Novel causative genes for heritable pulmonary arterial hypertension

Prof. Nicholas Morrell, Dr. Stefan Gräf , Matthias Haimel , Marta Bleda , Dr. Charaka Hadinnapola , Wei Li , Joshua Hodgson , Bin Liu , Richard Salmon , Dr. Mark Southwood , Dr. Laura Southgate , Rajiv Machado , Jennifer Martin , Carmen Treacy , Katherine Yates , Louise Daugherty , Olga Chamardina , Deborah Whitehorn , Simon Holden , Micheala Aldred , Harm Bogaard , Dr. Alistair Church , Gerry Coghlan , Robin Condliffe , Prof. Paul A Corris , Cesare Danesino , Melanie Eyries , Henning Gall , Stefano Ghio , Hossein-Ardeschir Ghofrani , Dr. Simon Gibbs , Barbara Girerd , Arjan Houweling , Luke Howard , Marc Humbert , David Kiely , Gabor Kovacs , Dr. Rob MacKenzie Ross , Shahin Moledina , Prof. David Montani , Michael Newnham , Prof. Andrea Olschewski , Horst Olschewski , Andrew Peacock , Joanna Pepke-Zaba , Dr. Inga Prokopenko , Christopher Rhodes , Laura Scelsi , Prof. Werner Seeger , Florent Soubrier , Jay Suntharalingam , Emilia Swietlik , Mark Toshner , Anton Vonk Noordegraaf , Dr. John Warton , Dr. Quinten Waisfisz , Stephen Wort , Prof. Willem Ouwehand , Prof. Nicole Soranzo , Dr. Allan Lawrie , Paul Upton , Prof. Richard Trembath , Prof. Martin Wilkins

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Received: 22nd September 17

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. 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 provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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