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Revista Española de Cardiología (English Edition) Revista Española de Cardiología (English Edition)
Rev Esp Cardiol. 2016;69:1011-9 - Vol. 69 Num.11 DOI: 10.1016/j.rec.2016.03.029

Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension

Paula Navas a,b, Jair Tenorio c,d, Carlos Andrés Quezada a,b, Elvira Barrios e, Gema Gordo c,d, Pedro Arias c,d, Manuel López Meseguer c,f, Alejandro Santos-Lozano g,h, Julian Palomino Doza b,i, Pablo Lapunzina c,d, Pilar Escribano Subías a,b,

a Red de Investigación Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
b Unidad Multidisciplinar de Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain
c Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
d Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, Madrid, Spain
e Servicio de Cardiología Pediátrica, Hospital Ramón y Cajal, Madrid, Spain
f Servicio de Neumología, Hospital Universitario Vall d’Hebron, Barcelona, Spain
g Grupo de Investigación en Discapacidad Física y Sensorial (GIDFYS), Departamento de Ciencias de la Salud, Universidad Europea Miguel de Cervantes, Valladolid, Spain
h Instituto de Investigación Hospital Universitario 12 Octubre (i+12), Madrid, Spain
i Unidad de Cardiopatías Familiares, Hospital Universitario 12 de Octubre, Madrid, Spain

Refers to

Molecular Genetic Diagnosis of Pulmonary Arterial Hypertension: An Increased Complexity
Mélanie Eyries, Florent Soubrier
Rev Esp Cardiol. 2016;69:1003-4
Full text - PDF


Idiopathic pulmonary arterial hypertension. Hereditary pulmonary arterial hypertension. BMPR2. TBX4. KCNK3. Screening.


Introduction and objectives

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).


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.


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.


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.

1885-5857/© 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved