Bone morphogenetic protein receptor type 2 mutations, clinical phenotypes and outcomes of Japanese patients with sporadic or familial pulmonary hypertension

Background and objective: Mutation of bone morphogenetic protein receptor type 2 (BMPR2) is a cause of pulmonary arterial hypertension (PAH). We measured the prevalence of this mutation and its impact on the phenotypes and long-term clinical outcomes in Japanese patients. Methods: Between 1999 and 2007, we consecutively enrolled and, until March 2012, followed 49 Japanese patients with PAH, including nine familial cases from seven families. We genotyped BMPR2, using direct sequencing and multiplex ligation-dependent probe amplification, to examine (i) the prevalence of BMPR2 mutations and gene rearrangement, (ii) the relationship between BMPR2 genotype and clinical phenotypes, and (iii) the long-term clinical outcomes of mutation carriers versus non-carriers under state-of-the-art medical therapy. Results: BMPR2 mutations were present in four of the seven families (57%) and in 14 of the 40 patients (35%) with sporadic PAH. The mean age at onset of PAH was 37.4 years in BMPR2 carriers, versus 25.9 years in non-carriers (P = 0.0025). The gender distribution and hemodynamic status at time of diagnosis were similar regardless of the mutation status. The 5-year survival rate after diagnosis of PAH was 88.5% in BMPR2 mutation carriers versus 80.9% in non-carriers (ns). Conclusions: The prevalence of BMPR2 mutations in Japanese with PAH was similar to that reported in other populations. At onset of PAH, BMPR2 mutation non-carriers were, on average, younger than carriers, possibly due to the heterogeneity of this subpopulation. With state-of-the-art therapy, the long-term survival of patients with PAH was high, regardless of the mutation status.