Erial Hypertension; APAH: Associated Pulmonary Arterial Hypertension; CTD: connective tissue disease; HIV: Human Immunodeficiency virus; P-P: Porto-pulmonary hypertension.Clinical features and hemodynamic parameters Number Gender Age at diagnosis (years) mPaP (mmHg) sPaP (mmHg) PVR (mmHg.l-1.m-1) CI (l.min-1.m-2) 6MWT (m) PAH types No response to treatmentTotal patients 57 20 M/37 F 49 ?16 49 ?14 70 ?19 8.1 ?3.3 2.4 ?0.7 415 ?146 28 IPAH/29 APAHTable 1. Clinical features and hemodynamic parameters of patients included in this study. Values are expressed as mean ?standard deviation; F: female, M: male; mPaP: mean pulmonary artery pressure; sPaP: systolic pulmonary artery pressure; PVR: pulmonary vascular resistence; CI: cardiac index; 6MWT: 6 minute walking test; IPAH: idiopathic pulmonary arterial hypertension; APAH: associated pulmonary arterial hypertension.Besides, there are genetic modifiers that affect PAH pathogenicity in combination with mutations in those genes already described25?7. TAPI-2 biological activity Recent findings point out that the penetrance and expressivity of PAH are likely to be directed by the mutational load of all genes involved in the disease. Thus, we aimed to analyse here the implication of harbouring a range of pathogenic mutations in PAH. In addition, we tried to establish a genotype-phenotype correlation between clinical and hemodynamic features of patients with several pathogenic mutations.Resultsconnective tissue disease, 4 related to HIV and 5 porto-pulmonary hypertension) (Fig. 1) were included. At the time of diagnosis 8 patients were in functional class (FC) I, 20 patients in FC II, 25 patients in FC III and 4 in FC IV (Table 1). This cohort has been partially characterized in previous studies12,25,28. We have recruited patients during the last years and we performed several genetic analyses with them. The clinical description is so similar for the cohort, but for the genotype-phenotype correlation, we select only those patients of interest.Description of the cohort. Fifty-seven unrelated, Caucasian PAH patients (28 idiopathic, 20 associated toMutational study of BMPR2, ACVRL1, ENG and KCNA5 genes. After mutational screening of BMPR2, ACVRL1, ENG and KCNA5 genes, we identified pathogenic mutations in 72 (40) patients. BMPR2 was the gene with a greater number of pathogenic mutations (44 of patients with mutations), followed by ENG (29 ), buy GS-4059 ACVRL1 (17 ) and, finally KCNA5 (10 ) gene (Fig. 2). These results have been partially reported in Pousada et al.12 and Pousada et al.28.Scientific RepoRts | 6:33570 | DOI: 10.1038/srepwww.nature.com/scientificreports/Figure 2. Graphical representation of the four genes analyzed here for the 57 patients included. The gene with more implication in these patients is BMPR2, followed by ENG gene and, finally, ACVRL1 and KCNA5 genes. During the mutational analysis, we found a high percentage of patients, 26 (15 patients), with several mutations classified as pathogenic after in silico analysis. Among them, some patients had several mutations in the same gene whereas others harboured several mutations in different genes (Table 2). Besides, 12 of these patients were carriers of at least one mutation in BMPR2 gene. ENG gene was the second most important gene involved, with 9 patients showing a mutation in this gene. However, ACVRL1 and KCNA5 genes were less represented, since they were mutated only in 5 and 1 patients, respectively (Fig. 3). None of these mutations were detected in 55 control sam.Erial Hypertension; APAH: Associated Pulmonary Arterial Hypertension; CTD: connective tissue disease; HIV: Human Immunodeficiency virus; P-P: Porto-pulmonary hypertension.Clinical features and hemodynamic parameters Number Gender Age at diagnosis (years) mPaP (mmHg) sPaP (mmHg) PVR (mmHg.l-1.m-1) CI (l.min-1.m-2) 6MWT (m) PAH types No response to treatmentTotal patients 57 20 M/37 F 49 ?16 49 ?14 70 ?19 8.1 ?3.3 2.4 ?0.7 415 ?146 28 IPAH/29 APAHTable 1. Clinical features and hemodynamic parameters of patients included in this study. Values are expressed as mean ?standard deviation; F: female, M: male; mPaP: mean pulmonary artery pressure; sPaP: systolic pulmonary artery pressure; PVR: pulmonary vascular resistence; CI: cardiac index; 6MWT: 6 minute walking test; IPAH: idiopathic pulmonary arterial hypertension; APAH: associated pulmonary arterial hypertension.Besides, there are genetic modifiers that affect PAH pathogenicity in combination with mutations in those genes already described25?7. Recent findings point out that the penetrance and expressivity of PAH are likely to be directed by the mutational load of all genes involved in the disease. Thus, we aimed to analyse here the implication of harbouring a range of pathogenic mutations in PAH. In addition, we tried to establish a genotype-phenotype correlation between clinical and hemodynamic features of patients with several pathogenic mutations.Resultsconnective tissue disease, 4 related to HIV and 5 porto-pulmonary hypertension) (Fig. 1) were included. At the time of diagnosis 8 patients were in functional class (FC) I, 20 patients in FC II, 25 patients in FC III and 4 in FC IV (Table 1). This cohort has been partially characterized in previous studies12,25,28. We have recruited patients during the last years and we performed several genetic analyses with them. The clinical description is so similar for the cohort, but for the genotype-phenotype correlation, we select only those patients of interest.Description of the cohort. Fifty-seven unrelated, Caucasian PAH patients (28 idiopathic, 20 associated toMutational study of BMPR2, ACVRL1, ENG and KCNA5 genes. After mutational screening of BMPR2, ACVRL1, ENG and KCNA5 genes, we identified pathogenic mutations in 72 (40) patients. BMPR2 was the gene with a greater number of pathogenic mutations (44 of patients with mutations), followed by ENG (29 ), ACVRL1 (17 ) and, finally KCNA5 (10 ) gene (Fig. 2). These results have been partially reported in Pousada et al.12 and Pousada et al.28.Scientific RepoRts | 6:33570 | DOI: 10.1038/srepwww.nature.com/scientificreports/Figure 2. Graphical representation of the four genes analyzed here for the 57 patients included. The gene with more implication in these patients is BMPR2, followed by ENG gene and, finally, ACVRL1 and KCNA5 genes. During the mutational analysis, we found a high percentage of patients, 26 (15 patients), with several mutations classified as pathogenic after in silico analysis. Among them, some patients had several mutations in the same gene whereas others harboured several mutations in different genes (Table 2). Besides, 12 of these patients were carriers of at least one mutation in BMPR2 gene. ENG gene was the second most important gene involved, with 9 patients showing a mutation in this gene. However, ACVRL1 and KCNA5 genes were less represented, since they were mutated only in 5 and 1 patients, respectively (Fig. 3). None of these mutations were detected in 55 control sam.
