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Novel Causative Genes for Heritable Pulmonary Arterial Hypertension
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A2732 - Novel Causative Genes for Heritable Pulmonary Arterial Hypertension
Author Block: S. Graf, M. Haimel, M. Bleda, C. Hadinnapola, UK PAH National Cohort Study, NIHR BioResource - Rare Diseases, N. W. Morrell; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within genes encoding components of the transforming growth factor-ß pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie the majority of heritable forms of PAH. Approximately 20% of heritable and 80% of idiopathic PAH cases remain genetically unexplained.
Our objective was to identify the missing genetic contribution to heritable PAH. Recognising that this likely involves mutations in genes confined to small numbers of PAH cases, we assembled a large cohort from the UK and Europe to undertake a case-control analysis.
In this study, we performed whole genome sequencing in 1038 PAH index cases and 6385 subjects with other rare diseases. Case-control analyses were undertaken to detect significant overrepresentation of rare variants in protein-coding genes in the PAH cohort.
Rare variant analyses identified mutations in novel causal 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 of the growth factor from transfected cells. In addition, we confirmed the presence of mutations predicted to be disruptive of function in most (BMPR2, TBX4, ENG, ACVRL1, SMAD9, KCNK3, EIF2AK4), but not all, previously reported PAH genes, and provide preliminary evidence for further putative genes.
Taken together these findings provide new insights into the molecular basis of PAH, indicate unexplored pathways for therapeutic intervention, and support a central role for endothelial dysfunction in this disorder.
Author Block: S. Graf, M. Haimel, M. Bleda, C. Hadinnapola, UK PAH National Cohort Study, NIHR BioResource - Rare Diseases, N. W. Morrell; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within genes encoding components of the transforming growth factor-ß pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie the majority of heritable forms of PAH. Approximately 20% of heritable and 80% of idiopathic PAH cases remain genetically unexplained.
Our objective was to identify the missing genetic contribution to heritable PAH. Recognising that this likely involves mutations in genes confined to small numbers of PAH cases, we assembled a large cohort from the UK and Europe to undertake a case-control analysis.
In this study, we performed whole genome sequencing in 1038 PAH index cases and 6385 subjects with other rare diseases. Case-control analyses were undertaken to detect significant overrepresentation of rare variants in protein-coding genes in the PAH cohort.
Rare variant analyses identified mutations in novel causal 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 of the growth factor from transfected cells. In addition, we confirmed the presence of mutations predicted to be disruptive of function in most (BMPR2, TBX4, ENG, ACVRL1, SMAD9, KCNK3, EIF2AK4), but not all, previously reported PAH genes, and provide preliminary evidence for further putative genes.
Taken together these findings provide new insights into the molecular basis of PAH, indicate unexplored pathways for therapeutic intervention, and support a central role for endothelial dysfunction in this disorder.
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