Complex inheritance in Pulmonary Arterial Hypertension patients with several mutations

Guillermo Pousada,Diana Valverde,Adolfo Baloira

doi:10.1038/srep33570

Abstract

Pulmonary Arterial Hypertension (PAH) is a rare and progressive disease with low incidence and prevalence, and elevated mortality. PAH is characterized by increased mean pulmonary artery pressure. The aim of this study was to analyse patients with combined mutations in BMPR2, ACVRL1, ENG and KCNA5 genes and to establish a genotype-phenotype correlation. Major genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Genotype-phenotype correlation was performed. Fifty-seven (28 idiopathic PAH, 29 associated PAH group I) were included. Several mutations in different genes, classified as pathogenic by in silico analysis, were present in 26% of PAH patients. The most commonly involved gene was BMPR2 (12 patients) followed by ENG gene (9 patients). ACVRL1 and KCNA5 genes showed very low incidence of mutations (5 and 1 patients, respectively). Genotype-phenotype correlation showed statistically significant differences for gender (p = 0.045), age at diagnosis (p = 0.035), pulmonary vascular resistance (p = 0.030), cardiac index (p = 0.035) and absence of response to treatment (p = 0.011). PAH is consequence of a heterogeneous constellation of genetic arrangements. Patients with several pathogenic mutations seem to display a more severe phenotype.

Highlights

Pulmonary Arterial Hypertension (PAH; OMIM #178600, ORPHA 422) is a progressive, poorly characterized disease with low incidence and prevalence in the general population[1], and a poor prognosis in terms of quality of life, morbidity and mortality[2]
The bone morphogenetic protein type 2 receptor gene (BMPR2; MIM #600799), a member of the transforming growth factor (TGF-β) superfamily, was the first causal gene identified in PAH and is mutated in approximately 10 to 40% of IPAH patients and 80% of patients with HPAH
Other genes have been associated with the disease, including Activin A type II receptor like kinase 1 (ALK1/ ACVRL1; MIM #601284), located on chromosome 12q1316,17, Endoglin (ENG; MIM #601284)[10], located on chromosome 9q33-3417,18, and Potassium voltage-gated channel, shakerrelated subfamily, member 5 (KCNA5; MIM #176267), located on chromosome 12p1319,20

Summary

Introduction

Pulmonary Arterial Hypertension (PAH; OMIM #178600, ORPHA 422) is a progressive, poorly characterized disease with low incidence and prevalence in the general population[1], and a poor prognosis in terms of quality of life, morbidity and mortality[2]. The bone morphogenetic protein type 2 receptor gene (BMPR2; MIM #600799), a member of the transforming growth factor (TGF-β) superfamily, was the first causal gene identified in PAH and is mutated in approximately 10 to 40% of IPAH patients and 80% of patients with HPAH. This gene is located on chromosome 2q3310,12–15. Other genes have been associated with the disease, including Activin A type II receptor like kinase 1 (ALK1/ ACVRL1; MIM #601284), located on chromosome 12q1316,17, Endoglin (ENG; MIM #601284)[10], located on chromosome 9q33-3417,18, and Potassium voltage-gated channel, shakerrelated subfamily, member 5 (KCNA5; MIM #176267), located on chromosome 12p1319,20. We tried to establish a genotype-phenotype correlation between clinical and hemodynamic features of patients with several pathogenic mutations

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