title: Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension.
abstract: OBJECTIVE
  Recent advances in genetics have led to the discovery of new genes associated with pulmonary arterial hypertension, such as TBX4 and KCNK3. The phenotype and prognosis associated with these new genes have been scarcely described and their role in the Spanish population is unknown. The aim of this study was to characterize the genetics of a Spanish cohort of patients with idiopathic and hereditary pulmonary arterial hypertension and to describe the phenotype and prognostic factors associated with BMPR2 and the new genes (KCNK3 and TBX4).
  
  
  METHODS
  A total of 165 adult patients were screened for BMPR2, KCNK3, and TBX4 mutations, 143 with idiopathic pulmonary arterial hypertension and 22 with hereditary pulmonary arterial hypertension. Baseline characteristics and survival were compared among the different subgroups and predictors of poor outcomes were analyzed. We also performed family screening.
  
  
  RESULTS
  The genetic study identified a possibly associated mutation in 11.10% of the idiopathic cases (n = 16) and in 68.18% of the hereditary cases (n = 15). There were 19 mutations in BMPR2, 4 in TBX4, and 3 in KCNK3. The forms associated with TBX4 showed the highest survival rate (P < .01). Advanced functional class at diagnosis was the only factor associated with poor outcomes in the hereditary forms. In the family screening, 37.5% of relatives tested positive.
  
  
  CONCLUSIONS
  The genetics of pulmonary arterial hypertension in the Spanish population may differ from other populations, with a lower proportion of BMPR2 causative mutations. In our cohort, TBX4-related forms of pulmonary arterial hypertension showed a more benign course and late diagnosis was the only predictor of adverse outcomes in the hereditary forms of the disease.
authors.affiliation: Red de Investigación Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain; Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Navas
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Jair
authors.initials: J
authors.lastname: Tenorio
authors.affiliation: Red de Investigación Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain; Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Carlos Andrés
authors.initials: CA
authors.lastname: Quezada
authors.affiliation: Servicio de Cardiología Pediátrica, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Barrios
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Gordo
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Arias
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: López Meseguer
authors.affiliation: Grupo de Investigación en Discapacidad Física y Sensorial (GIDFYS), Departamento de Ciencias de la Salud, Universidad Europea Miguel de Cervantes, Valladolid, Spain; Instituto de Investigación Hospital Universitario 12 Octubre (i+12), Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Santos-Lozano
authors.affiliation: Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain; Unidad de Cardiopatías Familiares, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Palomino Doza
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Red de Investigación Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain; Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain. Electronic address: mariapilar.escribano@salud.madrid.org.
authors.forename: Pilar
authors.initials: P
authors.lastname: Escribano Subías
mesh_terms: D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005541:Forced Expiratory Volume; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics*; D011379:Prognosis; D011653:Pulmonary Diffusing Capacity; D013030:Spain; D020825:T-Box Domain Proteins / Q000235:genetics*; D014655:Vascular Resistance; D014797:Vital Capacity; D000070857:Walk Test; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; D020825:T-Box Domain Proteins; C491193:TBX4 protein, human; C420132:potassium channel subfamily K member 3; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMPR2; Cribado; Hereditary pulmonary arterial hypertension; Hipertensión arterial pulmonar heredable; Hipertensión arterial pulmonar idiopática; Idiopathic pulmonary arterial hypertension; KCNK3; Screening; TBX4