title: Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations.
abstract: BACKGROUND
  Mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene can lead to idiopathic pulmonary arterial hypertension (IPAH). This study prospectively screened for BMPR2 mutations in a large cohort of PAH-patients and compared clinical features between BMPR2 mutation carriers and non-carriers.
  
  
  METHODS
  Patients have been assessed by right heart catheterization and genetic testing. In all patients a detailed family history and pedigree analysis have been obtained. We compared age at diagnosis and hemodynamic parameters between carriers and non-carriers of BMPR2 mutations. In non-carriers with familial aggregation of PAH further genes/gene regions as the BMPR2 promoter region, the ACVRL1, Endoglin, and SMAD8 genes have been analysed.
  
  
  RESULTS
  Of the 231 index patients 22 revealed a confirmed familial aggregation of the disease (HPAH), 209 patients had sporadic IPAH. In 49 patients (86.3% of patients with familial aggregation and 14.3% of sporadic IPAH) mutations of the BMPR2 gene have been identified. Twelve BMPR2 mutations and 3 unclassified sequence variants have not yet been described before. Mutation carriers were significantly younger at diagnosis than non-carriers (38.53 ± 12.38 vs. 45.78 ± 11.32 years, p < 0.001) and had a more severe hemodynamic compromise. No gene defects have been detected in 3 patients with HPAH.
  
  
  CONCLUSIONS
  This study identified in a large prospectively assessed cohort of PAH- patients new BMPR2 mutations, which have not been described before and confirmed previous findings that mutation carriers are younger at diagnosis with a more severe hemodynamic compromise. Thus, screening for BMPR2 mutations may be clinically useful.
authors.affiliation: Centre for Pulmonary Hypertension Thoraxclinic, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.forename: Justyna
authors.initials: J
authors.lastname: Szamalek-Hoegel
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.forename: Christian
authors.initials: C
authors.lastname: Nagel
authors.forename: Nicola
authors.initials: N
authors.lastname: Ehlken
authors.forename: Henning
authors.initials: H
authors.lastname: Tiede
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.forename: Frank
authors.initials: F
authors.lastname: Reichenberger
authors.forename: Ardeschir H A
authors.initials: AH
authors.lastname: Ghofrani
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grünig
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D006328:Cardiac Catheterization; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005858:Germany; D006439:Hemodynamics / Q000235:genetics*; D040941:Heredity; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011446:Prospective Studies; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II