04 February 2019 by melanie eyries

The bone morphogenetic protein (BMP10) gene widens the landscape of heritable pulmonary arterial hypertension mutations


In contrast to hereditary pulmonary veno-occlusive disease (PVOD) for which a single gene (EIF2AK4) has been identified and whose mutations provoke a recessively transmitted disease with high penetrance, several genes have been implicated in pulmonary arterial hypertension (PAH) since the discovery of BMPR2 mutations in 2000. Here, we sought to determine the genetic architecture of pulmonary hypertension (PH) according to gene mutations found in a cohort of French patients.


Genetic analysis was prospectively performed on 263 PAH and PVOD patients (adult and pediatric cases). We developed NGS-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analyzed simultaneously (BMPR2, TBX4, EIF2AK4, CAV1, KCNK3, SMAD9, ACVRL1, ENG, BMP9). The BMP10 gene, a BMP9 paralog, was also included in the capture design.


A pathogenic mutation was identified in 49 of the 263 analyzed patients. Mutations were identified in 19.5 % of sporadic PAH patients, 54.5% in familial PAH and 13.5% in PVOD/PCH patient. BMPR-2 is the most frequently mutated gene, followed by TBX4 in both pediatric and
adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 bi-allelic mutations are restricted to PVOD/PCH. A truncating mutation and a predicted loss of function variant were also identified in the BMP10 gene in two severely affected sporadic PAH patients.


Gene panel sequencing is an efficient tool to improve the knowledge of PH genetic architecture. Our results confirm that mutations are found in genes beyond BMPR2 in PAH, reveal the emerging role of TBX4 in adult PAH while this gene was initially described as a major gene in pediatric PAH and designate BMP10 as a new candidate

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melanie eyries




Key Contributors

Mélanie Eyries 1,2, David Montani 3, Sophie Nadaud2, Barbara Girerd 3, Marilyne Levy 4, Arnaud Bourdin5, Romain Trésorier6, Ari Chaouat7, Vincent Cottin8, Céline Sanfiorenzo9, Grégoire Prevot10, Martine Reynaud-Gaubert11, Claire Dromer12, Ali Houeijeh13, Karine Nguyen14, Florence Coulet 1, Damien Bonnet 4, Marc Humbert 3, Florent Soubrier 1, 2*. 1-Département de Génétique, hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, 2-UMR_S 1166, Sorbonne-Université ; INSERM and Institute for Cardiometabolism and Nutrition (ICAN), Paris, 3- Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire, INSERM UMR_S999, Hôpital de Bicêtre, AP-HP, Le Kremlin Bicêtre, France ; 4-M3C-cardiologie pédiatrique, hôpital Necker-enfants malades, AP-HP, Paris, 5- PhyMedExp, University of Montpellier, INSERM, CNRS, France. AND Département de pneumologie et addictologie; CHU Montpellier, Montpellier, France 6- Service de cardiologie maladies vasculaires, CHU Gabriel Montpied, Clermont-Ferrand, 7- Département de pneumologie-CHRU Nancy-Université de Lorraine, Vandoeuvre-lès-Nancy, Inserm, U1116; Université de Lorraine, Nancy, France 8- Service de pneumologie, Centre national de référence des maladies pulmonaires rares, Hôpital Louis Pradel, université Claude Bernard Lyon 1, UMR754, Lyon, 9- Service de pneumologie, hôpital Pasteur-CHU Nice, 10- Service de pneumologie, hôpital Larrey, Toulouse, 11- Service de pneumologie, CHU nord de Marseille, Assistance Publique-Hôpitaux de Marseille (AP-HM), Marseille, 12- Service de pneumologie, CHU de Bordeaux hôpital Haut-Levêque, Pessac, 13- Service de cardiologie infantile et congénitale, CHRU Lille-hôpital cardiologique, Lille, 14- Département de Génétique Médicale, CHU la Timone enfants, AP-HM, Marseille.

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