previously. The absence of clinical symptoms for PAH in the parents may be due to incomplete penetrance or various expressivities of the BMP9 mutations. Our study expands the spectrum of phenotypes related to BMP9 mutations.
authors.affiliation: John Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Ave, Suite 430.09, Houston, TX, 77030, USA. guolianw@bcm.edu.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: John Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Ave, Suite 430.09, Houston, TX, 77030, USA. Rui.Fan@bcm.edu.|Department of Pediatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, Shanxi, China. Rui.Fan@bcm.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Fan
authors.affiliation: John Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Ave, Suite 430.09, Houston, TX, 77030, USA. rji@bcm.edu.
authors.forename: Ruirui
authors.initials: R
authors.lastname: Ji
authors.affiliation: John Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Ave, Suite 430.09, Houston, TX, 77030, USA. wzou@bcm.edu.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Zou
authors.affiliation: John Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Ave, Suite 430.09, Houston, TX, 77030, USA. penny@bcm.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Penny
authors.affiliation: Section of Pulmonology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA. paulose@bcm.edu.
authors.forename: Nidhy P
authors.initials: NP
authors.lastname: Varghese
authors.affiliation: John Welsh Cardiovascular Diagnostic Laboratory, Section of Cardiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 1102 Bates Ave, Suite 430.09, Houston, TX, 77030, USA. yuxinf@bcm.edu.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Fan
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000077300:Bosentan; D002675:Child, Preschool; D018389:Codon, Nonsense; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000627:therapeutic use; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D000068677:Sildenafil Citrate / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D000959:Antihypertensive Agents; D018389:Codon, Nonsense; C525887:GDF2 protein, human; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D013449:Sulfonamides; D014665:Vasodilator Agents; D014859:Warfarin; D000068677:Sildenafil Citrate; D011464:Epoprostenol; D000077300:Bosentan; C427248:treprostinil