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

Mélanie Eyries (1, 2) , David Montani (3) , Sophie Nadaud (2) , Barbara Girerd (4, 5) , Marilyne Levy (6, 7) , Arnaud Bourdin (8, 9) , Romain Trésorier (10) , Ari Chaouat (11, 12) , Vincent Cottin (13) , Céline Sanfiorenzo (14) , Gregoire Prevot (15) , Martine Reynaud-Gaubert (16) , Claire Dromer (17) , Ali Houeijeh (18) , Karine Nguyen (19) , Florence Coulet (2) , Damien Bonnet (6, 7) , Marc Humbert (20, 4) , Florent Soubrier (1, 2)

1 CHU Pitié-Salpêtrière [AP-HP]
2 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
3 CCML - Centre Chirurgical Marie Lannelongue
4 Université Paris-Saclay
5 UPRES - EA2705 - Centre National de Référence de l'Hypertension Artérielle Pulmonaire
6 Hôpital Necker - Enfants Malades [AP-HP]
7 Service de cardiologie pédiatrique [CHU Necker]
8 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
9 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
10 CHU Gabriel Montpied [Clermont-Ferrand]
11 FST - Faculté des Sciences et Technologies [Université de Lorraine]
12 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
13 Department of Pneumology [Lyon]
14 CHU - Hôpital Pasteur [Nice]
15 Service de pneumologie [Toulouse]
16 APHM - Assistance Publique - Hôpitaux de Marseille
17 CHU Bordeaux
18 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
19 Département de génétique médicale [Hôpital de la Timone - APHM]
20 HPPIT - Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique

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.

Domaines: Pneumologie et système respiratoire; Génétique humaine; Génétique des populations [q-bio.PE]

Mélanie Eyries, David Montani, Sophie Nadaud, Barbara Girerd, Marilyne Levy, et al.. Widening the landscape of heritable pulmonary hypertension mutations in pediatric and adult cases. European Respiratory Journal, 2019, 53, pp.1801371. ⟨10.1183/13993003.01371-2018⟩. ⟨hal-01964973⟩