Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
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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), underlie most heritable forms of PAH. Since To identify the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses revealed reveal 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. We provide evidence fordemonstrate 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 identified identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
AuthorsVAN HEEL, DA; Gräf, S; Haimel, M; Bleda, M; Hadinnapola, C; Southgate, L; Li, W; Hodgson, J; Liu, B; Salmon, R; Southwood, M; Machado, D; Martin, J; Treacy, C; Yates, K; Daugherty, L; Shamardina, O; Whitehorn, D; Holden, S; Aldred, M; Bogaard, H J; Church, C; Coghlan, G; Condliffe, R; Corris, P A; Danesino, C; Eyries, M; Gall, H; Ghio, S; Ghofrani, H-A; Gibbs, J S R; Girerd, B; Houweling, A; Howard, L; Humbert, M; Kiely, D G; Kovacs, G; MacKenzie Ross, R V; Moledina, S; Montani, D; Newnham, M; Olschewski, A; Olschewski, H; Peacock, A; Pepke-Zaba, J; Prokopenko, I; Rhodes, C J; Scelsi, L; Seeger, W; Soubrier, F; Stein, D F; Suntharalingam, J; Swietlik, E M; Toshner, M R; Noordegraaf, A; Waisfisz, Q; Wharton, J; Wort, S; Ouwehand, W H; Soranzo, N; Lawrie, A; Upton, P D; Wilkins, M R; Trembath, R C; Morrell, N W
- Genomic Medicine