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Circulation. 2017 Nov 21;136(21):2022-2033. doi: 10.1161/CIRCULATIONAHA.117.028351. Epub 2017 Sep 28.

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

Collaborators (282)

Aitman T, Bennett D, Caulfield M, Chinnery P, Gale D, Koziell A, Kuijpers TW, Laffan MA, Maher E, Markus HS, Ouwehand WH, Perry D, Raymond FL, Roberts I, Smith K, Thrasher A, Watkins H, Williamson C, Woods G, Ashford S, Bradley JR, Fletcher D, Hammerton T, James R, Kingston N, Ouwehand WH, Penkett CJ, Raymond FL, Stirrups K, Veltman M, Young T, Ashford S, Brown M, Clements-Brod N, Davis J, Dewhurst E, Erwood M, Frary A, Linger R, Papadia S, Rehnstrom K, Stark H, Allsup D, Austin S, Bakchoul T, Bariana TK, Bolton-Maggs P, Chalmers E, Collins P, Erber WN, Everington T, Favier R, Freson K, Furie B, Gattens M, Gomez K, Greene D, Greinacher A, Hart D, Heemskerk JW, Henskens Y, Kazmi R, Keeling D, Kelly AM, Laffan MA, Lambert MP, Lentaigne C, Liesner R, Mangles S, Mathias M, Millar CM, Mumford A, Nurden P, Ouwehand WH, Papadia S, Payne J, Pasi J, Perry DJ, Peerlinck K, Richards M, Rondina M, Roughley C, Schulman S, Schulze H, Scully M, Sivapalaratnam S, Tait RC, Talks K, Thachil J, Turro E, Toh CH, Van Geet C, De Vries M, Warner TQ, Westbury S, Furnell A, Mapeta R, Simeoni I, Staines S, Stephens J, Stirrups K, Whitehorn D, Watt C, Attwood A, Daugherty L, Deevi SV, Halmagyi C, Hu F, James R, Matser V, Meacham S, Megy K, Penkett CJ, Stirrups K, Titterton C, Tuna S, Yu P, von Ziegenweldt J, Astle W, Carss K, Greene D, Lango-Allen H, Turro E, Astle W, Greene D, Richardson S, Turro E, Calleja P, Rankin S, Turek W, Bryson C, Anderson J, Fletcher D, McJannet C, Stock S, Young T, Wassmer E, Sohal A, Santra S, Vogt J, Chitre M, Krishnakumar D, Ambegaonkar G, Maw A, Armstrong R, Park SM, Mehta S, Paterson J, Carmichael J, Allen L, Hensiek A, Firth H, Stein P, Deegan P, Doffinger R, Parker A, Bitner-Glindzicz M, Scott R, Hurst J, Rosser E, Lees M, Clement E, Henderson R, Thompson D, Gardham A, Gissen P, Josifova D, Thomas E, Patch C, Deshpande C, Flinter F, Holder M, Canham N, Wakeling E, Holder S, Ghali N, Brady A, Clowes V, MacLaren R, Webster A, Moore A, Arno G, Michaelides M, Rankin J, Kurian M, Murphy E, Carss K, Sanchis-Juan A, Erwood M, Dewhurst E, Grozeva D, Raymond FL, Reid E, Woods G, Tischkowitz M, Sandford R, Ali S, Creaser-Myers A, Cookson V, DaCosta R, Dormand N, Ghataorhe PK, Greenhalgh A, Huis In't Veld A, Kennedy F, Mackenzie Ross R, Masati L, Meehan S, Othman S, Pollock V, Polwarth G, Rhodes CJ, Rue-Albrecht K, Schotte G, Shipley D, Tan Y, Wanjiku I, Wort J, Smith K, Kuijpers T, Thrasher A, Thaventhiran J, Brown M, Lango Allen H, Simeoni I, Staples E, Samarghitean C, Alachkar H, Antrobus R, Arumugakani G, Bacchelli C, Baxendale H, Bethune C, Bibi S, Booth C, Browning M, Burns S, Chandra A, Cooper N, Davies S, Devlin L, Doffinger R, Drewe E, Edgar D, Egner W, Ghurye R, Gilmour K, Goddard S, Gordins P, Grigoriadou S, Hackett S, Hague R, Hayman G, Herwadkar A, Huissoon A, Jolles S, Kelleher P, Kumararatne D, Lear S, Longhurst H, Lorenzo L, Maimaris J, Manson A, McDermott E, Murng S, Nejentsev S, Noorani S, Oksenhendler E, Ponsford M, Qasim W, Quinti I, Richter A, Sargur R, Savic S, Seneviratne S, Sewell C, Stauss H, Thomas M, Welch S, Willcocks L, Yeatman N, Yong P.

Author information

Department of Medicine, University of Cambridge, UK (C.H., M.B., M.H., J.M., C.T., K.Y., M.N., M.T., S. Gräf, N.W.M.).
NIHR BioResource-Rare Diseases (M.H., J.M., K.Y., P.R.-M., O.S., S. Gräf, N.W.M.).
Papworth Hospital, Cambridge, UK (N.S., S.D.P., M.S., J.H.-S., J.P.-Z., M.T.).
Sheffield University, UK (A.S., A.L.).
Université Paris-Sud, France (P.D., B.G., M.H., D.M.).
VU University Medical Centre, Amsterdam, the Netherlands (H.B., A.V.N.).
Golden Jubilee Hospital, Glasgow, UK (C.C., A.P.).
Royal Free Hospital, London, UK (G.C.).
Royal Hallamshire Hospital, Sheffield, UK (R.C., D.G.K.).
Newcastle University, UK (P.A.C.).
Imperial College London, UK (S. Gibbs, M.R.W., J.W.).
Addenbrooke's Hospital, Cambridge, UK (S.H.).
University of Lincoln, UK (R.M.).
Royal United Hospitals Bath NHS Foundation Trust, UK (R.M.R., J.S.).
Great Ormond Street Hospital, London, UK (S.M.).
Hôpital Pitié Salpétrière, Paris, France (F.S.).
King's College London, UK (L.S., R.T.).
St George's, University of London, UK (L.S.).
Royal Brompton Hospital, London, UK (S.J.W.).
Department of Haematology, University of Cambridge, UK (S. Gräf).
Department of Medicine, University of Cambridge, UK (C.H., M.B., M.H., J.M., C.T., K.Y., M.N., M.T., S. Gräf, N.W.M.)



Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.


Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.


Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival.


Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.


genetics; hypertension, pulmonary; mutation; prognosis; pulmonary veno-occlusive disease

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