Abstract
BackgroundPulmonary arterial hypertension (PAH) is a group of vascular diseases that produce right ventricular dysfunction, heart failure syndrome, and death. Although the majority of patients appear idiopathic, accumulated research work combined with current sequencing technology show that many gene variants could be an important component of the disease. However, current guidelines, clinical practices, and available gene panels focus the diagnosis of PAH on a relatively low number of genes and variants associated with the bone morphogenic proteins and transforming Growth Factor-β pathways, such as the BMPR2, ACVRL1, CAV1, ENG, and SMAD9.MethodsTo provide an expanded view of the genes and variants associated with PAH, we performed a systematic literature review. Facilitated by a web tool, we classified, curated, and annotated most of the genes and PubMed abstracts related to PAH, in which many of the mutations and variants were not annotated in public databases such as ClinVar from NCBI. The gene list generated was compared with other available tests.ResultsOur results reveal that there is genetic evidence for at least 30 genes, of which 21 genes shown specific mutations. Most of the genes are not covered by current available genetic panels. Many of these variants were not annotated in the ClinVar database and a mapping of these mutations suggest that next generation sequencing is needed to cover all mutations found in PAH or related diseases. A pathway analysis of these genes indicated that, in addition to the BMP and TGFβ pathways, there was connections with the nitric oxide, prostaglandin, and calcium homeostasis signalling, which may be important components in PAH.ConclusionOur systematic review proposes an expanded gene panel for more accurate characterization of the genetic incidence and risk in PAH. Their usage would increase the knowledge of PAH in terms of genetic counseling, early diagnosis, and potential prognosis of the disease.
Highlights
Pulmonary arterial hypertension (PAH) is a group of vascular diseases that produce right ventricular dysfunction, heart failure syndrome, and death
Pulmonary arterial hypertension (PAH) is a group of vascular diseases that are characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure with secondary vascular and right ventricular remodeling
PAH leads to right ventricular dysfunction, heart failure syndrome, and premature death [1]
Summary
Pulmonary arterial hypertension (PAH) is a group of vascular diseases that produce right ventricular dysfunction, heart failure syndrome, and death. PAH is characterized hemodynamically by the presence of precapillary pulmonary hypertension as defined by a pulmonary arterial wedge ≤15 mmHg and a pulmonary vascular resistance >3 Wood units in the absence of other causes of Garcia-Rivas et al BMC Medical Genetics (2017) 18:82 new field in patient care, which includes genetic counseling for severe diseases; the major predisposing gene for PAH, BMPR2, has a highly variable penetrance within families [5]. Recent studies have suggested that a BMPR2 mutation promotes cell division and prevents cell death, resulting in an overgrowth of cells in the small arteries throughout the lungs [8]. As a result, these arteries narrow in diameter, which increases the resistance to blood flow and, increases the end-diastolic volume and causes adverse right ventricular remodeling. The current genetic testing panels for PAH-associated autosomal dominant genes available mainly test for BMPR2-related genes; novel and not frequently represented genes are not included
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