A novel BMPR2 gene mutation associated with exercise-induced pulmonary hypertension in septal defects

Abstract Objective. Our study aimed to investigate the relationship between exercise-induced pulmonary arterial hypertension and genetic changes related to the transforming growth factor-β (TGF-β) signalling pathway in patients with cardiac septal defects. Design. In a population-based group of 44 patients (age 13-25 years) with either isolated ventricular septal defect (n=27) or isolated atrial septal defect (n=17), right ventricular systolic pressure response to submaximal exercise was studied by echocardiography and classified as normal (≤45 mmHg), borderline (45-50 mmHg) or abnormal (>50 mmHg). Three genes related to TGF-β, bone morphogenetic protein receptor type 2 (BMPR2), activin receptor-like kinase 1 (ALK1) and endoglin (ENG), were analyzed by DNA sequencing (only BMPR2) and multiplex ligand-dependent probe amplification (BMPR2, ALK1 and ENG). Results. Pressure response was borderline in five and abnormal in nine patients. Five patients showed mutations in exon 12 of the bone morphogenetic protein receptor type 2 gene. The previously described polymorphism S775N (c. 2324, G > A) was found in three patients with normal pressure response. The mutation Y589C (c. 1766, A > G), which has not been described previously, was found in two of 14 patients with borderline/abnormal pressure response. Conclusion. Genetic changes in the BMPR2 gene may be overrepresented in patients with cardiac septal defects and exercise-induced pulmonary hypertension.