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Background  Hereditary pulmonary arterial hypertension (HPAH) can be caused by autosomal dominant inherited mutations of TGF-β genes, such as the  bone morphogenetic protein receptor 2 (BMPR2)  and  Endoglin (ENG)  gene. Additional modifier genes may play a role in disease manifestation and severity. In this study we prospectively assessed two families with known  BMPR2  or  ENG  mutations clinically and genetically and screened for a second mutation in the  BMPR2  promoter region.    Methods  We investigated the  BMPR2  promoter region by direct sequencing in two index-patients with invasively confirmed diagnosis of HPAH, carrying a mutation in the  BMPR2  and  ENG  gene, respectively. Sixteen family members have been assessed clinically by non-invasive methods and genetically by direct sequencing.    Results  In both index patients with a primary  BMPR2  deletion (exon 2 and 3) and  Endoglin  missense variant (c.1633G>A, p.(G545S)), respectively, we detected a second mutation (c.-669G>A) in the promoter region of the  BMPR2  gene. The index patients with 2 mutations/variants were clinically severely affected at early age, whereas further family members with only one mutation had no manifest HPAH.    Conclusion  The finding of this study supports the hypothesis that additional mutations may lead to an early and severe manifestation of HPAH. This study shows for the first time that in the regulatory region of the  BMPR2  gene the promoter may be important for disease penetrance. Further studies are needed to assess the incidence and clinical relevance of mutations of the  BMPR2  promoter region in a larger patient cohort.

Mutation in BMPR2 Promoter: A ‘Second Hit’ for Manifestation of Pulmonary Arterial Hypertension?