04 February 2019 by Carmen Perez-Olivares Delgado

Identification of novel genetic markers in other forms of Pulmonary Hypertension


Genetic defects BMPR2 gene are the most frequently associated to idiopathic and heritable pulmonary arterial hypertension (IPAH, HPAH). However there is not evidence of the presence of genetic mutations in other forms of pulmonary hypertension such as connective tissue diseases (CTD) and congenital heart disease (PAH-CHD). Our objective is to assess the prevalence of genetic mutations related to PAH in a cohort of patients with PAH-CTD and PAH-CHD 


A targeted next generation sequencing (NGS) panel of 21 genes associated with PAH was performed in a cohort of 25 patients diagnosed with PAH-CTD and 41 patients with PAH-CHD. The genes included in the panel were divided into: TGF-β signaling pathway related genes (BMPR2, BMPR1B, GDF2, SMAD1, SMAD4, SMAD5, SMAD9, ENG, ACVRL1 and CAV1); recently described genes in PAH (KCNK3, KCNA5, NOTCH3, TBX4, TOPBP1, MMACHC9); genes associated with occlusive pulmonary disease (EIF2AK4) and research genes (SARS2, CPS1, ABCC8, CBLN2).


For the cohort with PAH-CTD we found genetic mutations in 5 patients (3 patients with systemic sclerosis presented variants unknown significance in NOTCH3, CPS1 and ABCC8 genes respectively, and 2 affected with other forms of CTD were carriers of pathogenic mutation in GDF2 and TBX4 respectively). Among patients with PAH-CHD we found a genetic mutation in 8 patients (2 patients with coincidental defects presented a pathogenic mutation in BMPR2 gen and 6 patients were carriers of variants unknown significance in CPS1, NOTCH3, SMAD5, ABCC8, TOBP1 genes,


These results remarked the importance of molecular defects in these two populations. Patients with PAH-CHD and PAH-CTD had a high prevalence of mutation in genes related HAP. The presence of genetic mutations may be a factor that contributes to the development of PAH in these cohorts.

About the author

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Key Contributors

C. Pérez-Olivares 1, A. Aurtenetxe 1, J. Tenorio 2, N. Ochoa 1, I. Hernández 3, R. López4, J.Segovia 5, P.Escribano 5 : 1 Cardiology Department, University 12 de Octubre Hospital, Madrid, Spain 2 Medical and Molecular Genetics Institute, University La Paz Hospital, Madrid, Spain 3 Cardiology Department, University Fundación Jiménez Díaz Hospital, Madrid, Spain 4 Respiratory Department, La Fe University Hospital, Valencia, Spain 5 University Hospital 12 de Octubre, CIBER Enfermedades Cardiovasculares, Madrid, Spain. FIS-PI15/02012 Actelion unrestricted grant

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