Phenotypic Characterization of
EIF2AK4
Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension
Authors: Hadinnapola Charaka , Bleda Marta , Haimel Matthias , Screaton Nicholas , Swift Andrew , Dorfmüller Peter , Preston Stephen D. , Southwood Mark , Hernandez-Sanchez Jules , Martin Jennifer , Treacy Carmen , Yates Katherine , Bogaard Harm , Church Colin , Coghlan Gerry , Condliffe Robin , Corris Paul A. , Gibbs Simon , Girerd Barbara , Holden Simon , Humbert Marc , Kiely David G. , Lawrie Allan , Machado Rajiv , MacKenzie Ross Robert , Moledina Shahin , Montani David , Newnham Michael , Peacock Andrew , Pepke-Zaba Joanna , Rayner-Matthews Paula , Shamardina Olga , Soubrier Florent , Southgate Laura , Suntharalingam Jay , Toshner Mark , Trembath Richard , Noordegraaf Anton Vonk , Wilkins Martin R. , Wort Stephen J. , Wharton John ,   NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH, Gräf Stefan , Morrell Nicholas W. , Aitman Timothy , Bennett David , Caulfield Mark , Chinnery Patrick , Gale Daniel , Koziell Ania , Kuijpers Taco W , Laffan Michael A , Maher Eamonn , Markus Hugh S , Ouwehand Willem H , Perry David , Raymond F Lucy , Roberts Irene , Smith Kenneth , Thrasher Adrian , Watkins Hugh , Williamson Catherine , Woods Geoffrey , Ashford Sofie , Bradley John R , Fletcher Debra , Hammerton Tracey , James Roger , Kingston Nathalie , Ouwehand Willem H , Penkett Christopher J , Raymond F Lucy , Stirrups Kathleen , Veltman Marijke , Young Tim , Ashford Sofie , Brown Matthew , Clements-Brod Naomi , Davis John , Dewhurst Eleanor , Erwood Marie , Frary Amy , Linger Rachel , Papadia Sofia , Rehnstrom Karola , Stark Hannah , Allsup David , Austin Steve , Bakchoul Tamam , Bariana Tadbir K , Bolton-Maggs Paula , Chalmers Elizabeth , Collins Peter , Erber Wendy N , Everington Tamara , Favier Remi , Freson Kathleen , Furie Bruce , Gattens Michael , Gomez Keith , Greene Daniel , Greinacher Andreas , Hart Daniel , Heemskerk Johan WM , Henskens Yvonne , Kazmi Rashid , Keeling David , Kelly Anne M , Laffan Michael A , Lambert Michele P , Lentaigne Claire , Liesner Ri , Mangles Sarah , Mathias Mary , Millar Carolyn M , Mumford Andrew , Nurden Paquita , Ouwehand Willem H , Papadia Sofia , Payne Jeanette , Pasi John , Perry David J , Peerlinck Kathelijne , Richards Michael , Rondina Matthew , Roughley Catherine , Schulman Sol , Schulze Harald , Scully Marie , Sivapalaratnam Suthesh , Tait R Campbell , Talks Kate , Thachil Jecko , Turro Ernest , Toh Cheng-Hock , Van Geet Chris , De Vries Minka , Warner Timothy Q , Westbury Sarah , Furnell Abigail , Mapeta Rutendo , Simeoni Ilenia , Staines Simon , Stephens Jonathan , Stirrups Kathleen , Whitehorn Deborah , Watt Christopher , Attwood Antony , Daugherty Louise , Deevi Sri VV , Halmagyi Csaba , Hu Fengyuan , James Roger , Matser Vera , Meacham Stuart , Megy Karyn , Penkett Christopher J , Stirrups Kathleen , Titterton Catherine , Tuna Salih , Yu Ping , von Ziegenweldt Julie , Astle William , Carss Keren , Greene Daniel , Lango-Allen Hana , Turro Ernest , Astle William , Greene Daniel , Richardson Sylvia , Turro Ernest , Calleja Paul , Rankin Stuart , Turek Wojciech , Bryson Christine , Anderson Julie , Fletcher Debra , McJannet Coleen , Stock Sophie , Young Tim , Wassmer Evangeline , Sohal Aman , Santra Saikat , Vogt Julie , Chitre Manali , Krishnakumar Deepa , Ambegaonkar Gautum , Maw Anna , Armstrong Ruth , Park Soo-Mi , Mehta Sarju , Paterson Joan , Carmichael Jenny , Allen Louise , Hensiek Anke , Firth Helen , Stein Penelope , Deegan Patrick , Doffinger Rainer , Parker Alasdair , Bitner-Glindzicz Maria , Scott Richard , Hurst Jane , Rosser Elisabeth , Lees Melissa , Clement Emma , Henderson Robert , Thompson Dorothy , Gardham Alice , Gissen Paul , Josifova Dragana , Thomas Ellen , Patch Chris , Deshpande Charu , Flinter Frances , Holder Muriel , Canham Natalie , Wakeling Emma , Holder Susan , Ghali Neeti , Brady Angie , Clowes Virginia , MacLaren Robert , Webster Andrew , Moore Anthony , Arno Gavin , Michaelides Michel , Rankin Julia , Kurian Manju , Murphy Elaine , Carss Keren , Sanchis-Juan Alba , Erwood Marie , Dewhurst Eleanor , Grozeva Detelina , Raymond F Lucy , Reid Evan , Woods Geoff , Tischkowitz Marc , Sandford Richard , Ali Sonia , Creaser-Myers Amanda , Cookson Victoria , DaCosta Rosa , Dormand Natalie , Ghataorhe Pavandeep K , Greenhalgh Alan , Huis in’t Veld Anna , Kennedy Fiona , Mackenzie Ross Rob , Masati Larahmie , Meehan Sharon , Othman Shokri , Pollock Val , Polwarth Gary , Rhodes Christopher J , Rue-Albrecht Kevin , Schotte Gwen , Shipley Debbie , Tan Yvonne , Wanjiku Ivy , Wort John , Smith Kenneth , Kuijpers Taco , Thrasher Adrian , Thaventhiran James , Brown Matthew , Lango Allen Hana , Simeoni Ilenia , Staples Emily , Samarghitean Crina , Alachkar Hana , Antrobus Richard , Arumugakani Gururaj , Bacchelli Chiara , Baxendale Helen , Bethune Claire , Bibi Shahnaz , Booth Claire , Browning Michael , Burns Siobhan , Chandra Anita , Cooper Nichola , Davies Sophie , Devlin Lisa , Doffinger Rainer , Drewe Elizabeth , Edgar David , Egner William , Ghurye Rohit , Gilmour Kimberley , Goddard Sarah , Gordins Pavel , Grigoriadou Sofia , Hackett Scott , Hague Rosie , Hayman Grant , Herwadkar Archana , Huissoon Aarnoud , Jolles Stephen , Kelleher Peter , Kumararatne Dinakantha , Lear Sara , Longhurst Hilary , Lorenzo Lorena , Maimaris Jesmeen , Manson Ania , McDermott Elizabeth , Murng Sai , Nejentsev Sergey , Noorani Sadia , Oksenhendler Eric , Ponsford Mark , Qasim Waseem , Quinti Isabella , Richter Alex , Sargur Ravishankar , Savic Sinisa , Seneviratne Suranjith , Sewell Carrock , Stauss Hans , Thomas Moira , Welch Steve , Willcocks Lisa , Yeatman Nigel , Yong Patrick 
Published: October 2017

Background:

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.

Methods:

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.

Results:

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 (K
co
; 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.

Conclusions:

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 K
co
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.