Related Papers
Novel causative genes for heritable pulmonary arterial hypertension
2017 •
Emilia Swietlik
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within genes encoding components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie the majority of heritable forms of PAH. Since the missing genetic contribution likely involves mutations in genes confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 subjects with other rare diseases. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. Mutations in GDF2, encoding a ligand for BMPR2, led to reduced secretion from transfected cells. In addition, we confirmed the presence of mutations in most, but not all, previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings prov...
Journal of the American …
Genetic Basis of Pulmonary Arterial Hypertension:: Current Understanding and Future Directions
2004 •
Fabio Coccolo
Nature communications
Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
2018 •
Arjan Houweling
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indica...
Journal of the American College of Cardiology
Genetic basis of pulmonary arterial hypertension
2004 •
John Newman
The Journal of Heart and Lung Transplantation
Novel loci interacting epistatically with bone morphogenetic protein receptor 2 cause familial pulmonary arterial hypertension
2010 •
Sreemanta Pramanik
The American Journal of Human Genetics
Familial Primary Pulmonary Hypertension (Gene PPH1) Is Caused by Mutations in the Bone Morphogenetic Protein Receptor–II Gene
2000 •
Nieves Cuervo
Defining the Clinical Validity of Genes Reported to Cause Pulmonary Arterial Hypertension
Memoona Shaukat
ABSTRACTBACKGROUNDPulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The disease is caused by both genetic and environmental factors, with genetic variants in at least 27 genes displaying putative evidence for disease causality. Genetic testing is currently recommended for adults diagnosed with heritable or idiopathic PAH, and all children diagnosed with PAH. However, testing panels vary in the number and list of genes included, and exome/genome sequencing data may reveal variants in genes with varying levels of evidence for a relationship with PAH.METHODSAn international panel of clinical and scientific experts in PAH was formed to perform an evidence-based review of heritable and idiopathic PAH gene-disease relationships. The panel performed literature searches and applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of PAH gene-dis...
Human mutation
Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects
2015 •
Steven Keiles
Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta (TGF-β) pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG) and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, mai...
Clinics in Chest Medicine
Genetics of Primary Pulmonary Hypertension
2001 •
James Knowles
Circulation
Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle
2016 •
Arjan Houweling
