Pulmonary arterial hypertension associated with several mutations

Abstract

Pulmonary arterial hypertension (PAH; OMIM #178600) is a progressive disease that causes the obstruction of precapillary pulmonary arteries. Syncope, dyspnea and chest pain are the main symptoms of PAH. Much of what is known about the genetic basis of PAH is related to BMPR2 gene. However, some other candidate genes have been advocated. The aim of this study was to analyse patients with combined mutations in BMPR2 , ACVRL1 , ENG and KCNA5 genes. We included 57 PAH patients and 50 controls. The DNA extraction was performed with the Qiagen DNA kit FlexiGene. Using specifically primers, we amplified and sequenced genes. Genotype-phenotype correlation was performed. After mutation screening of BMPR2 , ACVRL1 , ENG and KCNA5 genes, we identified pathogenic mutations in 40 patients. We found a high percentage of patients with several mutations classified as pathogenic by in silico analysis. Some patients had several mutations in the same gene whereas others harboured several mutations in different genes. We found combined mutations in BMPR2 gene in 25% of patients with several mutations included in this study. We detected one patient that show two pathogenic mutations in ENG gene. We found significant differences, comparing patients with several mutations and patients with one pathogenic mutation, for gender (p=0.045), age at diagnosis (p=0.040), PVR (p=0.030), CI (p=0.042) and no response to therapy (p=0.011). We show a series of patients with PAH with a high percentage of them being carriers of more than one pathogenic mutation in several genes. We wonder whether these additional mutations act as a second event in the development of the disease, increasing the penetrance or simply modifying the phenotype of patients.