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Eur Respir J. 2019 Mar 14;53(3). pii: 1801371. doi: 10.1183/13993003.01371-2018. Print 2019 Mar.

Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases.

Author information

1
Département de Génétique, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.
2
UMR_S1166, Sorbonne Université, INSERM, and Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
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, France.
5
PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
6
Département de Pneumologie et Addictologie, CHU Montpellier, Montpellier, France.
7
Service de Cardiologie Maladies Vasculaires, CHU Gabriel Montpied, Clermont-Ferrand, France.
8
Département de Pneumologie, CHRU Nancy, Université de Lorraine, INSERM U1116, Nancy, France.
9
Service de Pneumologie, Centre National de Référence des Maladies Pulmonaires Rares, Hôpital Louis Pradel, Université Claude Bernard Lyon 1, UMR754, Lyon, France.
10
Service de Pneumologie, Hôpital Pasteur, CHU Nice, Nice, France.
11
Service de Pneumologie, Hôpital Larrey, Toulouse, France.
12
Service de Pneumologie, CHU Nord de Marseille, AP-HM, Marseille, France.
13
Service de Pneumologie, CHU de Bordeaux Hôpital Haut-Levêque, Pessac, France.
14
Service de Cardiologie Infantile et Congénitale, CHRU Lille-Hôpital Cardiologique, Lille, France.
15
Département de Génétique Médicale, CHU la Timone Enfants, AP-HM, Marseille, France.

Abstract

BACKGROUND:

Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the BMPR2 gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known.

METHODS:

We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously. Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases).

RESULTS:

Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. BMPR2 was the most frequently mutated gene, followed by TBX4 in both paediatric and adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in BMP10 in two severely affected sporadic PAH female patients.

CONCLUSION:

Our results confirm that mutations are found in genes beyond BMPR2 in heritable PAH, emphasise the role of TBX4 and BMP9, and designate BMP10 as a new PAH gene.

Conflict of interest statement

Conflict of interest: M. Eyries reports personal fees from Roche Diagnostics France, during the conduct of the study. Conflict of interest: D. Montani reports personal fees from Actelion, GSK, MSD and Pfizer, outside the submitted work. Conflict of interest: S. Nadaud has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: M. Levy has nothing to disclose. Conflict of interest: A. Bourdin reports grants, personal fees for speaking and nonfinancial support from GSK, grants, personal fees for speaking and advisory board work, and nonfinancial support from AstraZeneca and Boehringer Ingelheim, personal fees for speaking and advisory board work, and nonfinancial support from Novartis, grants from MSD, grants and personal fees for speaking from Actelion, and personal fees for speaking and nonfinancial support from Chiesi Farmaceuticals, outside the submitted work. Conflict of interest: R. Trésorier has nothing to disclose. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for consultancy, lectures and travel to medical meetings from Actelion and Roche, personal fees for development of educational presentations, consultancy, lectures and travel to medical meetings from Boehringer Ingelheim, personal fees for consultancy from Bayer, personal fees for adjudication committee work from Gilead, personal fees for consultancy and travel to medical meetings from MSD, personal fees for consultancy and lectures from Novartis and Sanofi, institutional grants from Boehringer Ingelheim and Roche, personal fees for data and safety monitoring board work from Promedior and Celgene, and personal fees for consultancy and data and safety monitoring board work from Galapagos, outside the submitted work. Conflict of interest: C. Sanfiorenzo has nothing to disclose. Conflict of interest: G. Prevot has nothing to disclose. Conflict of interest: M. Reynaud-Gaubert has nothing to disclose. Conflict of interest: C. Dromer has nothing to disclose. Conflict of interest: A. Houeijeh has nothing to disclose. Conflict of interest: K. Nguyen has nothing to disclose. Conflict of interest: F. Coulet has nothing to disclose. Conflict of interest: D. Bonnet reports personal fees for advisory board work from Actelion Pharmaceuticals, Bayer Health Care and Novartis, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Actelion, Bayer, GSK, Johnson & Johnson, Merck and United Therapeutics, outside the submitted work. Conflict of interest: F. Soubrier has nothing to disclose.

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