Abstract
BackgroundMutations 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.MethodsPatients 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.ResultsOf 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.ConclusionThis 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.
Highlights
Pulmonary arterial hypertension (PAH) is a rare vascular disorder characterised by increased pulmonary vascular resistance and right heart failure
Most data comparing clinical features between bone morphogenetic protein receptor 2 (BMPR2) mutation carriers and non-carriers have been obtained from registries as from the French Network of Pulmonary Hypertension [6,13,14,15], and from centres in the United States as the New York Presbyterian Pulmonary Hypertension Center [12], the Utah Pulmonary Hypertension Genetics Project [16] or the Vanderbilt University School of Medicine, Nashville, Tennessee [7,17,18] and are retrospective in design
We describe the clinical features of families with confirmed familial aggregation of PAH but no detectable mutations of the BMPR2 gene and tested these families for mutations of the genes ACVRL1, Endoglin, and SMAD8
Summary
Pulmonary arterial hypertension (PAH) is a rare vascular disorder characterised by increased pulmonary vascular resistance and right heart failure. Heterozygous germline mutations in the bone morphogenetic protein type 2 receptor (BMPR2) have proportion of patients with familial aggregation of PAH in which no gene defects can be detected so far [7,11]. A recent study of Austin et al [17] showed that HPAH female patients with missense mutations in the BMPR2 gene had a more severe disease than patients with truncating mutations. These publications indicate that the clinical phenotype of PAH can be affected by the type of mutation. 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
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