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Nat Commun. 2018 Apr 12;9(1):1416. doi: 10.1038/s41467-018-03672-4.

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Author information

1
Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom. sg550@cam.ac.uk.
2
Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, United Kingdom. sg550@cam.ac.uk.
3
NIHR BioResource-Rare Diseases, Cambridge, CB2 0PT, United Kingdom. sg550@cam.ac.uk.
4
Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom.
5
Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, United Kingdom.
6
NIHR BioResource-Rare Diseases, Cambridge, CB2 0PT, United Kingdom.
7
Molecular and Clinical Sciences Research Institute, St George's, University of London, London, SW17 0RE, United Kingdom.
8
Division of Genetics & Molecular Medicine, King's College London, London, WC2R 2LS, United Kingdom.
9
Royal Papworth Hospital, Papworth Everard, Cambridge, CB23 3RE, United Kingdom.
10
Institute of Medical and Biomedical Education, St George's University of London, London, SW17 0RE, United Kingdom.
11
Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom.
12
Cleveland Clinic, Cleveland, Ohio, 44195, United States.
13
VU University Medical Center, Amsterdam, 1007 MB, The Netherlands.
14
Golden Jubilee National Hospital, Glasgow, G81 4DY, United Kingdom.
15
Royal Free Hospital, London, NW3 2QG, United Kingdom.
16
Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, S10 2JF, United Kingdom.
17
University of Newcastle, Newcastle, NE1 7RU, United Kingdom.
18
Department of Molecular Medicine, University of Pavia, Pavia, 27100, Italy.
19
Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy.
20
Département de génétique, hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, and UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités, Paris, 75252, France.
21
University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary System (ECCCPS), Giessen, 35392, Germany.
22
Imperial College London, London, SW7 2AZ, United Kingdom.
23
National Heart & Lung Institute, Imperial College London, London, SW3 6LY, United Kingdom.
24
Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay; AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire; INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, 94270, France.
25
Ludwig Boltzmann Institute for Lung Vascular Research, Graz, 8010, Austria.
26
Medical University of Graz, Graz, 8036, Austria.
27
Royal United Hospitals Bath NHS Foundation Trust, Bath, BA1 3NG, United Kingdom.
28
Great Ormond Street Hospital, London, WC1N 3JH, United Kingdom.
29
Blizard Institute, Queen Mary University of London, London, E1 2AT, United Kingdom.
30
Royal Brompton Hospital, London, SW3 6NP, United Kingdom.
31
Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, United Kingdom.
32
Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, S10 2RX, United Kingdom.
33
Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom. nwm23@cam.ac.uk.
34
NIHR BioResource-Rare Diseases, Cambridge, CB2 0PT, United Kingdom. nwm23@cam.ac.uk.

Abstract

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), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate 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 identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

PMID:
29650961
PMCID:
PMC5897357
DOI:
10.1038/s41467-018-03672-4
[Indexed for MEDLINE]
Free PMC Article

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